Histopathologic Classification of Breast Cancer

Table 1 describes the histologic classification of breast cancer based on tumor location.

Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

Table 1. Tumor Location and Related Histologic Subtype

Tumor Location	Histologic Subtype
Carcinoma, NOS
Ductal	Intraductal (in situ)
	Invasive with predominant component
	Invasive, NOS
	Comedo
	Inflammatory
	Medullary with lymphocytic infiltrate
	Mucinous (colloid)
	Papillary
	Scirrhous
	Tubular
	Other
Lobular	Invasive with predominant in situ component
	Invasive
Nipple	Paget disease, NOS
	Paget disease with intraductal carcinoma
	Paget disease with invasive ductal carcinoma
Other	Undifferentiated carcinoma
	Metaplastic
NOS = not otherwise specified.

The following tumor subtypes occur in the breast but are not considered typical breast cancers:

Phyllodes tumor.

Angiosarcoma.

Primary lymphoma.

ReferenceSection

Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.

Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222 (4): 549-59; discussion 559-61, 1995.

Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000.

Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but also according to other clinical factors such as the following, some of which are included in the determination of stage:

Tumor size.

Lymph node status.

Estrogen-receptor and progesterone-receptor levels in the tumor tissue.

Human epidermal growth factor receptor 2 (HER2/neu) status in the tumor.

Tumor grade.

Menopausal status.

General health of the patient.

The standards used to define biomarker status are described as follows:

Estrogen receptor (ER) expression: ER expression is measured primarily by immunohistochemistry (IHC). Any staining of 1% of cells or more is considered positive for ER.

Progesterone receptor (PR) expression: PR expression is measured primarily by IHC. Any staining of 1% of cells or more is considered positive for PR.

HER2 expression: HER2 is measured primarily by either IHC to assess expression of the HER2 protein or by in situ hybridization (ISH) to assess gene copy number. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines for cases when either IHC or ISH testing is equivocal.

IHC:

Negative: 0 or 1+ staining

Equivocal: 2+ staining

Positive: 3+ staining

ISH (dual probe):

Possible negative results:

HER2/chromosome enumeration probe (CEP17) ratio <2.0 AND HER2 copy number <4

Possible equivocal results: (requires performing alternative ISH test to confirm equivocal or IHC if not previously performed)

HER2/CEP17 ratio <2.0 AND HER2 copy number ≥4 but <6

Possible positive results:

HER2/CEP17 ratio ≥2.0 by ISH

HER2 copy number ≥6 regardless of ratio by ISH

ISH (single probe):

Negative: <4 HER2 copies

Equivocal: ≥4 HER2 copies but <6 HER2 copies

Positive: ≥6 HER2 copies

TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define breast cancer.

The grade of the tumor is determined by its morphologic features, such as tubule formation, nuclear pleomorphism, and mitotic count.

Table 2. Definition of Primary Tumor (T) – Clinical and Pathological a

Table 3. Definition of Regional Lymph Nodes – Clinical (cN) a,b

Table 4. Definition of Regional Lymph Nodes – Pathological (pN) a,b

Table 5. Definition of Distant Metastasis (M) a

Table 6. DDefinition of Histologic Grade (G) a

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

T Category	T Criteria
cN Category	cN Criteria
pN Category	pN Criteria
M Category	M Criteria
G	G Definition
G	G Definition
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tisb	DCIS.
Tis (Paget)	Paget disease of the nipple NOT associated with invasive carcinoma and/or DCIS in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
T1	Tumor ≤20 mm in greatest dimension.
–T1mi	Tumor ≤1 mm in greatest dimension.
–T1a	Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >1.0–1.9 mm to 2 mm).
–T1b	Tumor >5 mm but ≤10 mm in greatest dimension.
–T1c	Tumor >10 mm but ≤20 mm in greatest dimension.
T2	Tumor >20 mm but ≤50 mm in greatest dimension.
T3	Tumor >50 mm in greatest dimension.
T4	Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4.
–T4a	Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4.
–T4b	Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d'orange) of the skin that does not meet the criteria for inflammatory carcinoma.
–T4c	Both T4a and T4b are present.
–T4d	Inflammatory carcinoma (see Rules for Classificationc).
cN Category	cN Criteria
cNX c	Regional lymph nodes cannot be assessed (e.g., previously removed).
cN0	No regional lymph node metastases (by imaging or clinical examination).
cN1	Metastases to movable ipsilateral Level I, II axillary lymph nodes(s).
–cN1mi d	Micrometastases (approximately 200 cells, >0.2 mm, but ≤2.0 mm).
cN2	Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;
	or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
–cN2a	Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
–cN2b	Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
cN3	Metastases in ipsilateral infraclavicular (Level Ill axillary) lymph node(s) with or without Level l, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level l, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.
–cN3a	Metastases in ipsilateral infraclavicular lymph node(s).
–cN3b	Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
–cN3c	Metastases in ipsilateral supraclavicular lymph node(s).
pN Category	pN Criteria
pNX	Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed).
pN0	No regional lymph node metastasis identified or ITCs only.
–pN0(i+)	ITCs only (malignant cell clusters ≤0.2 mm) in regional lymph node(s).
–pN0(mol+)	Positive molecular findings by RT-PCR; no ITCs detected.
pN1	Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
–pN1mi	Micrometastases (~200 cells, >0.2 mm, but ≤2.0 mm).
–pN1a	Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
–pN1b	Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs.
–pN1c	pN1a and pN1b combined.
pN2	Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
–pN2a	Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
–pN2b	Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes.
pN3	Metastases in ≥10 axillary lymph nodes; or in infraclavicular (Level Ill axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level l, II axillary lymph nodes; or in >3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
–pN3a	Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodes.
–pN3b	pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
	or pN2a in the presence of pN1b.
–pN3c	Metastases in ipsilateral supraclavicular lymph nodes.
M Category	M Criteria
M0	No clinical or radiographic evidence of distant metastases. b
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1	Distant metastases detected by clinical and radiographic means.
pM1	Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.
G	G Definition
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.
G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
DCIS = ductal carcinoma in situ.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bLobular carcinoma in situ is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th ed.
cRules for Classification - The anatomic TNM system is a method for coding extent of disease. This is done by assigning a category of extent of disease for the tumor (T), regional lymph nodes (N), and distant metastases (M). T, N, and M are assigned by clinical means and by adding surgical findings and pathological information to the clinical information. The documented prognostic impact of postneoadjuvant extent of disease and response to therapy warrant clear definitions of the use of the yp prefix and response to therapy. The use of neoadjuvant therapy does not change the clinical (pretreatment) stage. As per TNM rules, the anatomic component of clinical stage is identified with the prefix c (e.g., cT). In addition, clinical staging can include the use of fine-needle aspiration (FNA) or core-needle biopsy and sentinel lymph node biopsy before neoadjuvant therapy. These are denoted with the postscripts f and sn, respectively. Nodal metastases confirmed by FNA or core-needle biopsy are classified as macrometastases (cN1), regardless of the size of the tumor focus in the final pathological specimen. For example, if, prior to neoadjuvant systemic therapy, a patient with a 1 cm primary has no palpable nodes but has an ultrasound-guided FNA biopsy of an axillary lymph node that is positive, the patient will be categorized as cN1 (f) for clinical (pretreatment) staging and is assigned to Stage IIA. Likewise, if the patient has a positive axillary sentinel node identified before neoadjuvant systemic therapy, the tumor is categorized as cN1 (sn) (Stage IIA). As per TNM rules, in the absence of pathological T evaluation (removal of the primary tumor), which is identified with prefix p (e.g., pT), microscopic evaluation of nodes before neoadjuvant therapy, even by complete removal such as sentinel node biopsy, is still classified as clinical (cN).
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively.
cThe cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.
dcN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.
ITCs = isolated tumor cells; RT-PCR = reverse transcriptase-polymerase chain reaction.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively, with NO further resection of nodes.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

Table 3. Definition of Regional Lymph Nodes – Clinical (cN) a,b

Table 4. Definition of Regional Lymph Nodes – Pathological (pN) a,b

Table 5. Definition of Distant Metastasis (M) a

Table 6. DDefinition of Histologic Grade (G) a

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

cN Category	cN Criteria
pN Category	pN Criteria
M Category	M Criteria
G	G Definition
G	G Definition
cNX c	Regional lymph nodes cannot be assessed (e.g., previously removed).
cN0	No regional lymph node metastases (by imaging or clinical examination).
cN1	Metastases to movable ipsilateral Level I, II axillary lymph nodes(s).
–cN1mi d	Micrometastases (approximately 200 cells, >0.2 mm, but ≤2.0 mm).
cN2	Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;
	or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
–cN2a	Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
–cN2b	Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
cN3	Metastases in ipsilateral infraclavicular (Level Ill axillary) lymph node(s) with or without Level l, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level l, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.
–cN3a	Metastases in ipsilateral infraclavicular lymph node(s).
–cN3b	Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
–cN3c	Metastases in ipsilateral supraclavicular lymph node(s).
pN Category	pN Criteria
pNX	Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed).
pN0	No regional lymph node metastasis identified or ITCs only.
–pN0(i+)	ITCs only (malignant cell clusters ≤0.2 mm) in regional lymph node(s).
–pN0(mol+)	Positive molecular findings by RT-PCR; no ITCs detected.
pN1	Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
–pN1mi	Micrometastases (~200 cells, >0.2 mm, but ≤2.0 mm).
–pN1a	Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
–pN1b	Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs.
–pN1c	pN1a and pN1b combined.
pN2	Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
–pN2a	Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
–pN2b	Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes.
pN3	Metastases in ≥10 axillary lymph nodes; or in infraclavicular (Level Ill axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level l, II axillary lymph nodes; or in >3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
–pN3a	Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodes.
–pN3b	pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
	or pN2a in the presence of pN1b.
–pN3c	Metastases in ipsilateral supraclavicular lymph nodes.
M Category	M Criteria
M0	No clinical or radiographic evidence of distant metastases. b
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1	Distant metastases detected by clinical and radiographic means.
pM1	Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.
G	G Definition
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.
G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively.
cThe cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.
dcN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.
ITCs = isolated tumor cells; RT-PCR = reverse transcriptase-polymerase chain reaction.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively, with NO further resection of nodes.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

Table 4. Definition of Regional Lymph Nodes – Pathological (pN) a,b

Table 5. Definition of Distant Metastasis (M) a

Table 6. DDefinition of Histologic Grade (G) a

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

pN Category	pN Criteria
M Category	M Criteria
G	G Definition
G	G Definition
pNX	Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed).
pN0	No regional lymph node metastasis identified or ITCs only.
–pN0(i+)	ITCs only (malignant cell clusters ≤0.2 mm) in regional lymph node(s).
–pN0(mol+)	Positive molecular findings by RT-PCR; no ITCs detected.
pN1	Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
–pN1mi	Micrometastases (~200 cells, >0.2 mm, but ≤2.0 mm).
–pN1a	Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
–pN1b	Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs.
–pN1c	pN1a and pN1b combined.
pN2	Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
–pN2a	Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
–pN2b	Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes.
pN3	Metastases in ≥10 axillary lymph nodes; or in infraclavicular (Level Ill axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level l, II axillary lymph nodes; or in >3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
–pN3a	Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodes.
–pN3b	pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
	or pN2a in the presence of pN1b.
–pN3c	Metastases in ipsilateral supraclavicular lymph nodes.
M Category	M Criteria
M0	No clinical or radiographic evidence of distant metastases. b
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1	Distant metastases detected by clinical and radiographic means.
pM1	Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.
G	G Definition
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.
G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
ITCs = isolated tumor cells; RT-PCR = reverse transcriptase-polymerase chain reaction.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively, with NO further resection of nodes.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

Table 5. Definition of Distant Metastasis (M) a

Table 6. DDefinition of Histologic Grade (G) a

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

M Category	M Criteria
G	G Definition
G	G Definition
M0	No clinical or radiographic evidence of distant metastases. b
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1	Distant metastases detected by clinical and radiographic means.
pM1	Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.
G	G Definition
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.
G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

Table 6. DDefinition of Histologic Grade (G) a

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

G	G Definition
G	G Definition
GX	Grade cannot be assessed.
G1	Low combined histologic grade (favorable), SBR score of 3–5 points.
G2	Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3	High combined histologic grade (unfavorable); SBR score of 8–9 points.
G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

Table 7. Ductal Carcinoma in situ: Nuclear Grade a

AJCC Anatomic and Prognostic Stage Groups

G	G Definition
GX	Grade cannot be assessed.
G1	Low nuclear grade.
G2	Intermediate nuclear grade.
G3	High nuclear grade.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.

AJCC Anatomic and Prognostic Stage Groups

There are three stage group tables for invasive cancer:

Anatomic Stage Group. The Anatomic Stage Group table is used in regions of the world where tumor grading and/or biomarker testing for ER, PR, and HER2 are not routinely available. (Refer to Table 8.)

Clinical Prognostic Stage Group. The Clinical Prognostic Stage Group table is used for all patients in the United States. Patients who have neoadjuvant therapy as their initial treatment should have the clinical prognostic stage and the observed degree of response to treatment recorded, but these patients are not assigned a pathological prognostic stage. (Refer to Table 9.)

