除了性别为女性，年龄增长是乳腺癌的最大风险因素。增加内源性雌激素暴露的生殖因素如初潮提前和绝经延迟会增加乳腺癌风险，绝经后雌孕激素联合使用也会增加乳腺癌风险。未生育和饮酒也与乳腺癌风险增加有关。
有浸润性乳腺癌、原位导管癌或原位小叶癌家族史或个人史，或乳腺活检显示良性增生性疾病的女性患乳腺癌的风险增加。
乳腺密度增加与乳腺癌风险增加有关。其通常具有遗传特性，但也常见于未生育、首次怀孕年龄晚的女性，以及绝经后使用激素和饮酒的女性。
电离辐射暴露，尤其是在青春期或青年期，以及有害基因突变的遗传可增加乳腺癌风险。
Besides female sex, advancing age is the biggest risk factor for breast cancer. Reproductive factors that increase exposure to endogenous estrogen, such as early menarche and late menopause, increase risk, as does the use of combination estrogen-progesterone hormones after menopause. Nulliparity and alcohol consumption also are associated with increased risk.
Women with a family history or personal history of invasive breast cancer, ductal carcinoma in situ or lobular carcinoma in situ, or a history of breast biopsies that show benign proliferative disease have an increased risk of breast cancer.
Increased breast density is associated with increased risk. It is often a heritable trait but is also seen more frequently in nulliparous women, women whose first pregnancy occurs late in life, and women who use postmenopausal hormones and alcohol.
Exposure to ionizing radiation, especially during puberty or young adulthood, and the inheritance of detrimental genetic mutations increase breast cancer risk.
注：独立的PDQ总结，包括乳腺癌筛查、乳腺癌治疗（成人）、男性乳腺癌治疗、妊娠期乳腺癌治疗，以及癌症筛查和预防研究，可以从相应章节获取。
基于确凿证据，性别为女性和年龄增长是乳腺癌发生的主要风险因素。
影响程度：女性一生患乳腺癌的风险大约是男性的100倍。70岁女性患乳腺癌的短期风险大约是30岁女性的10倍。
基于确凿证据，有乳腺癌家族史的女性，特别是一级亲属，患乳腺癌的风险增加。
影响程度：如果一个一级亲属确诊，风险会增加一倍；如果两个一级亲属确诊，风险会增加五倍。
基于确凿证据，遗传基因突变的女性患乳腺癌风险增加。
影响程度：不定，取决于基因突变、家族史和其他影响基因表达的风险因素。
有确凿证据表明致密乳腺可增加女性患乳腺癌风险。乳腺密度具有一定的遗传性，但生育行为、药物和饮酒在某种程度上也可以影响乳腺密度。
影响程度：乳腺致密的女性罹患乳腺癌风险增加，且风险与密度成正相关。相比乳腺密度最低的女性，相对危险度（RR）从乳腺密度稍高女性的1.79倍上升到乳腺密度非常高女性的4.64倍。
基于确凿证据，联合激素治疗（HT）（雌孕激素）与乳腺癌发病风险升高相关。
影响程度：浸润性乳腺癌的发病率大约增加了26%；每超额发生一例乳腺癌所需联合激素治疗的人数为 237。
基于确凿证据，暴露于电离辐射与乳腺癌发病风险升高相关，从暴露后10年开始增加并持续终生。乳腺癌发病风险取决于辐射剂量和暴露时的年龄，如果暴露发生在青春期乳房发育时，风险尤其高。
影响程度：不定，但总体上大约增加了六倍。
基于确凿证据，肥胖与未使用激素治疗的绝经后女性患乳腺癌的风险增加有关。目前尚不清楚减肥是否能降低肥胖女性患乳腺癌的风险。
影响程度：女性健康行动对85917例绝经后女性的观察性研究发现，体重与乳腺癌有关。将体重超过82.2公斤和低于58.7公斤的女性进行对比，RR为2.85（95%置信区间[CI]，1.81–4.49）。
基于确凿证据，饮酒与乳腺癌风险增加呈剂量依赖关系。目前尚不确定的是，大量饮酒者减少酒精摄入是否会降低风险。
影响程度：与非饮酒者相比，每天饮用约4杯酒精饮料的女性的RR为1.32（95%置信区间为1.19-1.45）。每天每喝一杯，RR增加7%（95%CI，5.5%-8.7%）。
基于确凿证据，20岁以前足月妊娠的女性患乳腺癌风险降低。