Pathological Prognostic Stage Group. The Pathological Prognostic Stage Group table is used for all patients in the United States who have surgery as initial treatment and have pathological T and N information reported. (Refer to Table 10.)

In the United States, cancer registries and clinicians must use the Clinical and Pathological Prognostic Stage Group tables for reporting. It is expected that testing is performed for grade, HER2, ER, and PR status and that results are reported for all cases of invasive cancer in the United States.

Table 8. Definition of Anatomic Stage Groups a

Stage	TNM
0	Tis, N0, M0
IA	T1, N0, M0
IB	T0, N1mi, M0
	T1, N1mi, M0
IIA	T0, N1, M0
	T1, N1, M0
	T2, N0, M0
IIB	T2, N1, M0
	T3, N0, M0
IIIA	T0, N2, M0
	T1, N2, M0
	T2, N2, M0
	T3, N1, M0
	T3, N2, M0
IIIB	T4, N0, M0
	T4, N1, M0
	T4, N2, M0
IIIC	Any T (Tis, T1, T0, T2, T3, T4; N3, M0)
IV	Any T (Tis, T1, T0, T2, T3, T4; Any N = N0, N1mi, N1, N2, N3, M1)
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
Notes:
1. T1 includes T1mi.
2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.
4. M0 includes M0(i+).
5. The designation pM0 is not valid; any M0 is clinical.
6. If a patient presents with M1 disease before receiving neoadjuvant systemic therapy, the stage is Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.
7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.
8. Staging following neoadjuvant therapy is denoted with a yc or ypn prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoadjuvant therapy, for example, ypT0, ypN0, cM0.

The Clinical Prognostic Stage is used for clinical classification and staging of patients in the United States with invasive breast cancer. It uses TNM information based on the patient’s history, physical examination, imaging results (not required for clinical staging), and biopsies.

Table 9. Definition of Clinical Prognostic Stage Groups a

AJCC Pathological Prognostic Stage Groups

TNM	Grade	HER2 Status	ER Status	PR Status	Stage Group
Tis, N0, M0	Any (refer to Table 6 and Table 7)	Any	Any	Any	0
T1b, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IA
T0, N1mi, M0			Negative	Positive	IA
				Negative	IA
T1b, N1mi, M0		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G2	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IB
T0, N1c, M0; T1b, N1c, M0; T2, N0, M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
	G3	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
T2, N1d, M0; T3, N0, M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIIB
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
T0, N2, M0; T1b, N2, M0; T2, N2, M0; T3, N1d, M0; T3, N2, M0	G1	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G2	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G3	Positive	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIC
			Negative	Positive	IIIC
				Negative	IIIC
Any T, Any N, M1	Any (refer to Table 6 and Table 7)	Any	Any	Any	IV
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0, and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. Because N1mi categorization requires evaluation of the entire node, and cannot be assigned on the basis of an fine-needle aspiration or core biopsy, N1mi can only be used with Clinical Prognostic Staging when clinical staging is based on a resected lymph node in the absence of resection of the primary cancer, such as in the situation where sentinel node biopsy is performed before receiving neoadjuvant chemotherapy or endocrine therapy.
2. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
3. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.
4. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).

AJCC Pathological Prognostic Stage Groups

The Pathological Prognostic Stage applies to patients with invasive breast cancer initially treated with surgery. It includes all information used for clinical staging, surgical findings, and pathological findings following surgery to remove the tumor. Pathological Prognostic Stage is not used for patients treated with neoadjuvant therapy before surgery to remove the tumor.

Table 10. Definition of Pathological Prognostic Stage Groups a

TNM	Grade	HER2 Status	ER Status	PR Status	Stage Group
Tis, N0, M0	Any (refer to Table 6 and Table 7)	Any	Any	Any	0
T1b, N0, M0; T0, N1mi, M0; T1b, N1mi, M0	G1	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
	G2	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
T0, N1c , M0; T1b, N1c, M0; T2, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
	G2	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
	G3	Positive	Positive	Positive	IA
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
T2, N1c, M0; T3, N0, M0	G1	Positive	Positive	Positive	IA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G2	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIIA
T0, N2, M0; T1b, N2, M0; T2, N2, M0, T3, N1d, M0; T3, N2, M0	G1	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
	G2	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
	G3	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIC
			Negative	Positive	IIIC
				Negative	IIIC
Any T, Any N, M1	Any (refer to Table 6 and Table 7)	Any	Any	Any	IV
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0 and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
2. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.
3. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).

ReferenceSection

Barnes DM, Harris WH, Smith P, et al.: Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 74 (9): 1445-51, 1996.

Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018.

Breast. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 589–628.

Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31 (31): 3997-4013, 2013.

Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138 (2): 241-56, 2014.

Early/Localized/Operable Breast Cancer

Treatment Option Overview for Early/Localized/Operable Breast Cancer

Standard treatment options for early, localized, or operable breast cancer may include the following:

Breast-conserving surgery (lumpectomy) and sentinel lymph node (SLN) biopsy with or without axillary lymph node dissection for positive SLNs.

Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Axillary node–negative breast cancer (postmastectomy):

No additional therapy.

Radiation therapy.

Axillary node–positive breast cancer (postmastectomy):

For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.

For four or more nodes or extranodal involvement, regional radiation therapy is advised.

Axillary node–negative or positive breast cancer (post–breast-conserving therapy):

Whole-breast radiation therapy.

Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu–negative] status). Adjuvant treatment options may include the following:

Tamoxifen.

Aromatase inhibitor (AI) therapy.

Ovarian function suppression.

Chemotherapy.

Chemotherapy.

HER2 targeted therapy.

Endocrine therapy.

Surgery

Stages I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:

Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.

Surgical procedure. After the presence of a malignancy is confirmed by biopsy, the following surgical treatment options can be discussed with the patient before a therapeutic procedure is selected:

Breast-conserving surgery.

Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.

Locoregional treatment

Selection of a local therapeutic approach depends on the following:

Location and size of the lesion.

Analysis of the mammogram.

Breast size.

Patient’s desire to preserve the breast.

Options for surgical management of the primary tumor include the following:

Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.

However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.

Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is equivalent with any of these options, as documented in the trial of the European Organization for Research and Treatment of Cancer (EORTC) (EORTC-10801) and other prospective randomized trials.

Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER positive or PR positive; ER negative and PR negative but HER2/neu positive; and triple negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.

The rate of local recurrence in the breast after conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated.

However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:

Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.

More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.

There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re-excision. A clinical trial of 235 patients with stage 0 to III breast cancer who underwent partial mastectomy, with or without resection of selective margins, randomly assigned patients to have additional cavity shave margins resected (shave group) or not (no-shave group).

Patients in the shave group had a significantly lower rate of positive margins than those in the no-shave group (19% vs. 34%, P = .01) and a lower rate of second surgery for clearing margins (10% vs. 21%, P = .02).

[Level of evidence: 1iiDiv]

Axillary lymph node management

Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.

Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.

[Level of evidence: 3iiiA]

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.

Because of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

Evidence (SLN biopsy):

A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.

[Level of evidence: 1iiC]

Quality of life (QOL) at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% deteriorating in the SLN biopsy group vs. 35% in the ALND group; P = .001). Arm function was also better in the SLN group.

The National Surgical Adjuvant Breast and Bowel Project’s (NSABP-B-32 [NCT00003830]) multicenter, phase III trial randomly assigned women (N = 5,611) to undergo either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.

[Level of evidence: 1iiA]

The study showed no detectable difference in overall survival (OS), disease-free survival (DFS), and regional control. OS was 91.8% for SLN plus ALND versus 90.3% for SLN resection alone (P = .12).

Because of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.

Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):

A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.

[Level of evidence: 1iiA]

At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone.

The secondary endpoint of 5-year DFS was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.

In a similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to ALND or no ALND.

[Level of evidence: 1iiA]

Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11).

No difference in OS was observed.

The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node.

[Level of evidence: 1iiA]

ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.

The use of axillary radiation therapy was also associated with significantly less morbidity.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).

Breast contour can be restored by the following:

Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA] website for more information on breast implants.)

Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.

Postoperative Radiation Therapy

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.

Post–breast-conserving surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women.

Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death.

Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Evidence (breast-conserving surgery followed by radiation therapy):

A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.

[Level of evidence: 1iiA]

Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% for whole-breast radiation therapy vs. 35% for breast-conserving surgery alone; relative risk (RR) = 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% for whole-breast radiation therapy vs. 25% for breast-conserving surgery alone; RR, 0.82; 95% CI, 0.75–0.90).

Regarding radiation dosing and schedule, the following has been noted:

Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.

Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),

[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).

[Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.

[Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.

Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.

A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule.

The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).

Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to receive conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.

[Level of evidence: 1iiDii]

A meta-analysis that included the three trials mentioned above plus six others confirmed that differences with respect to local recurrence or cosmesis between shorter and conventional fractionation schedules were neither statistically nor clinically significant.

Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.

Regional nodal irradiation

Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes; however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear. A randomized trial (NCT00005957) of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence (10-year DFS, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS, 82.8% vs. 81.8%; HR, 0.91; 95% CI, 0.72–1.13; P = .38).

[Level of evidence: 1iiA]

Similar findings were reported from the EORTC trial (NCT00002851). Women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to receive whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Breast-conserving surgery was performed for 76.1% of the study population, and the remaining study population underwent mastectomy. No improvement in OS was seen at 10 years among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal radiation (82.3% vs. 80.7%, P = .06). Distant DFS was improved among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal irradiation (78% vs. 75%, P = .02).

[Level of evidence: 1iiA]

A meta-analysis that combined the results of the two trials mentioned above found a marginally statistically significant difference in OS (HR, 0.88; 95% CI, 0.78–0.99; P = .034; absolute difference, 1.6% at 5 years).

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for locoregional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:

Four or more positive axillary nodes.

Grossly evident extracapsular nodal extension.

Large primary tumors.

Very close or positive deep margins of resection of the primary tumor.

In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.

Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.

Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):

The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.

[Level of evidence: 1iiA]

For women with node-positive disease postmastectomy and axillary clearance (removal of axillary lymph nodes and surrounding fat), radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95% CI, 15.2%–18.8%). This translated into a significant reduction (P = .002) in breast cancer mortality, 54.7% versus 60.1%, with an absolute gain of 5.4% (95% CI, 2.9%–7.9%).

In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P [2-sided significance level] < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).

[Level of evidence: 1iiA]

In contrast, for women at low risk of local recurrence with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality (absolute gain, 1.0%; P > .1; 95% CI, -0.8%–2.8%).

Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.

Timing of postoperative radiation therapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.

Evidence (timing of postoperative radiation therapy):

In a randomized trial, patients received one of the following regimens:

[Level of evidence: 1iiA]

Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation.

Breast radiation first (n = 122), followed by the same chemotherapy.

The following results were observed:

With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).

The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and 14% in the chemotherapy-first group for local recurrence and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07).

Further analyses revealed that differences in recurrence patterns persisted for most subgroups except for those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses was low.

Potential explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages because of increased myelosuppression.

Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.

In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of cyclophosphamide, methotrexate, and 5-FU (CMF) (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.

[Level of evidence: 1iiA]

No differences in DFS, distant DFS, and OS were observed between these two arms.

The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.

These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.

[Level of evidence: 1iiA]

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu–positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.

Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Late toxic effects of radiation

Late toxic effects of radiation therapy are uncommon and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:

Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.

The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.

[Level of evidence: 3iii]

Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.

This was probably caused by the radiation received by the left myocardium.

Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.

An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) data from 1973 to 1989 that reviewed deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.

[Level of evidence: 3iB]

Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy.

(Refer to the PDQ summary on Lymphedema for more information.)

Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were monitored for 5.5 years to assess the rate of brachial plexus injury.

The diagnosis of such injury was made clinically with computerized tomography (CT) to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy.

No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy.

Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.

Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years.

In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.

An international consensus panel proposed a risk classification system and systemic therapy treatment options.

This classification, with some modification, is described below:

Table 11. Systemic Treatment for Early Breast Cancer by Subtype a

Subtype	Treatment Options	Comments
Luminal A–like
– Hormone receptor–positive	Endocrine therapy alone in most cases	Consider chemotherapy if:
– HER2-negative		– High tumor burden (≥4 LNs, T3 or higher)
– PR >20%
– Ki67 low		– Grade 3
Luminal B–like
– Hormone receptor–positive	Endocrine therapy plus chemotherapy in most cases
– HER2-negative
– Either Ki67 high or PR low
HER2-positive	Chemotherapy plus anti-HER2 therapy	Use endocrine therapy if also hormone receptor–positive
		May consider omitting chemotherapy plus anti-HER2 for small node-negative tumors
Triple-negative	Chemotherapy	May consider omitting chemotherapy for small node-negative tumors
HER2 = human epidermal growth factor receptor 2; LN = lymph node; PR = progesterone receptor.
aModified from Senkus et al.

The selection of therapy is most appropriately based on knowledge of an individual’s risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their situation. The treatment options described below should be modified based on both patient and tumor characteristics.

Table 12. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast Cancer

Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (CMF)

Patient Group	Treatment Options
Premenopausal, hormone receptor–positive (ER or PR)	No additional therapy
	Tamoxifen
	Tamoxifen plus chemotherapy
	Ovarian function suppression plus tamoxifen
	Ovarian function suppression plus aromatase inhibitor
Premenopausal, hormone receptor–negative (ER or PR)	No additional therapy
	Chemotherapy
Postmenopausal, hormone receptor–positive (ER or PR)	No additional therapy
	Upfront aromatase inhibitor therapy or tamoxifen followed by aromatase inhibitor with or without chemotherapy
Postmenopausal, hormone receptor–negative (ER or PR)	No additional therapy
	Chemotherapy
ER = estrogen receptor; PR = progesterone receptor.

Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (CMF)

The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and 5-FU). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.

Evidence (anthracycline-based regimens):

The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of 5-FU, epirubicin, and cyclophosphamide [FEC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]) with CMF (either PO or intravenous [IV]) in approximately 14,000 women, 64% of whom were younger than 50 years.

Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.

[Level of evidence: 1iiA]

Of note, few women older than 70 years were studied, and specific conclusions could not be reached for this age group.

Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to hormone-receptor status, and the trials were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.

As a result, the data may not reflect treatment outcomes based on evolving treatment patterns.

Study results suggest that tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.

Evidence (anthracycline-based regimen in women with HER2/neu amplification):

Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and 5-FU (CAF),

or the addition of doxorubicin to the adjuvant regimen,

is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]

A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and 5-FU(CEF).

[Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods.

The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in relapse-free survival (RFS) and OS.

In patients with HER2/neu amplification, the RFS and OS were increased by CEF.

In the absence of HER2/neu amplification, CEF and CMF were similar with regard to RFS (HR for relapse, 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HRdeath, 1.06; 95% CI, 0.83–1.44; P = .68).

Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with non–anthracycline-containing regimens.

Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy

Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.

Evidence (adding a taxane to an anthracycline-based regimen):

A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).

[Level of evidence: 1iiA]

Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens.

There were no differences in benefit observed in patient subsets defined by nodal status, hormone-receptor status, or age and menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies that were reviewed involved a direct comparison between paclitaxel and docetaxel.

A U.S. intergroup study (CLB-9344 [NT00897026]) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to receive paclitaxel (175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with hormone receptor-positive tumors also received tamoxifen for 5 years.

[Level of evidence: 1iiA]

Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).

The NSABP-B-28 (NCT01420185) trial randomly assigned 3,060 women with node-positive breast cancer to receive four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.

[Level of evidence: 1iiA]

DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%).

The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).

In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.

[Level of evidence: 1iiA]

There was a 75% DFS rate at 5 years in the TAC group compared with a 68% DFS rate in the FAC group (P = .001).

TAC was associated with a 30% overall lower risk of death (5% absolute difference) than was FAC (HR, 0.70; 98% CI, 0.53–0.91; P < .008).

Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group. (Refer to the PDQ summary on Fatigue for information on anemia.)

An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.

[Level of evidence: 1iiA] Study findings include the following:

There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).

There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).

Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).

Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.

Chemotherapy schedule: Dose-density

Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.

Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):

A U.S. intergroup trial (CLB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.

[Level of evidence: 1iiA]

At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P = .018), but not OS (HR, 0.85; P = .12).

[Level of evidence: 1iiA]

There was no interaction between density and sequence.

Severe neutropenia was less frequent in patients who received the dose-dense regimens.

[Level of evidence: 1iiA]

An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.

For the dose-density comparison, DFS at 5 years was 81% (95% CI, 79–84) in patients treated every 2 weeks and 76% (95% CI, 74–79) in patients treated every 3 weeks (HR, 0.77; 95% CI, 0.65–0.92; P = .004).

OS rates at 5 years were 94% (95% CI, 93–96) and 89% (95% CI, 87–91; HR, 0.65; 0.51–0.84; P = .001).

[Level of evidence: 1iiA]

A meta-analysis of dose-dense versus standard dosing included data from eight trials including 17,188 patients.

The patients who received dose-dense chemotherapy had better OS (HR, 0.86; 95% CI, 0.79–0.93; P = .0001) and DFS (HR, 0.84; 95% CI, 0.77–0.91; P < .0001) than those on the conventional schedule. A statistically significant OS benefit was observed in patients with ER-negative tumors (HR, 0.8; P = .002) but not in those with ER-positive breast cancer (HR, 0.93; 95% CI, 0.82–1.05; P = .25).

A meta-analysis of 26 randomized trials that included 37,298 women treated with anthracycline- and taxane-containing chemotherapy compared standard regimens (administered every 3–4 weeks) with more dose-intense regimens. Regimens that increased dose intensity by shortening the interval between cycles (i.e., dose-dense therapy or administration of the same dose over a shorter time period) and regimens that increased dose intensity by administering individual drugs in sequence to allow for higher doses (i.e., sequential scheduling).

Patients who received more dose-intense regimens had superior recurrence-free survival (28.0% vs. 31.4%; RR, 0.86; 95% CI, 0.82–0.89; P < .0001) and OS (18.9% vs. 21.3%; RR, 0.87; 95% CI, 0.83–0.92; P < .0001) at 10 years. The difference was present and statistically significant in receptor-positive and receptor-negative subgroups.

A randomized, phase III, double-blinded study (NCT01519700) demonstrated noninferiority for the duration of severe neutropenia of a biosimilar filgrastim, EP2006, compared with the U.S.-licensed product.

[Level of evidence: 1iDiv]

Docetaxel and cyclophosphamide

Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):

The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.

[Level of evidence: 1iiA]

At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS.

DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033).

OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032).

Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.

Timing of postoperative chemotherapy

The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:

A single-institution study of early-stage breast cancer patients diagnosed between 1997 and 2011 revealed that delays in initiation of adjuvant chemotherapy adversely affected survival outcomes.

[Level of evidence: 3iiiA]

Initiation of chemotherapy 61 days or more after surgery was associated with adverse outcomes among patients with stage II breast cancer (distant relapse-free survival: HR, 1.20; 95% CI, 1.02–1.43) and stage III breast cancer (OS: HR, 1.76; 95% CI, 1.26–2.46; RFS: HR, 1.34; 95% CI, 1.01–1.76; and distant relapse-free survival: HR, 1.36; 95% CI, 1.02–1.80).

Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.

Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.

Toxic effects of chemotherapy

Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include the following:

Nausea and vomiting.

Myelosuppression.

Alopecia.

Mucositis.

Less common, but serious, toxic effects include the following:

Heart failure (if an anthracycline is used).

Thromboembolic events.

Premature menopause.

Second malignancy (leukemia).

(Refer to the PDQ summary on Treatment-Related Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)

The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.

This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.

However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.

This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.

HER2/neu–negative breast cancer

For HER2/neu–negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.

Triple-negative breast cancer (TNBC)

TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Combination chemotherapy

Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.

Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):

A prospective analysis studied 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC.

[Level of evidence: 3iiDiv]

The study observed that patients with TNBC had higher pathologic complete response (pCR) rates than did non-TNBC patients (22% vs. 11%; P = .034). Improved pCR rates may be important because in some studies, pCR is associated with improved long-term outcomes.

Platinum agents

Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.

[Level of evidence: 3iiiDiv] A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.

Poly (ADP-ribose) polymerase (PARP) inhibitor agents

The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC.

PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.

HER2/neu–positive breast cancer

Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.

Trastuzumab

Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.

Evidence (duration of trastuzumab therapy):

The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.

[Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:

Observation (n = 1,693).

1 year of trastuzumab (n = 1,694).

2 years of trastuzumab (n = 1,694).

Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.

One year of trastuzumab versus observation:

After a median follow-up of 11 years,

the finding was that 1 year of trastuzumab improved DFS (HR, 0.76; 95% CI, 0.68–0.86; 10-year DFS, 72% vs. 66%; P < .0001), despite a crossover of 52% of the patients on observation.

One year of trastuzumab also improved OS (HR, 0.74; 95% CI, 0.64–0.86; 12-year OS, 79% vs. 73%; P < .0001).

[Level of evidence: 1iiA]

One year versus 2 years of trastuzumab:

After a median follow-up of 11 years, there was no benefit to an additional year of trastuzumab for DFS (HR, 1.02; 95% CI, 0.89–1.17).

Symptomatic cardiac events occurred in 1% of the patients on trastuzumab and in 0.1% of the observation group.

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.

[Level of evidence: 1iiA]

The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%) was observed, as was a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS, 91.4% in the trastuzumab group vs. 86.6% in the control group).

Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).

In an updated analysis with a median follow-up of 8.4 years, the addition of trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR, 0.63; 95% CI, 0.54–0.73; P < .001) and an increase in the 10-year OS rate from 75.2% to 84%.

In the BCIRG-006 (NCT00021255) trial, 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a non–anthracycline-containing regimen).

[Level of Evidence: 1iiA]

A significant DFS and OS benefit was seen in both groups treated with trastuzumab compared with the control group that did not receive trastuzumab.

For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04). The control group had a 5-year DFS rate of 75% and an OS rate of 87%.

The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.

The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).

These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.

This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.

[Level of evidence: 1iiA]

At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3-year DFS, 89% vs. 78%).

The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).

Several studies have compared 6 months of trastuzumab administration to 12 months.

In an interim analysis of the PHARE (NCT00381901) trial, the 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).

[Level of evidence: 1iiA]

In the final analysis, after 704 events were observed, the adjusted HR was 1.08 (95% CI, 0.93–1.25), and the prespecified noninferiority HR of 1.15 was not excluded.

Similar results were noted in a much smaller study of 481 patients led by the Hellenic Oncology Research Group.

[Level of evidence: 1iiA]

In contrast, the PERSEPHONE (NCT00712140) trial, which enrolled 4,088 patients who experienced 512 DFS events at the time of analysis, excluded its prespecified noninferiority margin (HR, 1.07; 90% CI, 0.93−1.24; noninferiority, P = .011).

[Level of evidence: 1iiA]

Several studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.

Cardiac toxic effects with adjuvant trastuzumab

Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:

In the HERA (BIG-01-01) trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab.

Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.

In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.

The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).

In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).

In the AVENTIS-TAX-GMA-302 (BCIRG 006) (NCT00021255) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm.

There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.

In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.

Lapatinib

Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu–positive breast cancer.

Evidence (against the use of lapatinib for HER2-positive early breast cancer):

In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting was investigated.

[Level of evidence: 1iiA]

In the primary analysis, at the median follow-up of 4.5 years (range, 1 day–6.4 years), a 16% reduction in the HR for DFS was observed in the lapatinib-plus-trastuzumab arm, compared with the trastuzumab-alone arm (555 DFS events; HR, 0.84; 97.5% CI, 0.70–1.02; P = .048), which was not statistically significant at the .025 significance level.

The HR for DFS for the superiority comparison of trastuzumab to lapatinib versus trastuzumab alone in the intention-to-treat population was 0.96 (97.5% CI, 0.80–1.15; P = .61).

The 4-year OS was 95% for the lapatinib-plus-trastuzumab arm, 95% for the trastuzumab-to-lapatinib arm, and 94% for the trastuzumab-alone arm. The HR for OS was 0.80 (95% CI, 0.62–1.03; P = .078) for the comparison of lapatinib plus trastuzumab versus trastuzumab alone and 0.91 (95% CI, 0.71–1.16; P = .433) for the comparison of trastuzumab to lapatinib versus trastuzumab alone.

The lapatinib-versus-trastuzumab component of the study was closed because, at interim analysis, the HR for DFS was 1.52 in favor of trastuzumab alone and noninferiority was excluded.

Combination therapy with lapatinib and trastuzumab also resulted in worsened grade 3 diarrhea (15% vs. 1%), grade 3 rash (5% vs. 1%), and grade 3 hepatobiliary adverse events (3% vs. 1%) compared with trastuzumab alone.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Its use, in combination with trastuzumab, has been evaluated in a randomized trial in the postoperative setting.

Evidence (pertuzumab):

The Breast Intergroup (BIG) trial enrolled 4,805 women with HER2-positive cancer cells in a blinded comparison study for 12 months of trastuzumab plus placebo versus 12 months of trastuzumab plus pertuzumab, which were given in conjunction with standard chemotherapy and hormone therapy.

At the time of the final analysis of the primary endpoint (breast cancer, RFS), there was a significant difference in favor of the combination regimen (HR, 0.81; 95% CI, 0.66–1.00; P = .045; 3-year invasive DFS, 94.1% vs. 93.2%).

There was no statistically significant difference in OS at the first interim analysis for this endpoint.

Patients receiving pertuzumab had more grade 3 diarrhea (9.8% vs. 3.7%) and were more likely to develop heart failure (0.6% vs. 0.2%).

Neratinib

Neratinib is an irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4, which has been approved by the FDA for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.

Evidence (Neratinib):

In the ExteNET (NCT00878709) trial, the safety and efficacy of 12 months of adjuvant neratinib was investigated in patients with early-stage HER2-positive breast cancer (n = 2,840) who had completed neoadjuvant trastuzumab up to 2 years before randomization. Patients received neratinib 240 mg oral daily for 1 year or a placebo.