影响程度：与未生育女性或35岁后生育的女性相比，乳腺癌风险降低50%。
基于确凿证据，母乳喂养的女性患乳腺癌的风险降低。
影响程度：每哺乳12个月，乳腺癌的相对风险降低4.3%，此外，每次生育可降低7%的乳腺癌风险。
基于确凿证据，每周高强度运动4小时以上与乳腺癌风险降低有关。
影响程度：平均RR降低30%至40%。对于体重正常或较轻的绝经前女性，效果可能最显著。
基于合理证据，既往做过子宫切除术，同时联合雌激素治疗的女性，乳腺癌发病率较低。然而，不同流行病学研究，结果不同。
影响程度：RCT发现接受雌激素治疗的女性6.8年后乳腺癌发病率比安慰剂组低23%（每年0.27%，服用年限中位数为5.9年，而服用安慰剂的女性为每年0.35%），但在一项观察性研究中，接受雌激素治疗的女性发病率高出30%。两项研究中，两组人群不同的筛查行为可以解释两组之间的差异。
基于确凿证据，子宫切除术后和绝经后服用雌激素的女性患卒中和心血管疾病的风险增加。
影响程度：卒中发病率增加39%（RR，1.39；95%CI，1.1-1.77），心血管疾病发病率增加12%（RR，1.12；95%CI，1.01-1.24）。
基于确凿证据，他莫昔芬和雷洛昔芬可降低绝经后女性乳腺癌的发病率，他莫昔芬可降低绝经前高危女性乳腺癌的风险。对他莫昔芬和雷洛昔芬的疗效观察显示，在停用有效治疗数年后，他莫昔芬的疗效持续时间比雷洛昔芬长。
SERM治疗可减少骨折的发生，主要是雷洛昔芬治疗，而非他莫昔芬治疗。骨折减少主要为椎体骨折减少（减少34%）和非椎体骨折的小幅度减少（7%）。
影响程度：他莫昔芬在5年的治疗中使乳腺癌高危女性的发病率降低30%-50%，但仅限于雌激素受体阳性（ER阳性）乳腺癌和乳腺导管原位癌（DCIS）。从开始治疗到停用他莫昔芬治疗11年后，ER阳性浸润性乳腺癌的减少率至少维持在此水平约16年。与第0-10年相比，在开始使用他莫昔芬（5年）后的第10-16年之间，效果依然维持。对乳腺癌死亡率没有影响。
基于确凿证据，他莫昔芬的治疗会增加子宫内膜癌的风险，这在随访的前5年中很明显。 血栓性血管疾病（即肺栓塞，卒中和深静脉血栓形成）和白内障的患病风险也会增加。 停用他莫昔芬治疗后，许多风险都降低了。 基于确凿证据，雷洛昔芬也可增加静脉肺栓塞和深静脉血栓形成，但不会增加子宫内膜癌风险。
影响程度：荟萃分析显示子宫内膜癌的相对危险度（RR）为2.4（95%CI，1.5-4.0），静脉血栓栓塞的RR为1.9（95%CI，1.4-2.6）。他莫昔芬和雷洛昔芬对子宫内膜癌的风险比（HR）分别为2.18（95%CI，1.39-3.42）和1.09（95%CI，0.74-1.62）。总的来说，静脉血栓栓塞的HR为1.73（95%CI，1.47–2.05）。50岁以上女性的危害明显高于年轻女性。
基于确凿证据，芳香化酶抑制剂或失活剂（AI）可以降低绝经后女性患乳腺癌的风险。
影响程度：随访35个月（中位随访期）后，35岁及以上的女性至少有一种危险因素（年龄> 60岁，Gail模型5年危险> 1.66％，或行乳腺切除术的DCIS）并且每天服用25 mg的依西美坦可降低浸润性乳腺癌的发生率（HR，0.35； 95％CI，0.18–0.70）。在超过35个月随访的2280名受试者中，有21例癌症患者绝对风险降低。需治疗人数约为100人。
根据随访超过35个月的4,560名女性的单项RCT研究的一般证据表明，与安慰剂相比，依西美坦使用与潮热和疲劳有关，但与骨折，骨质疏松或心血管疾病无关。
影响程度：潮热绝对风险增加8%，疲劳绝对风险增加2%。
基于确凿证据，双侧预防性乳房切除术可以降低有强家族史的女性罹患乳腺癌的风险，并且大多数女性都可以缓解对乳腺癌风险的焦虑。 没有研究探讨同侧乳腺癌手术后进行对侧预防性乳房切除术的女性的乳腺癌结局。
影响程度：高危女性双侧预防性乳房切除术后患乳腺癌的风险降低了90％，但已发表的研究设计可能会造成结局的高估。
基于确凿证据，患有BRCA基因突变的绝经前妇女接受预防性卵巢切除术的乳腺癌发病率较低。 同样，卵巢切除术或卵巢去势与正常绝经前女性和因胸部照射导致乳腺癌风险增加的女性乳腺癌发生率降低相关。
影响程度：乳腺癌的发病率可降低50%，但是已发布的研究设计可能会造成高估。
基于确凿证据，卵巢去势可能导致更年期症状的突然出现，如潮热、失眠、焦虑和抑郁。长期影响包括性欲下降、阴道干燥、骨密度降低。
影响程度：几乎所有的女性都会经历一些睡眠障碍、情绪变化、潮热和骨质疏松，但这些症状的严重程度差别很大。
Note: Separate PDQ summaries on Breast Cancer Screening; Breast Cancer Treatment (Adult); Male Breast Cancer Treatment; Breast Cancer Treatment During Pregnancy; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Based on solid evidence, female sex and increasing age are the major risk factors for the development of breast cancer.