[Level of evidence: 1iiA]

The primary endpoint was invasive DFS.

After a median follow-up of 5.2 years (interquartile range, 2.1–5.3), patients in the neratinib group had significantly fewer invasive DFS events than those in the placebo group (neratinib group, 116 events vs. placebo group, 163 events; stratified HR, 0.73; 95% CI, 0.57–0.92; P = .0083). The 5-year invasive DFS was 90.2% (95% CI, 88.3–91.8) in the neratinib group and 87.7% (85.7–89.4) in the placebo group.

OS data are not mature.

The most common grade 1 to 2 adverse events included diarrhea (neratinib, 55% vs. placebo, 34%), nausea (41% vs. 21%), fatigue (25% vs. 20%), vomiting (23% vs. 8%), and abdominal pain (22% vs. 10%). Prophylactic loperamide is recommended on the FDA label during the first 56 days of therapy, and as needed thereafter to help manage diarrhea.

The most common grade 3 to 4 adverse event was diarrhea (neratinib, 40% vs. placebo, 2%). All other grade 3 to 4 adverse events occurred in 2% or less of patients.

Hormone receptor–positive breast cancer

Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients.

Five years of adjuvant endocrine therapy has been shown to substantially reduce the risks of locoregional and distant recurrence, contralateral breast cancer, and death from breast cancer.

The optimal duration of endocrine therapy is unclear, with the preponderance of evidence supporting at least 5 years of endocrine therapy. A meta-analysis of 88 clinical trials involving 62,923 women with hormone receptor–positive breast cancer who were disease free after 5 years of endocrine therapy showed a steady risk of late recurrence 5 to 20 years after diagnosis.

[Level of evidence: 3iiiD] The risk of distant recurrence correlated with the original tumor (T) and node (N) status, with risks ranging from 10% to 41%.

Tamoxifen

Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

Evidence (tamoxifen for hormone receptor–positive early breast cancer):

The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. An analysis published in 2005 included information on 80,273 women in 71 trials of adjuvant tamoxifen.

[Level of evidence: 1iiA]

In this analysis, the benefit of tamoxifen was found to be restricted to women with hormone receptor–positive or hormone receptor–unknown breast tumors. In these women, the 15-year absolute reduction associated with 5 years of use was 12% for recurrence and 9% for mortality.

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.

The meta-analysis also confirmed the benefit of adjuvant tamoxifen in hormone receptor–positive premenopausal women. Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the node-positive breast cancer group (5.3% vs. 12.5% with 5 years of use).

Similar results were found in the IBCSG-13-93 trial.

Of 1,246 women with stage II disease, only the women with hormone receptor–positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.

Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.

Evidence (duration of tamoxifen therapy):

The EBCTCG meta-analysis demonstrated that 5 years of tamoxifen was superior to shorter durations. The following results were reported:

A highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01) was observed.

Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS [NCT00003016]) trial demonstrated that 10 years of tamoxifen therapy was superior to 5 years of tamoxifen therapy. Between 1996 and 2005, 12,894 women with early breast cancer were randomly assigned to receive 10 years or 5 years of tamoxifen therapy. The following results were reported:

[Level of Evidence: 1iiA]

Study results revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences for 10 years of tamoxifen vs. 711 recurrences for 5 years of tamoxifen; P = .002), reduced breast-cancer mortality (331 deaths for 10 years of tamoxifen vs. 397 deaths for 5 years of tamoxifen; P = .01), and reduced overall mortality (639 deaths for 10 years of tamoxifen vs. 722 deaths for 5 years of tamoxifen; P = .01).

Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% at 10 years and 12.2% at 5 years.

Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:

Pulmonary embolus RR, 1.87; (95% CI, 1.13–3.07; P = .01).

Stroke RR, 1.06; (95% CI, 0.83–1.36).

Ischemic heart disease RR, 0.76; (95% CI, 0.6–0.95; P = .02).

Endometrial cancer RR, 1.74; (95% CI, 1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.

The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial.

Women who have become menopausal after 5 years of tamoxifen may also be treated with AIs. (Refer to the Aromatase inhibitors section in the Hormone receptor–positive therapy section of this summary for more information.)

Tamoxifen and chemotherapy

Because of the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy.

However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.

Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.

Evidence (tamoxifen plus ovarian suppression):

The largest study (SOFT [NCT00066690]) to examine the addition of ovarian ablation to tamoxifen with or without chemotherapy randomly assigned 2,033 premenopausal women (53% of whom had received previous chemotherapy) to receive tamoxifen or tamoxifen plus ovarian suppression with triptorelin or ablation with surgery or radiation therapy.

[Level of evidence: 1iiDii]

Upon initial report, with a median follow-up of 5.6 years, there was no significant difference in the primary outcome of DFS (HR, 0.83; 95% CI, 0.66–1.04; P = .10); 5-year DFS was 86% in the tamoxifen-plus-ovarian-suppression group versus 84.7% in the tamoxifen-alone group. However, updated results with a median follow-up of 8 years, demonstrated improved DFS with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.76; 95% CI, 0.62–0.93, P = .009); the 8-year DFS was 83.2% in the tamoxifen-plus-ovarian-suppression group versus 78.9% in the tamoxifen-alone group. In addition, OS at 8 years was improved with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.67; 95% CI, 0.48–0.92; P = .01); 8-year OS was 93.3% in the tamoxifen-plus-ovarian-suppression group versus 91.5% in the tamoxifen-alone group.

Despite overall negative initial results, subgroup analysis suggested a benefit with ovarian suppression in women who underwent chemotherapy and remained premenopausal afterwards. Follow-up results at 8 years, however, did not demonstrate heterogeneity of treatment effect according to whether chemotherapy was administered, although recurrences were more frequent among patients who received chemotherapy.

Aromatase inhibitors (AIs)

Premenopausal women

AIs have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Evidence (comparison of an AI with tamoxifen in premenopausal women):

In one study (NCT00295646), 1,803 women who received goserelin were randomly assigned to a 2 × 2 factorial design trial that compared anastrozole and tamoxifen, with or without zoledronic acid.

At a median follow-up of 62 months, there was no difference in DFS (HR, 1.08; 95% CI, 0.81–1.44; P = .59).

OS was superior with tamoxifen (HR, 1.75; 95% CI, 1.08–2.83; P = .02).

In two unblinded studies that were analyzed together (TEXT [NCT00066703] and SOFT [NCT00066690]), exemestane was also compared with tamoxifen in 4,690 premenopausal women who underwent ovarian ablation.

The use of exemestane resulted in a significant difference in DFS (HR, 0.77; 95% CI, 0.67–0.90; P < .001; 8-year DFS, 86.8% in the exemestane-ovarian suppression group vs. 82.8% in the tamoxifen-ovarian-suppression group).

[Level of evidence: 1iDii]

The 8-year rate of freedom from distant recurrence was also higher in the exemestane-ovarian-suppression group (HR, 0.80; 95% CI, 0.66–0.96; P = .02); 8-year rate of freedom from distant recurrence was 91.8% in the exemestane-ovarian-suppression group versus 89.7% in the tamoxifen-ovarian-suppression group.

Despite improvements in DFS and freedom from distant recurrence, no difference in OS was observed with the use of exemestane in combination with ovarian suppression compared with tamoxifen in combination with ovarian suppression (HR, 0.98; 95% CI, 0.79–1.22; P = .84; 8-year OS, 93.4% in the exemestane-ovarian suppression group vs. 93.3% in the tamoxifen-ovarian-suppression group).

[Level of evidence: 1iiA]

A follow-up report on the differences in QOL for the exemestane-ovarian-suppression group versus the tamoxifen-ovarian-suppression group observed the following (the differences cited below were all significant at P < .001 and occurred in patients who did and did not receive chemotherapy):

Patients who received tamoxifen plus ovarian function suppression were more affected by hot flushes and sweats over 5 years than were those who received exemestane plus ovarian function suppression, although these symptoms improved.

Patients who received exemestane plus ovarian function suppression reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients who received tamoxifen plus ovarian function suppression; these differences persisted over time.

An increase in bone or joint pain was more pronounced, particularly in the short term, in patients who received exemestane plus ovarian function suppression than in patients who received tamoxifen plus ovarian function suppression.

Changes in global QOL indicators from baseline were small and similar between treatments over the 5 years.

[Level of evidence: 1iC]

Postmenopausal women

In postmenopausal women, the use of AIs in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.

Initial therapy

Evidence (AI vs. tamoxifen as initial therapy in postmenopausal women):

A large, randomized trial of 9,366 patients compared the use of the AI anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with lymph node-negative or lymph node-positive disease. Most (84%) of the patients in the study were hormone receptor-positive. Slightly more than 20% had received chemotherapy.

;

[Level of evidence: 1iDii]

With a median follow-up of 33.3 months, no benefit in DFS was observed for the combination arm relative to tamoxifen alone.

Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted after a median follow-up of 100 months among hormone receptor-positive patients, DFS was significantly (P = .003) longer in patients on anastrozole (HR, 0.85; 95% CI, 0.76–0.94), but OS was not improved (HR, 0.97; 95% CI, 0.86–1.11; P = .7).

Patients on tamoxifen more frequently developed endometrial cancer and cerebrovascular accidents, whereas patients on anastrozole had more fracture episodes. The frequency of myocardial infarction was similar in both groups. Except for a continued increased frequency of endometrial cancer in the tamoxifen group, these differences did not persist in the posttreatment period.

A large, double-blinded, randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole with tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years.

An updated analysis from the International Breast Cancer Study Group (IBCSG-1-98 [NCT00004205]) reported results on the 4,922 women who received tamoxifen or letrozole for 5 years at a median follow-up of 51 months.

[Level of evidence: 1iDii]

DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS, 84.0% vs. 81.1%).

OS was not significantly different in patients treated with letrozole (HR, 0.91; 95% CI, 0.75–1.11; P = .35).

In the meta-analysis, which included 9,885 women from multiple trials, the 10-year recurrence risk was 19.1% in the AI group versus 22.7% in the tamoxifen group (RR, 0.80; 95% CI, 0.73–0.88; P < .001). The overall 10-year mortality rate was also reduced from 24.0% to 21.3%. (RR, 0.89; 95% CI, 0.8–0.97; P = .01).

[Level of evidence: 1A]

Sequential tamoxifen and AI versus 5 years of tamoxifen

Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.

The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.

Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):

Two trials carried out in sequence by the same group enrolled a total of 828 patients and were reported together; one trial used aminoglutethimide as the AI, and the other trial used anastrozole. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed in the AI groups.

[Level of evidence: 1iiA]

Two other trials were reported together.

A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. There was a significant difference in event-free survival (EFS) (HR, 0.80; 95% CI, P = .0009), but not in OS (5-year OS, 97% CI for the switched arm vs. 96% CI for the tamoxifen-alone arm; P = .16).

[Level of evidence: 1iDii]

A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) (NCT00003418) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.

[Level of evidence: 1iDii]

After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.

After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.

[Level of evidence: 1iA]

At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).

In the meta-analysis, which included 11,798 patients from six trials, the 10-year recurrence rate was reduced from 19% to 17% in the AI-containing groups (RR, 0.82; 95% CI, 0.75–0.91; P = .0001). The overall 10-year mortality was 17.5% in the tamoxifen group and 14.6% in the AI-containing group (RR, 0.82; 95% CI, 0.73–0.91; P = .0002).

[Level of evidence: 1A]

Sequential tamoxifen and AI for 5 years versus 5 years of an AI

The evidence indicates that there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.

Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):

A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years. The primary endpoints were DFS at 2.75 years and 5.0 years.

[Level of evidence: 1iDii]

Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).

Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole.

[Level of evidence: 1iDii]

There was no difference in DFS when the two sequential arms were compared with 5 years of letrozole (letrozole to tamoxifen HR, 1.06; 95% CI, 0.91–1.23; P = .45 and tamoxifen to letrozole HR, 1.07; 95% CI, 0.92–1.25; P = .36).

The FATA-GIM3 (NCT00541086) trial, which was not included in the meta-analysis, compared 2 years of tamoxifen followed by 3 years of one of the three AIs with 5 years of an AI. No significant difference in 5-year DFS was found between the two approaches (88.5% for switching; 89.8% for upfront AI; HR, 0.89; 95% CI, 0.73–1.08; P = .23).

In the meta-analysis, which included 12,779 patients from the trials, the 7-year recurrence rate was slightly reduced from 14.5% to 13.8% in the groups that received 5 years of an AI (RR, 0.90; 95% CI, 0.81–0.99; P = .045). Overall mortality at 7 years was 9.3% in the tamoxifen-followed-by-AI groups and 8.2% in the AI-alone groups (RR, 0.89; 95% CI, 0.78–1.03; P = .11).

[Level of evidence: 1A]

One AI versus another for 5 years

The mild androgen activity of exemestane prompted a randomized trial that evaluated whether exemestane might be preferable to anastrozole, in terms of its efficacy (i.e., EFS) and toxicity, as upfront therapy for postmenopausal women diagnosed with hormone receptor-positive breast cancer.

[Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.

At a median follow-up of 4.1 years, no difference in efficacy was seen (HR, 1.02; 95% CI, 0.87–1.18; P = .86).

[Level of evidence: 1iiD]

The two therapies also were not significantly different in terms of impact on bone mineral density or fracture rates.

[Level of evidence: 1iiD]

In the Femara Versus Anastrozole Clinical Evaluation (FACE [NCT00248170]) study, 4,136 patients with hormone receptor-positive disease were randomly assigned to receive either letrozole or anastrozole.

There was no significant difference in DFS (HR, 0.93; 95% CI, 0.80–1.07; P = .3150) at the time of a final analysis that was conducted when there were 709 of the planned 959 events.

There were no substantial differences in adverse events between the arms.

In the FATA-GIM3 trial, 3,697 patients with HR-positive disease were randomly assigned among the three AIs either for 5 years or after 2 years of tamoxifen. No significant difference in 5-year DFS (90.0% for anastrozole, 88.0% for exemestane, and 89.4% for letrozole; P = .24) was noted among the three AIs.

Switching to an AI after 5 years of tamoxifen

The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.

A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 years (range, 4.5–6.0) years.

[Level of evidence: 1iDii]

After the first planned interim analysis, when median follow-up for patients in the study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57), favoring the letrozole arm.

After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.

An updated analysis including all events before unblinding confirmed the results of the interim analysis.

In addition, a statistically significant improvement in distant DFS was found for patients who received letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no statistically significant difference was found in the total study population, the lymph node-positive patients who received letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), although the P value was not corrected for multiple comparisons.

The NSABP B-33 (NCT00016432) trial that was designed to compare 5 years of exemestane with placebo after 5 years of tamoxifen was stopped prematurely when the results of CAN-NCIC-MA17 became available. At the time of analysis, 560 of the 783 patients who were randomly assigned to receive exemestane remained on that drug and 344 of the 779 patients who were randomly assigned to receive placebo had crossed over to exemestane.

[Level of evidence: 1iDii]

An intent-to-treat analysis of the primary study endpoint, DFS, demonstrated a nonsignificant benefit of exemestane (HR, 0.68; P = .07).

Duration of AI therapy

The optimal duration of AI therapy is uncertain, and multiple trials have evaluated courses longer than 5 years.

Evidence regarding extension of endocrine therapy beyond 5 years of initial AI-based adjuvant therapy:

A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.

Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI.

At a median follow-up of 6.3 years, DFS, the primary study endpoint, was significantly improved in patients randomly assigned to receive letrozole (HR, 0.66; 95% CI, 0.48–0.91; P = .01), and 5-year DFS was improved from 91% to 95%.

[Level of evidence: 1iDii]

OS rates showed no difference (HR, 0.97; 95% CI, 0.73–1.28; P = .83). More patients on letrozole had fractures (14%) than did patients on placebo (9%) (P = .001).

QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.

No between-group differences were found on the four MENQOL subscales or on the SF-36 summary score.

SF-36 role-emotional and bodily pain scores were statistically significantly worse (P = .03) among patients receiving letrozole, but the differences observed were fewer than the minimum clinically important differences for the SF-36 instrument.

A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.

[Level of evidence: 1iiDii]

DFS events were similar in both groups (HR, 0.92; 95% CI, 0.74–1.16). The distant metastasis-free interval was also similar (HR, 1.06; 95% CI, 0.78–1.45).

A subgroup analysis did not identify patients who benefited from 5-year extended therapy.

This study did not show that 10 years of AI therapy was superior to 7.5 years of AI therapy.

A phase III trial (NSABP-B42 [NCT00382070]) randomly assigned, in a double-blind fashion, 3,966 women who received 5 years of initial adjuvant therapy with an AI or received tamoxifen for 2 to 3 years followed by an AI to receive 5 mg of letrozole or placebo for 5 additional years.

[Level of evidence: 1iDii] The planned analysis of DFS was carried out after a median follow-up of 6.9 years.

The 7-year DFS was 81.3% in the placebo group and 84.7% in the letrozole group (HR, 0.85; 95% CI, 0.73–0.999; P = .048). The observed difference was not statistically significant when interim analyses were accounted for.

There were no statistically significant differences in adverse events between the arms.

A phase III trial conducted by the IBCSG (SOLE [NCT00553410]) randomly assigned 4,851 eligible receptor-positive postmenopausal women who had completed 5 years of adjuvant therapy with an AI, a selective estrogen receptor modulator, or both, to receive 2.5 mg of letrozole daily for 5 years or to an intermittent schedule in which there was a 3-month break at the end of each of the first 4 years, but not in the final year.

There was no observed advantage to the intermittent schedule with respect to DFS (HR, 1.08; 95% CI, 0.93–1.26; P = .31) or in the frequency of adverse events.

[Level of evidence: 1iiDii]

A phase III trial conducted by the Dutch Breast Cancer Study Group (DATA [NCT00301457]) randomly assigned 1,860 eligible receptor-positive postmenopausal women who had received 2 to 3 years of tamoxifen to receive either 3 or 6 years of anastrozole (1 mg daily).

At 3 years, 1,660 of these women were free of disease: among them, DFS was observed to be improved, but not statistically significantly so, on the extended-therapy arm (HR, 0.79; 95% CI, 0.62–1.02).

[Level of evidence: 1iiDii] Myalgia and osteoporosis/osteopenia were more frequent on the extended-therapy arm.

The phase III ABCSG-16 study, published in abstract form, enrolled 3,484 postmenopausal women with hormone receptor–positive breast cancer who had completed 5 years of endocrine therapy with tamoxifen and/or an AI to either 2 or 5 years of extended therapy with anastrozole. The primary endpoint was DFS. Secondary endpoints included OS, time to contralateral breast cancer, time to second primary cancer, fractures, and toxicity.

After 10 years of follow-up, there was no difference in DFS between the two arms (71.1% for the 2-year course vs. 70.3% for the 5-year course [HR, 0.997; 95% CI, 0.86–1.15; P = .982]). In addition, there was no difference in OS, time to second primary cancer, and time to contralateral breast cancer between the arms.

There was an insignificant trend towards more fractures in the 5-year arm.

Bone-modifying therapy

Both bisphosphonates and denosumab have been evaluated as adjuvant therapies for early-stage breast cancer; however, the role of these agents as adjuvant therapy for early-stage breast cancer is unclear. Compared with denosumab, the amount of evidence supporting bisphosphonates is greater, and there is evidence supporting breast cancer mortality—an endpoint that is more clinically relevant.

Evidence (bisphosphonates in the treatment of early breast cancer):

A meta-analysis has been conducted that included the individual patient data of 18,766 patients from 26 adjuvant trials of bisphosphonates of any type.

Overall, reductions associated with bisphosphonate use in recurrence (RR, 0.94; 95% CI, 0.87–1.01; 2P = .08), distant recurrence (RR, 0.92; 95% CI, 0.85–0.99; 2P = .03), and breast cancer mortality (RR, 0.91; 95% CI, 0.83–0.99; 2P = .04) were of only borderline significance, but the reduction in bone recurrence was more definite (RR, 0.83; 95% CI, 0.73–0.94; 2P = .004).

In a prespecified subgroup analysis, among premenopausal women, treatment had no apparent effect on any outcome, but among 11,767 postmenopausal women, it produced highly significant reductions in recurrence (RR, 0.86; 95% CI, 0.78–0.94; 2P = .002), distant recurrence (RR, 0.82; 95% CI, 0.74–0.92; 2P = .0003), bone recurrence (RR, 0.72; 95% CI, 0.60–0.86; 2P = .0002), and breast cancer mortality (RR, 0.82; 95% CI, 0.73–0.93; 2P = .002).

The ABCSG-18 (NCT00556374) trial randomly assigned 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI to receive denosumab or a placebo every 6 months during AI therapy.

The patients were unblinded when results related to bone events were reported, and patients on placebo were allowed to cross over to the active drug.

In an intent-to-treat analysis according to the original assignment, DFS, a secondary endpoint, was improved in patients randomly assigned to receive denosumab (HR, 0.82; 95% CI, 0.69–0.98; P = .0260; 5-year DFS, 89.2% vs. 87.3%).

[Level of evidence: 1iiDii]

The frequency of adverse events was similar in the two groups.

An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.

Preoperative Systemic Therapy

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for some patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple, randomized clinical trials performed in 2005 demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.

[Level of evidence: 1iiA]

In 2019, the Early Breast Cancer Trialists’ Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting.

Compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation (65% vs. 49%). There were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause; however, neoadjuvant therapy was associated with higher 15-year local recurrence (21.4% vs. 15.9%; rate ratio, 1.37; 95% CI, 1.17−1.61; P = .001).

[Level of evidence: 1iiA]

Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).

[Level of evidence: 1iiDiv]

A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains.

pCR has been utilized as a surrogate endpoint for long-term outcomes, such as DFS, EFS, and OS, in preoperative clinical trials in breast cancer. A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), provided a better association with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is).

pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.

[Level of evidence: 3iiiD] Because of a strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the FDA has supported use of pCR as an endpoint in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.

Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.

Patient selection, staging, treatment, and follow-up

Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

Patient selection.

Choice of systemic therapy.

Management of the axilla and surgical approach.

Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone-receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline-taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:

CT scan of the chest and abdomen and a bone scan.

Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.

The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:

If suspicious lymph nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.

[Level of evidence: 2Div];

[Level of evidence: 3iiD];

[Level of evidence: 3iiDiv] Alternatively, it is acceptable in this circumstance to perform ALND, based on the possibility of undetected positive nodes.

In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy.

If the SLN biopsy is negative, ALND can be omitted.

If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.

When considering preoperative therapy, treatment options include the following:

For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.

For HER2-positive disease, chemotherapy and HER2-targeted therapy.

Ideally, the entire treatment regimen is administered before surgery.

For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.

For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.

Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible.

Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

HER2/neu–negative breast cancer

Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Evidence (preoperative anthracycline-based regimen):

A randomized clinical trial (NSABP-B-18) was designed to determine whether the preoperative combination of four cycles of AC would more effectively prolong DFS and OS than the same chemotherapy given in the adjuvant setting.

[Level of evidence: 1iiA]

After preoperative therapy, 36% of the patients had a complete clinical response.

More patients treated with preoperative chemotherapy were able to have breast-conserving procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%; P = .001).

No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.

An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.

[Level of evidence: 1iiA]

To improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.

Evidence (anthracycline-taxane–based chemotherapy regimen):

In an effort to improve on the results observed with AC alone, the NSABP (NSABP B-27 [NCT00002707]) trial was conducted.

[Level of evidence: 1iiD]

The administration of preoperative AC followed by docetaxel was associated with a higher clinical complete response rate compared with the administration of AC alone (63.6% for AC followed by docetaxel and 40.1% for AC alone; P < .001); a higher pCR rate was also observed (26.1% for AC followed by docetaxel and 13.7% for AC alone; P < .001).

Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline-taxane–based regimens in women with initial response or with relative resistance to anthracyclines.

Alternative anthracycline-taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.

[Level of evidence: 1iiDiv]

The phase III GeparSepto (NCT01583426) trial investigated an alternative taxane (nab-paclitaxel) in patients with untreated primary breast cancer.

Patients (n = 1,229) were randomly assigned to receive 12 weeks of nab-paclitaxel or paclitaxel followed by epirubicin and cyclophosphamide (EC) for four cycles. The pCR rate was higher in the nab-paclitaxel arm (233 patients, 38%; 95% CI, 35%–42%) when compared with the paclitaxel arm (174 patients, 29%; 95% CI, 25%–33%).

[Level of evidence: 1iiDiv]

The incorporation of many additional cytotoxic agents to anthracycline-taxane–based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.

[Level of evidence: 1iiDiv]

Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Evidence (adding carboplatin to an anthracycline-taxane–based chemotherapy regimen in patients with TNBC):

In the GeparSixto (NCT01426880) trial, carboplatin was added to an anthracycline-taxane–based backbone.

[Level of evidence: 1iiDiv]

Higher pCR rates were observed with the addition of carboplatin to an anthracycline-taxane–based backbone compared with anthracycline-taxane alone (36.9% vs. 53.2%; P = .005) in patients with TNBC.

The more intensive regimen was also associated with increased toxicity and treatment discontinuations (39% vs. 48%).

The CALGB 40603 (NCT00861705) trial compared an anthracycline-taxane backbone alone with an anthracycline-taxane backbone-plus-carboplatin in patients with stage II and stage III TNBC.

[Level of evidence: 1iiDiv]

The pCR rate for the breast and axilla was 54% for the anthracycline-taxane backbone-plus-carboplatin group versus 41% for the anthracycline-taxane backbone-alone group (P = .0029)

Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).

[Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.

HER2/neu-positive breast cancer

After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline-taxane–based regimens.

[Level of evidence: 1iiDiv] This has been confirmed in phase III studies.

Trastuzumab

Evidence (trastuzumab):

The phase III NeOAdjuvant Herceptin (NOAH) study randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to undergo preoperative chemotherapy with or without 1 year of trastuzumab therapy.

[Level of evidence:1iiA]

Study results confirmed that the addition of trastuzumab to preoperative chemotherapy resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.