Magnitude of Effect: Women have a lifetime risk of developing breast cancer that is approximately 100 times the risk for men. The short-term risk of breast cancer in a 70-year-old woman is about ten times that of a 30-year-old woman.
Based on solid evidence, women who have a family history of breast cancer, especially in a first-degree relative, have an increased risk of breast cancer.
Magnitude of Effect: Risk is doubled if a single first-degree relative is affected; risk is increased fivefold if two first-degree relatives are diagnosed.
Based on solid evidence, women who inherit gene mutations associated with breast cancer have an increased risk.
Magnitude of Effect: Variable, depending on gene mutation, family history, and other risk factors affecting gene expression.
Based on solid evidence, women with dense breasts have an increased risk of breast cancer. This is most often an inherent characteristic, to some extent modifiable by reproductive behavior, medications, and alcohol.
Magnitude of Effect: Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.
Based on solid evidence, combination hormone therapy (HT) (estrogen-progestin) is associated with an increased risk of developing breast cancer.
Magnitude of Effect: Approximately a 26% increase in incidence of invasive breast cancer; the number needed to produce one excess breast cancer is 237.
Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on radiation dose and age at exposure, and is especially high if exposure occurs during puberty, when the breast develops.
Magnitude of Effect: Variable but approximately a sixfold increase overall.
Based on solid evidence, obesity is associated with an increased breast cancer risk in postmenopausal women who have not used HT. It is uncertain whether weight reduction decreases the risk of breast cancer in obese women.
Magnitude of Effect: The Women's Health Initiative observational study of 85,917 postmenopausal women found body weight to be associated with breast cancer. Comparing women weighing more than 82.2 kg with those weighing less than 58.7 kg, the RR was 2.85 (95% confidence interval [CI], 1.81–4.49).
Based on solid evidence, alcohol consumption is associated with increased breast cancer risk in a dose-dependent fashion. It is uncertain whether decreasing alcohol intake by heavy drinkers reduces the risk.
Magnitude of Effect: The RR for women consuming approximately four alcoholic drinks per day compared with nondrinkers is 1.32 (95% CI, 1.19–1.45). The RR increases by 7% (95% CI, 5.5%–8.7%) for each drink per day.
Based on solid evidence, women who have a full-term pregnancy before age 20 years have decreased breast cancer risk.
Magnitude of Effect: 50% decrease in breast cancer, compared with nulliparous women or women who give birth after age 35 years.
Based on solid evidence, women who breast-feed have a decreased risk of breast cancer.
Magnitude of Effect: The RR of breast cancer is decreased 4.3% for every 12 months of breast-feeding, in addition to 7% for each birth.
Based on solid evidence, exercising strenuously for more than 4 hours per week is associated with reduced breast cancer risk.
Magnitude of Effect: Average RR reduction is 30% to 40%. The effect may be greatest for premenopausal women of normal or low body weight.
Based on fair evidence, women who have undergone a prior hysterectomy and who are treated with conjugated equine estrogen have a lower incidence of breast cancer. However, epidemiological studies yield conflicting results.
Magnitude of Effect: After 6.8 years, incidence was 23% lower in women treated with estrogen in an RCT (0.27% per year, with a median of 5.9 years of use, compared with 0.35% per year among those taking a placebo), but was 30% higher in women treated with estrogen in an observational study. The difference in these results may be explained by different screening behavior by the women in both studies.
Based on solid evidence, women who have undergone hysterectomy and who are taking postmenopausal estrogen have an increased risk of stroke and total cardiovascular disease.