[Level of evidence:1iiA]

After a median follow-up of 5.4 years, the EFS benefit was 58% with the addition of trastuzumab to chemotherapy (95% CI, 48–66) and 43% (95% CI, 34–52) in patients in the chemotherapy group. The unadjusted HR for EFS between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44–0.93; two-sided log-rank P = .016). EFS was strongly associated with pCR in patients who received trastuzumab.

Symptomatic cardiac failure occurred in two patients who received concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (Refer to the Cardiac toxic effects with adjuvant trastuzumab section in this summary for more information.)

[Level of evidence: 1iiD]

A phase III trial (Z1041 [NCT00513292]) randomly assigned patients with operable HER2-positive breast cancer to receive trastuzumab sequential to or concurrent with the anthracycline component (5-FU, epirubicin, cyclophosphamide) of the preoperative chemotherapy regimen.

[Level of evidence: 1iiDiv]

There was no significant difference in pCR rate in the breast between the arms (56.5% sequential, 54.2% concurrent; difference, 2.3% with 95% CI, -9.3–13.9).

In addition, asymptomatic declines in LVEF during preoperative chemotherapy were identified in similar proportions of patients in each arm.

The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.

A subcutaneous formulation of trastuzumab has also been approved.

The SafeHer (NCT01566721) trial evaluated the safety and tolerability of self-administered versus clinician-administered SQ trastuzumab in stage I to stage III HER2-positive breast cancer.

Chemotherapy was administered concurrently or sequentially.

A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to undergo preoperative chemotherapy (anthracycline-taxane–based), with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.

[Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. EFS and OS were secondary endpoints. Six-year EFS was 65% in both arms (HR, 0.98; 95% CI, 0.74−1.29). Six-year OS was 84% in both arms (HR, 0.94; 95% CI, 0.61−1.45).

Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):

In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial,

417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:

[Level of evidence: 1iiDiv]

Docetaxel plus trastuzumab.

Docetaxel plus trastuzumab and pertuzumab.

Pertuzumab plus trastuzumab.

Docetaxel plus pertuzumab.

The following results were observed:

The pCR rates were 29% for docetaxel plus trastuzumab, 46% for docetaxel plus trastuzumab and pertuzumab, 17% for pertuzumab plus trastuzumab, and 24% for docetaxel plus pertuzumab. Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy.

The addition of pertuzumab to the docetaxel-plus-trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.

Despite the high pCR rate observed with dual HER2 blockade plus chemotherapy, PFS and DFS rates were not improved, although the NeoSPHERE trial was not powered to detect differences in long-term efficacy outcomes.

The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.

[Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens:

Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.

FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3).

Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6).

The following results were observed:

The pCR rate was equivalent across all three treatment arms: (62% for concurrent FEC plus trastuzumab plus pertuzumab followed by concurrent docetaxel plus trastuzumab plus pertuzumab; 57% for FEC alone followed by concurrent docetaxel plus trastuzumab plus pertuzumab; and 66% for concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab).

All three arms were associated with a low incidence of cardiac adverse events of 5% or less.

Because of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of a preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive.

The FDA approval of pertuzumab was subsequently converted to regular approval following the results of the confirmatory APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, which demonstrated improved invasive DFS with the combination of chemotherapy and dual HER2-targeted therapy with pertuzumab plus trastuzumab compared with chemotherapy and trastuzumab alone.

Pertuzumab is now approved both in combination with trastuzumab and chemotherapy for the neoadjuvant therapy of locally advanced, inflammatory, or early-stage HER2-positive breast cancer, which is larger than 2 cm or node-positive, as part of a complete treatment regimen and in combination with chemotherapy and trastuzumab as adjuvant treatment for HER2-positive early breast cancer at a high risk of recurrence.

Lapatinib

Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Evidence (against the use of lapatinib for HER2-positive early breast cancer):

The role of lapatinib in the preoperative setting was examined in the GeparQuinto [NCT00567554] trial.

This phase III trial randomly assigned women with HER2-positive early-stage breast cancer to receive chemotherapy with trastuzumab or chemotherapy with lapatinib, with pCR as the primary endpoint.

[Level of evidence: 1iiDiv]

pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04).

Other endpoints of DFS, RFS, and OS have not been reported.

CALGB 40601 (NCT00770809) was a phase III trial that randomly assigned patients with stage II and III HER2-positive breast cancer to receive either paclitaxel plus trastuzumab or paclitaxel plus trastuzumab plus lapatinib. The primary endpoint of the study was pCR in the breast.

[Level of evidence: 1iiDiv]

pCR in patients who received paclitaxel plus trastuzumab was 46% (95% CI, 37%–55%), and pCR in the patients who received paclitaxel plus trastuzumab plus lapatinib was 56% (95% CI, 47%–65%; P = .13), indicating no benefit with the addition of lapatinib.

The NeoALTTO [NCT00553358] phase III trial randomly assigned 455 women with HER2-positive early-stage breast cancer (tumor size >2 cm) to receive preoperative lapatinib, or preoperative trastuzumab, or preoperative lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks. The primary endpoint of this study was pCR.

pCR was significantly higher in the lapatinib-plus-trastuzumab combination arm (51.3%; 95% CI, 43.1–59.5) than in the trastuzumab-alone arm (29.5%; 95% CI, 22.4–37.5).

No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference, -4.8%, -17.6 to 8.2; P = .34).

An updated analysis for the prespecified secondary endpoints of EFS and OS indicate no difference between the groups.

More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to receive trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.

The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.

Cardiac toxic effects with pertuzumab and lapatinib

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.

[Level of evidence: 3iiiD]

Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a non–anthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5).

Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.

[Level of evidence: 3iiiD]

LVEF decline was observed in 3.1% of the patients who received monotherapy (95% CI, 2.2%–4.4%) and 2.9% of the patients who received dual therapy (95% CI, 2.1%–4.1%).

Symptomatic heart failure was observed in 0.88% of the patients who received monotherapy (95% CI, 0.47%–1.64%) and 1.49% of the patients who received dual therapy (95% CI, 0.98%–2.23%).

Preoperative endocrine therapy

Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor-positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.

[Level of Evidence: 1iDiv]

Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients.

A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P-value for trend < .04).

[Level of Evidence: 1iiDiv]

AIs have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months of preoperative therapy were either statistically significantly improved in the AI-treated women

or comparable to tamoxifen-associated outcomes.

An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy

Capecitabine

One clinical trial suggested that there is a benefit to using capecitabine as adjuvant therapy in patients who did not obtain a pCR after preoperative chemotherapy.

Evidence (capecitabine):

In a study conducted in Japan and Korea, 910 women with HER2/neu–negative breast cancers, who had residual disease after preoperative chemotherapy with anthracyclines, taxanes, or both, were randomly assigned in a nonblinded fashion to receive 6 to 8 four-weekly cycles of capecitabine or no further chemotherapy.

The study was terminated because of the results of a planned interim analysis, and a final analysis was done.

In the final analysis, which included 887 eligible patients, DFS, the primary endpoint, was statistically significantly prolonged (HR, 0.70; 95% CI, 0.53–0.92; P = .01; 5-year DFS, 74.1% vs. 67.6%).

OS, a secondary endpoint, was also longer in the capecitabine group (HR, 0.59; 95% CI, 0.39–0.90; P = .01; 5-year OS, 89.2% vs. 83.6%).

In the capecitabine group, 73.4% of the patients experienced hand-foot syndrome of varying degrees of severity.

Trastuzumab emtansine (T-DM1)

Evidence (T-DM1):

In a phase III trial (KATHERINE [NCT01772472]), 1,486 women with HER2-positive disease who received a preoperative taxane-containing chemotherapy (with or without an anthracycline) along with trastuzumab with or without a second HER2 targeted agent, but who had residual disease after surgery, were randomly assigned to receive 14 cycles of adjuvant trastuzumab or T-DM1.

[Level of evidence: 1iDii]

At the time of a planned interim analysis, invasive DFS (the primary study endpoint) was significantly higher in the T-DM1 group than in the trastuzumab group (HRinvasive disease or death, 0.50; 95% CI, 0.39–0.64; P < .001; invasive DFS at 3 years, 88.3% vs. 77%).

Data on OS are immature and not significant (HR, 0.70; 95% CI, 0.47–1.05).

Patients receiving T-DM1 were more likely to discontinue treatment because of an adverse event (18% vs. 2.1%) and had a higher frequency of sensory neuropathy (18.6% vs. 6.9%), most cases of which had resolved at the time of the analysis.

On subgroup analysis, the benefit of T-DM1 was observed in all subgroups, including participants who received dual HER2 targeted therapy in the preoperative setting.

These approaches and participation in clinical trials of novel therapies should be considered for patients with residual disease after preoperative therapy. EA1131 (NCT02445391) is a randomized phase III clinical trial that randomly assigned patients with residual basal-like TNBC after preoperative therapy to receive platinum-based chemotherapy or capecitabine. S1418/BR006 (NCT02954874) is a phase III trial evaluating the efficacy of pembrolizumab as adjuvant therapy for patients with residual TNBC (≥1 cm invasive cancer or residual nodes) after preoperative therapy.

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor-positive disease and adjuvant trastuzumab for those with HER2-positive disease. (Refer to the Hormone receptor–positive breast cancer subsection in the Early/Localized/Operable Breast Cancer section of this summary for more information.)

Posttherapy Surveillance

The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations.

Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.

On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

Physical examination.

Annual mammography.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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Carey LA, Berry DA, Cirrincione CT, et al.: Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 34 (6): 542-9, 2016.

de Azambuja E, Holmes AP, Piccart-Gebhart M, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15 (10): 1137-46, 2014.

Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012.

Valachis A, Nearchou A, Polyzos NP, et al.: Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer 133 (9): 2245-52, 2013.

Eiermann W, Paepke S, Appfelstaedt J, et al.: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12 (11): 1527-32, 2001.

Preece PE, Wood RA, Mackie CR, et al.: Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 284 (6319): 869-70, 1982.

Masuda N, Lee SJ, Ohtani S, et al.: Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 376 (22): 2147-2159, 2017.

von Minckwitz G, Huang CS, Mano MS, et al.: Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 380 (7): 617-628, 2019.

Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994.

Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994.

Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006.

Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

On the basis of the available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.

The standard treatment options for locally advanced or inflammatory breast cancer may include the following:

Breast-conserving surgery or total mastectomy with axillary lymph node dissection.

Chemotherapy.

Radiation therapy.

Hormone therapy.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.

The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting (refer to the Postoperative Systemic Therapy section of this summary for more information), although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy.

For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy.

Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.

Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.

Evidence (multimodality therapy):

In a retrospective series, 70 patients with locally advanced breast cancer and supraclavicular metastases received preoperative chemotherapy. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection or breast-conserving surgery and axillary lymph node dissection before or after radiation therapy. Patients who did not respond to preoperative chemotherapy were treated with surgery and/or radiation therapy. After completion of local therapy, chemotherapy was continued for 4 to 15 cycles, followed by radiation therapy.

Approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined-modality therapy.

These results have been confirmed in a separate series of patients treated in British Columbia.

A series of 178 patients with inflammatory breast cancer were treated with a combined-modality approach. Patients were treated with induction chemotherapy, then local therapy (radiation therapy or mastectomy), followed by chemotherapy, and, if mastectomy was performed, radiation therapy.

[Level of evidence: 3iiiDii]

Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.

All patients are considered candidates for clinical trials to evaluate the most appropriate way to administer the various components of new multimodality regimens.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

ReferenceSection

Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016.

Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994.

Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001.

Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003.

Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997.

Locoregional Recurrent Breast Cancer

Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.

The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy.

The rates are somewhat higher (up to 10%) for those treated with mastectomy.

Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.

Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.

ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence.

Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.

Treatment options for locoregional recurrent breast cancer include the following:

Chemotherapy.

Hormone therapy.

Radiation therapy.

Surgery.

Targeted therapy (e.g., trastuzumab).

Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.

Treatment options also depend on the site of recurrence, as follows:

Cutaneous: A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.

[Level of evidence: 1iiDiii]

Chest wall: Local chest wall recurrence after mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative.

Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater-than-2-year disease-free interval before recurrence have the best chance for prolonged survival.

The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%.

The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.

Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR [NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR, 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.

[Level of evidence: 1iiDii]

In ER-negative patients, the HR for DFS for chemotherapy versus no chemotherapy was 0.29 (95% CI, 0.13–0.67; 10 years DFS, 70% vs. 34%), whereas in ER-positive patients, the HR was 1.07 (95% CI, 0.57–2.00; 10 years DFS, 50% vs. 59%). The interaction between chemotherapy and ER status with respect to DFS was significant (P = .013).

This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer in patients with ER-negative tumors.

(Refer to the Metastatic (systemic) disease section of this summary for information about treatment for recurrent metastatic breast cancer.) All patients with recurrent breast cancer are considered candidates for ongoing clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

ReferenceSection

Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011.

Buchanan CL, Dorn PL, Fey J, et al.: Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 203 (4): 469-74, 2006.

Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986.

Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993.

Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991.

Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996.

Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987.

Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001.

Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991.

Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992.

Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990.

Aebi S, Gelber S, Anderson SJ, et al.: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15 (2): 156-63, 2014.

Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018.

Metastatic Breast Cancer

Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months overall,

survival varies according to subtype. The longest median outcomes have been observed in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor–positive metastatic breast cancer, and less favorable outcomes have been observed in patients with triple-negative metastatic breast cancer.

Treatment options for metastatic breast cancer include the following:

Hormone therapy (tamoxifen, aromatase inhibitors).

HER2 targeted therapy.

CDK 4/6 inhibitors.

mTOR inhibitors.

PIK3CA inhibitors.

Chemotherapy.

Immunotherapy.

Surgery, for patients with limited symptomatic metastases.

Radiation therapy, for patients with limited symptomatic metastases.

Bone-modifying therapy, for patients with bone metastases.

In many cases, these therapies are given in sequence and used in various combinations.

Cytologic or histologic documentation of metastatic disease, with testing of estrogen receptor (ER), progesterone receptor, and HER2 status, should be obtained whenever possible.

All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Hormone Receptor–Positive Breast Cancer

Endocrine therapy and cyclin-dependent kinase inhibitor therapy

CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in combination with endocrine therapy in both first-line and later-line treatment of advanced hormone receptor–positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.

Overall, the addition of CDK 4/6 inhibitors to endocrine therapy is associated with improved breast cancer outcomes and, in general, either maintained or improved quality of life.

First-line palbociclib and endocrine therapy

Evidence (first-line palbociclib and endocrine therapy):

PALOMA-2 (NCT01740427) confirmed the results of the phase II PALOMA-1 trial.

This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666).

The primary endpoint (investigator-assessed progression-free survival [PFS]) was met with a median PFS of 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46–0.72; P < .001).

[Level of evidence: 1iDiii]

Overall survival (OS) data are not yet mature.

Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3 to 4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3 to 4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).

First-line ribociclib and endocrine therapy

Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients and premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line ribociclib and endocrine therapy):

The phase III, placebo-controlled MONALEESA-2 trial (NCT01958021) randomly assigned 668 patients to receive first-line ribociclib plus letrozole or placebo plus letrozole.

The primary endpoint (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6–70.3) in the ribociclib group and 42.2% (95% CI, 34.8–49.5) in the placebo group.

[Level of evidence: 1iDiii]

OS data were immature at the time of publication.

Adverse events in patients included neutropenia in the ribociclib group (74.3%) and in the placebo group (5.2%), nausea (51.5% and 28.5%), infection (50.3% and 42.4%), fatigue (36.5% and 30.0%), and diarrhea (35.0% and 22.1%).

These events were mostly grade 1 to 2 with the exception of cytopenia.

Grade 3 to 4 neutropenia occurred in 59.3% of patients in the ribociclib group and 0.9% of patients in the placebo group.

The rate of febrile neutropenia was 1.5% in the ribociclib group and 0% in the placebo group.

An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 milliseconds from baseline was observed in nine patients (2.7%) in the ribociclib arm compared with zero patients in the placebo arm.

Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer. The MONALEESA-3 (NCT02422615) trial included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.

The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, .593; 95% CI, .480–.732; P <.001).

[Level of evidence: 1iDiii]

OS was superior in the ribociclib group (HR, 0.724; 95% CI, 0.568–0.924; P = .004). The result crossed the prespecified stopping boundary (P = .011) for superior efficacy. Results were similar in all subgroups.

[Level of evidence: 1iA]

Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Grade 3 to 4 neutropenia occurred in 53.4% of patients in the ribociclib group and 0.0% of patients in the placebo group.

The rate of febrile neutropenia was 1.0% in the ribociclib group and 0% in the placebo group.

An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 6.5% of patients in the ribociclib arm and 0.4% in the placebo arm.

Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin.

In the MONALEESA-7 (NCT02278120) trial, 672 premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo.

The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, .55; 95% CI, 0.44–0.69; P < .0001).

[Level of evidence: 1iC]

OS was a secondary endpoint. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (42-month OS, 70.2% vs. 46%; HRdeath, 0.71; 95% CI, 0.54−0.95, P = .01).

[Level of evidence: 1iA] The survival benefit was observed both in patients who received an AI plus goserelin and in those who received tamoxifen, but it was not statistically significant in the much-smaller tamoxifen group.

Adverse events were similar to those in other studies of CDK4/6 inhibitors.

Grade 3 to 4 neutropenia occurred in 61% of patients in the ribociclib group and 4% of patients in the placebo group.

The rate of febrile neutropenia was 2.0% in the ribociclib group and 1.0% in the placebo group.

An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 10.0 % of patients in the ribociclib arm and 2.0% in the placebo arm. Sixty-millisecond increases were more common in patients receiving tamoxifen (16% on ribociclib and 7% on placebo).

First-line abemaciclib and endocrine therapy

Abemaciclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line abemaciclib and endocrine therapy):

MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal AI in 493 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer.

The primary endpoint, investigator-assessed PFS, was met. After a median follow-up of 17.8 months, the PFS was not reached in the abemaciclib arm and was reached at 14.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41–0.72; P = .000021).

OS data are not yet mature.

The side effect profile of abemaciclib differs from the other CDK4/6 inhibitors. Diarrhea was the most frequent adverse event in the abemaciclib arm, although most of the diarrhea cases were grade 1.

Neutropenia was more common in the abemaciclib arm; however, only 21.1% of participants experienced grade 3 to 4 neutropenia.

Second-line palbociclib and endocrine therapy

Evidence (second-line palbociclib and endocrine therapy):

PALOMA-3 (NCT01942135) is a double-blind, phase III trial of 521 patients with hormone receptor–positive, HER2/neu–negative, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin.

[Level of Evidence: 1iC]

The final PFS analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P < .0001).

[Level of Evidence: 1iC]

Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.

A prespecified analysis of OS was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm (34.9 months vs. 28.0 months) was found, which did not reach statistical significance (HR, 0.81; 95% CI, 0.64–1.03, P = .09).

In a preplanned subgroup analysis, improved OS was observed in patients who had demonstrated sensitivity to hormone therapy (HR, 0.72; 95% CI, 0.55−0.94), whereas in patients without sensitivity, OS was not improved in the palbociclib group (HR, 1.14; 95% CI, 0.71−1.84; P = .12 for interaction).

Second-line ribociclib and endocrine therapy

The MONALEESA-3 trial included patients receiving second-line therapy. (Refer to the evidence on first-line ribociclib and endocrine therapy above for more information.)

Second-line abemaciclib and endocrine therapy

Evidence:

The MONARCH 2 (NCT02107703) study tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with hormone receptor–positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.

The primary endpoint (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P < .001).

[Level of evidence: 1iDiii]

OS data are mature and demonstrate an improvement in OS for patients receiving abemaciclib, and showed a median OS of 46.7 months for abemaciclib plus fulvestrant versus 37.3 months for placebo (HR, 0.757; 95% CI, 0.606–0.945; P = .01).

[Level of Evidence: 1iA]

Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).

These events were mostly grade 1 to 2. Grade 1 to 2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.

Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.

Grade 3 to 4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.

Single-agent cyclin-dependent kinase inhibitor therapy

Evidence (single-agent cyclin-dependent kinase inhibitor therapy):

Single-agent abemaciclib was approved by the FDA for use in hormone receptor–positive, HER2-negative breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 (NCT02102490) trial.

Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with hormone receptor–positive and HER2-negative advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated, and most participants had visceral disease. Patients who had previous CDK inhibitors were excluded.

The primary endpoint, investigator-assessed objective response rate, was 19.7% at 12 months (95% CI, 13.3–27.5%).

The clinical benefit rate was 42.4%.

Median PFS was 6.0 months (95% CI, 4.2–7.5 months).

The most common adverse event was diarrhea, which occurred in 90.2% of the participants. However, the majority was grade 1 to 2, and only 19.7% of participants experienced grade 3 diarrhea. There was no grade 4 diarrhea.

Neutropenia occurred in 97.7% of participants; however, the majority was grade 1 to 2, and only 26.9% of participants experienced grade 3 to 4 neutropenia.

Mammalian target of rapamycin (mTOR) inhibitor therapy plus endocrine therapy

Preclinical models and clinical studies suggest that mTOR inhibitors might overcome endocrine resistance.

Evidence (mTOR inhibitor therapy):

The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor–positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.

[Level of evidence: 1iDiii]

At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001).

The addition of everolimus to exemestane was more toxic than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

OS differences were not significant after further follow-up.

TAMRAD (NCT01298713) was an open-label randomized phase II trial comparing tamoxifen to tamoxifen plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. The trial randomly assigned 57 women to receive tamoxifen and 54 women to receive the combination therapy.

Median time to progression was 8.6 months in the combination group and 4.5 months in the tamoxifen group (HR, 0.54; 95% CI, 0.56−0.81; P = .002).

Toxicities were greater on the everolimus arm and similar to those in the BOLERO2 trial.

In an exploratory analysis, OS was 32.9 months in the tamoxifen group and not reached in the combination group (HR, 0.45; 95% CI, 0.24−0.81; P = .007).

[Level of evidence: 1iiA]

PrE0102 (NCT01797120) was a double-blind randomized phase II trial comparing fulvestrant to fulvestrant plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. Sixty-six women were randomly assigned to the combination arm and 65 to fulvestrant alone.

Median PFS was 10.3 months on the combination arm and 5.1 months on the fulvestrant-alone arm (HR, 0.61; 95% CI, 0.40−0.92; P = .02).

[Level of evidence: 1iDiii]

Toxicities were similar to those in previous studies.

The was no observed difference in OS between the arms.

The SWISH trial (NCT02069093) was a single-arm trial assessing the efficacy of a dexamethasone oral solution (0.5 mg per 5 mL) in the prevention of stomatitis in women receiving exemestane plus everolimus.

The incidence of grade 2 or worse stomatitis was 2% in the 85 evaluable patients in this study compared with 33% in the BOLERO-2 trial.

Alpelisib plus endocrine therapy

Activating mutations in PIK3CA are identified in approximately 40% of hormone receptor–positive and HER2-negative breast cancers. Alpelisib is an alpha-specific PI3K inhibitor.

Evidence (alpelisib plus endocrine therapy):

SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant to placebo plus fulvestrant in 572 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer who had received previous endocrine therapy.

[Level of evidence: 1iiDiii]

PIK3CA mutations were confirmed in 341 participants. The primary endpoint was PFS in the cohort of patients with PIK3CA mutations.

In this cohort, median PFS was 11 months in the alpelisib-plus-fulvestrant arm compared with 5.7 months in the placebo-plus-fulvestrant arm (HRprogression or HRdeath, 0.65; 95% CI, 0.50−0.85; P < .001).

PFS did not differ between arms in the cohort of participants without PIK3CA mutations (median PFS, 7.4 months in the alpelisib-plus-fulvestrant arm vs. 5.6 months in the placebo-plus-fulvestrant arm).

OS in the cohort with PIK3CA mutations was a secondary endpoint. OS data are not yet mature.

Very few study participants had received previous CDK4/6 inhibitor therapy.

Common toxicities associated with alpelisib included hyperglycemia, diarrhea, nausea, anorexia, and rash. Careful monitoring and management of hyperglycemia are required during alpelisib use.

Alpelisib is approved by the FDA for use in combination with fulvestrant in advanced PIK3CA-mutated, hormone receptor–positive, HER2-negative breast cancer after previous endocrine therapy.

Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 (NCT01007942) trial.

[Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant, breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.

At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067).

Serious adverse events were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group.

Final OS outcomes for this trial have not yet been reported.

Endocrine therapy alone

With the PFS and OS advantages associated with combination therapy with targeted agents and endocrine therapy as discussed above, single-agent endocrine therapy is less frequently used, especially in the first-line setting. However, its use remains appropriate in select cases as first-line therapy and in later-line therapy after progression on targeted therapies and before the use of chemotherapy in cases in which endocrine-sensitive disease is still thought to be present.

Commonly used single-agent endocrine therapies include tamoxifen, nonsteroidal AI (letrozole, anastrozole), the steroidal AI exemestane, and fulvestrant. In general, premenopausal women with metastatic breast cancer undergo ovarian suppression or ablation and are treated in the same manner as postmenopausal women.

Tamoxifen and AI therapy

While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and PFS for the AI compared with tamoxifen.

[Level of evidence: 1iiDiii]

Evidence (tamoxifen and AI therapy):

A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).

[Level of evidence: 1iA]

Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath, 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).

Fulvestrant

Fulvestrant is a selective estrogen receptor degrader that has been studied in the first-line and second-line setting in women with advanced or metastatic breast cancer.

First-line fulvestrant

Evidence (first-line fulvestrant):

FALCON (NCT01602380) was a phase III double-blind randomized trial that compared fulvestrant (500 mg) to anastrozole (1 mg) in patients with advanced or metastatic receptor-positive breast cancer who had not received previous endocrine therapy.

The trial randomly assigned 230 patients to receive fulvestrant and 232 patients to receive anastrozole.

Median PFS was 16.6 months in the fulvestrant group and 13.8 months in the anastrozole group (HR, 0.797; 95% CI, 0.637−0.999; P = .049).

[Level of evidence: 1iDiii]

The frequency of adverse events was similar in the two groups, and there was no difference in quality of life.

OS results were not reported.

Second-line fulvestrant

Evidence (second-line fulvestrant):

Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS.

The proper sequence of these therapies is not known.

EFECT (NCT00065325) was a phase III double-blind randomized trial that compared fulvestrant given in a loading-dose regimen (500 mg day 0, 250 mg days 14 and 28, and 250 mg every 28 days thereafter) to exemestane (25 mg) in women who had developed progressive disease after previous nonsteroidal AI (anastrozole or letrozole) therapy.

The trial randomly assigned 351 women to receive fulvestrant and 342 women to receive exemestane.

Median time to progression was 3.7 months in both groups (HR, 0.93; 95% CI, 0.819−1.133; P = .65).

[Level of evidence: 1iDiii]

The frequency of adverse events was similar in both groups, and there was no difference in quality of life.

OS results were not reported.

CONFIRM (NCT00099437) was a double-blind phase III trial that compared two doses of fulvestrant (500 mg vs. 250 mg, each given in a loading-dose schedule) in 736 women whose disease had progressed on previous endocrine therapy.

PFS was significantly better on the higher-dose arm (HR, 0.80; 95% CI, 0.68–0.94; P = .006).

[Level of evidence: 1iDiii]

Adverse events and quality of life were similar on the two arms.

Combination endocrine therapy with an AI and fulvestrant

Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant (refer to the section on Fulvestrant for more information about this drug) and anastrozole with anastrozole alone in the first-line treatment of hormone receptor–positive postmenopausal patients with recurrent or metastatic disease.

In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.

Evidence (combination endocrine therapy with an AI and fulvestrant):

The SWOG trial (SWOG-0226 [NCT00075764]), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and OS (HR, 0.81; 95% CI, 0.65–1.00; P = .05).

[Level of evidence: 1iA]

In an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (HR, 0.82; 95% CI, 0.69–0.98; P = .03).

[Level of evidence: 1iA]

In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).

[Level of evidence: 1iA]

Sequencing Therapy for Hormone Receptor–Positive Metastatic Breast Cancer

The optimal sequence of therapies for hormone receptor–positive metastatic breast cancer is not known. In general, in the absence of a visceral crisis, most patients receive sequential endocrine-based regimens before transitioning to chemotherapy. On the basis of the PFS and OS improvements mentioned above, a combination of a CDK4/6 inhibitor therapy and endocrine therapy in the first line is an appropriate choice.

Hormone Receptor–Negative Breast Cancer

The treatment for hormone receptor–negative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)

HER2/neu–Positive Breast Cancer

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab

Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu.

Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.

In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.

[Level of evidence: 3iiiDiv]

Evidence (trastuzumab):

In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.

[Level of evidence: 1iiA]

Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P = .05).

[Level of evidence: 1iiA]

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.

Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.

In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone.

[Level of evidence: 1iDiii]

However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.

[Level of evidence: 1iiA]

Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.

Evidence (pertuzumab):

The phase III CLEOPATRA (NCT00567190) trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting.

[Level of evidence: 1iA]

With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).

Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P < .001).

The toxicity profile was similar in both treatment groups, with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.

Evidence (T-DM1):

The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.

[Level of evidence: 1iiA] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.

Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001).

Median OS was longer with trastuzumab emtansine versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88]).

The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar syndrome were higher in patients who received lapatinib plus capecitabine.

Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.

[Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.

At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97).

Preliminary OS results were similar between treatment arms.

T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).

Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA (NCT01419197) study of T-DM1 versus physician’s choice of treatment.

[Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.

At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s-choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s-choice group (HR, 0.528; 95% CI, 0.422–0.661; P < .0001).

OS was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).

The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE (NCT01120184) trial.

[Level of evidence: 1iDiii] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.

The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.

There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).

Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

Tyrosine kinase inhibitor therapy

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.

Evidence (lapatinib):

A nonblinded randomized trial (GSK-EGF100151 [NCT00078572]) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.

[Level of evidence: 1iiA]

Median time-to-disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR, 0.49; 95% CI, 0.34–0.71; P < .001).

There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).

[Level of evidence: 1iiA]

Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. (Refer to the PDQ summary on Gastrointestinal Complications for more information about diarrhea.)

No data are available on quality of life or treatment after disease progression.

Germline BRCA Mutation

For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

Olaparib

Evidence (olaparib):

The OlympiAD (NCT02000622) trial was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine).

All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor–positive disease had also received endocrine therapy previously.

Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2. months; HR for disease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001).

[Level of evidence: 1iiA]

OS did not differ between the two treatment groups with median time to death (HRdeath, 0.90; 95% CI, 0.63–1.29; P = .57).

Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy.

Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the triple-negative breast cancer subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the hormone receptor–positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

Talazoparib

Evidence (talazoparib):

The EMBRACA (NCT01945775) trial was a randomized, open label, phase III trial that assigned 431 patients with a deleterious germline BRCA or BRCA2 mutation and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).

All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor–positive and hormone receptor–negative patients were enrolled.

Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; HR for disease progression or death, 0.54; 95% CI, 0.41–0.71; P < .001).

Benefits were observed in all subgroups, although CIs were wide in the subgroup of patients who had received previous platinum therapy.

Median OS did not differ between the two groups (22.3 months vs. 19.5 months; HRdeath, 0.76; 95% CI, 0.55–1.06; P = .11), although survival data are not yet mature.

The primary toxicity observed with talazoparib was myelosuppression, especially anemia.

Patient-reported outcome data demonstrated more favorable effects of talazoparib than standard chemotherapy on quality-of-life measures.

(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Chemotherapy

Patients receiving hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor–negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.

Single agents that have shown activity in metastatic breast cancer include the following:

Anthracyclines.

Doxorubicin.

Epirubicin.

Liposomal doxorubicin.

Mitoxantrone.

Taxanes.

Paclitaxel.

Docetaxel.

Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).

Alkylating agents.

Cyclophosphamide.

Fluoropyrimidines.

Capecitabine.

Fluorouracil (5-FU).

Antimetabolites.

Methotrexate.

Vinca alkaloids.

Vinorelbine.

Vinblastine.

Vincristine.

Platinum.

Carboplatin.

Cisplatin.

Other.

Gemcitabine.

Mitomycin C.

Eribulin mesylate.

Ixabepilone.

Combination regimens that have shown activity in metastatic breast cancer include the following:

AC: Doxorubicin and cyclophosphamide.

EC: Epirubicin and cyclophosphamide.

Docetaxel and doxorubicin.

CAF: Cyclophosphamide, doxorubicin, and 5-FU.

CMF: Cyclophosphamide, methotrexate, and 5-FU.

Doxorubicin and paclitaxel.

Docetaxel and capecitabine.

Vinorelbine and epirubicin.

Capecitabine and ixabepilone.

Carboplatin and gemcitabine.

Gemcitabine and paclitaxel.

There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An Eastern Cooperative Oncology intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially.

Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.

[Level of evidence: 1iiA];

The selection of therapy in individual patients is influenced by the following:

Rate of disease progression.

Presence or absence of comorbid medical conditions.

Physician/patient preference.

Currently, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents.

A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.

[Level of evidence: 1iiA]

Decisions regarding the duration of chemotherapy may consider the following:

Patient preference and goals of treatment.

Presence of toxicities from previous therapies.

Availability of alternative treatment options.

The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.

[Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies,

survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation

or a different chemotherapy regimen given at higher versus lower doses.

[Level of evidence: 1iiA] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.

[Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Chemotherapy plus immunotherapy

The addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1)–positive antibody, to first-line chemotherapy for patients with hormone receptor–negative and HER2-negative advanced breast cancer was evaluated in the phase III randomized placebo-controlled IMpassion130 trial (NCT02425891).

Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 score of 1% or greater was defined as positive. Co-primary endpoints included PFS and OS, both of which were evaluated in the intention-to-treat population and in the PD-L1–positive population (n = 369).

PFS data are final with a median follow-up of 12.9 months and included the following:

In the intention-to-treat population, PFS was improved with the addition of atezolizumab (median PFS, 7.2 months vs. 5.5 months; HR, 0.80; 95% CI, 0.69–0.92; P = .0025).

In the PD-L1–positive population, PFS was improved with the addition of atezolizumab (median PFS, 7.5 months vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; P < .001).

OS data are not yet mature. Results of the first interim analysis for OS, performed at the time of the final PFS analysis, included the following:

In the intention-to-treat population, there was a nonsignificant trend toward improved OS with the addition of atezolizumab (median OS, 21.3 months vs. 17.6 months; HR, 0.84; 95% CI, 0.69–1.02; P = .08).

The study design used hierarchical testing for OS requiring that the OS be statistically significantly improved with atezolizumab in the intention-to-treat population before OS could be compared between the arms in the PD-L1–positive population. Because this requirement was not met at the time of the first interim analysis, a P-value could not be determined at that time for the comparison of OS between the two arms in the PD-L1–positive population. Median OS was, however, 9.5 months longer in the atezolizumab arm in the PD-L1–positive population (25 months vs. 15.5 months; HR, 0.62; 95% CI, 0.45–0.86).

[Level of evidence: 1iDiii]

Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.

Atezolizumab was granted accelerated approval by the FDA for use in combination with protein-bound paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

Sacituzumab govitecan

Sacituzumab govitecan is an antibody drug conjugate that combines an anti–trophoblast cell-surface antigen 2 antibody with an active metabolite of irinotecan.

In a phase I/II trial, 108 women with triple-negative breast cancer who had received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.

A response rate of 33.3% (95% CI, 24.6%–43.1%) was observed.

The median duration of response was 7.7 months (95% CI, 4.9–10.8).

[Level of evidence: 3iiiDiv]

The main toxicity was neutropenia, and four deaths occurred during treatment.

The FDA granted a breakthrough therapy designation for sacituzumab govitecan, and a confirmatory randomized trial is under way.

Cardiac toxic effects with anthracyclines

The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:

Advanced age.

Previous chest-wall radiation therapy.

Previous anthracycline exposure.

Hypertension and known underlying heart disease.

Diabetes.

The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin.

The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.

The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit.

Dexrazoxane has a similar protective effect in patients receiving epirubicin.

Surgery

Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:

Fungating/painful breast lesions (mastectomy).

Parenchymal brain or vertebral metastases with spinal cord compression.

Isolated lung metastases.

Pathologic (or impending) fractures.

Pleural or pericardial effusions.

(Refer to the PDQ summary on Cancer Pain for more information; refer to the PDQ summary on Cardiopulmonary Syndromes for information about pleural and pericardial effusions.)

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases.

Indications for external-beam radiation therapy include the following:

Painful bony metastases.

Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).

Bronchial obstruction.

Fungating/painful breast or chest wall lesions.

After surgery for decompression of intracranial or spinal cord metastases.

After fixation of pathologic fractures.

Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.

Bone-Modifying Therapy

The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.

Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.

[Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.

The optimal dosing schedule for zoledronate was studied in CALGB-70604 [Alliance; NCT00869206], which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks.

Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).

[Level of evidence: 1iiD] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.

The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.

(Refer to the PDQ summary on Cancer Pain for more information on bisphosphonates.)

Bevacizumab

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor–A. Its role in the treatment of metastatic breast cancer remains controversial.

Evidence (bevacizumab for metastatic breast cancer):

The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.

The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.

[Level of evidence: 1iiA]

The study failed to demonstrate a statistically significant effect on PFS (4.9 months with combination therapy vs. 4.2 months with capecitabine alone; HR, 0.98) or OS (15.1 months vs. 14.5 months).

[Level of Evidence: 1iiA]

ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.

[Level of evidence: 1iiA]

The trial demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P < .001).

[Level of Evidence: 1iiA]

The addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months; P = .16).

Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.

The AVADO (NCT00333775) trial randomly assigned 736 patients to receive docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer.

[Level of evidence: 1iiA]

The combination of docetaxel plus bevacizumab at 15 mg/kg, but not 7.5 mg/kg, modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).

[Level of Evidence: 1iiA]

More toxicity was seen in patients in the bevacizumab-containing arms, with significantly higher rates of bleeding and hypertension compared with patients in the placebo arms.

The RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.

[Level of evidence: 1iiA]

Median PFS was longer for each bevacizumab-containing combination (capecitabine cohort: increased from 5.7 months to 8.6 months; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and taxane-anthracycline cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).

[Level of Evidence: 1iiA]

No statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed.

Toxicities associated with bevacizumab were similar to those seen in previous bevacizumab clinical trials.

The RIBBON 2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.

[Level of evidence: 1iA]

Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64–0.93; P = .0072).

However, no statistically significant difference in OS was seen (16.4 months for chemotherapy plus placebo vs. 18.0 months for chemotherapy plus bevacizumab, P = .3741).

[Level of evidence: 1iA]

Toxicities associated with bevacizumab were similar to those seen in previous clinical trials.

In November 2011, because of the consistent finding that bevacizumab improved PFS only modestly but did not improve OS, and given bevacizumab’s considerable toxicity profile, the FDA revoked approval of bevacizumab for the treatment of metastatic breast cancer.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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