Magnitude of Effect: There is a 39% increase in the incidence of stroke (RR, 1.39; 95% CI, 1.1–1.77) and a 12% increase in cardiovascular disease (RR, 1.12; 95% CI, 1.01–1.24).
Based on solid evidence, tamoxifen and raloxifene reduce the incidence of breast cancer in postmenopausal women, and tamoxifen reduces the risk of breast cancer in high-risk premenopausal women. The effects observed for tamoxifen and raloxifene show persistence several years after active treatment is discontinued, with longer duration of effect noted for tamoxifen than for raloxifene.
All fractures were reduced by SERMs, primarily noted with raloxifene but not with tamoxifen. Reductions in vertebral fractures (34% reduction) and small reductions in nonvertebral fractures (7%) were noted.
Magnitude of Effect: Tamoxifen reduced breast cancer incidence in high-risk women from about 30% to about 50% over 5 years of treatment but only for estrogen receptor–positive (ER-positive) cancer and ductal carcinoma in situ (DCIS). The reduction in ER-positive invasive breast cancer was maintained at about this level for at least 16 years after starting treatment, 11 years after cessation of tamoxifen. There was no loss of effect between years 10 and 16 after starting tamoxifen (for 5 years) compared with years 0 to 10. There was no effect on breast cancer mortality.
Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, which was apparent in the first 5 years of follow-up but not beyond; thrombotic vascular events (i.e., pulmonary embolism, stroke, and deep venous thrombosis); and cataracts. Many of these risks are reduced after active treatment with tamoxifen is discontinued. Based on solid evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.
Magnitude of Effect: Meta-analysis showed RR of 2.4 (95% CI, 1.5–4.0) for endometrial cancer and 1.9 (95% CI, 1.4–2.6) for venous thromboembolic events. Meta-analysis showed the hazard ratio (HR) for endometrial cancer was 2.18 (95% CI, 1.39–3.42) for tamoxifen and 1.09 (95% CI, 0.74–1.62) for raloxifene. Overall, HR for venous thromboembolic events was 1.73 (95% CI, 1.47–2.05). Harms were significantly higher in women over 50 years than in younger women.
Based on solid evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have an increased risk.
Magnitude of Effect: After a median follow-up of 35 months, women aged 35 years and older who had at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or DCIS with mastectomy) and who took 25 mg of exemestane daily had a decreased risk of invasive breast cancer (HR, 0.35; 95% CI, 0.18–0.70). The absolute risk reduction was 21 cancers avoided out of 2,280 participants over 35 months. The number needed to treat was about 100.
Based on fair evidence from a single RCT of 4,560 women over 35 months, exemestane is associated with hot flashes and fatigue but not with fractures, osteoporosis, or cardiovascular events, compared with placebo.
Magnitude of Effect: The absolute increase in hot flashes was 8% and the absolute increase in fatigue was 2%.
Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history, and most women experience relief from anxiety about breast cancer risk. There are no studies examining breast cancer outcomes in women who undergo contralateral prophylactic mastectomy after surgery for ipsilateral breast cancer.
Magnitude of Effect: Breast cancer risk after bilateral prophylactic mastectomy in women at high risk is reduced as much as 90%, but published study designs may have produced an overestimate.
Based on solid evidence, premenopausal women with BRCA gene mutations who undergo prophylactic oophorectomy have lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation is associated with decreased breast cancer incidence in normal premenopausal women and in women with increased breast cancer risk resulting from thoracic irradiation.
Magnitude of Effect: Breast cancer incidence is decreased by 50%, but published study designs may have produced an overestimate.
Based on solid evidence, castration may cause the abrupt onset of menopausal symptoms such as hot flashes, insomnia, anxiety, and depression. Long-term effects include decreased libido, vaginal dryness, and decreased bone mineral density.
Magnitude of Effect: Nearly all women experience some sleep disturbances, mood changes, hot flashes, and bone demineralization, but the severity of these symptoms varies greatly.
2019年美国女性最常诊断的非皮肤恶性肿瘤为乳腺癌，预计有268600例。据我国最新发布的癌症统计数据，我国女性最常诊断的恶性肿瘤为乳腺癌，每年发病约为30.4万例。
同样在2019年，乳腺癌将导致41,760名妇女死亡，仅次于肺癌，这是导致女性癌症死亡的原因。 乳腺癌也发生在男性中，估计2019年将诊断出2670例新病例。2015年，乳腺癌导致约7万名中国女性死亡。死亡位居我国恶性肿瘤死亡的第5位。
尽管先前女性乳腺癌发病率呈逐渐上升的趋势，但SEER数据库显示，从2007年到2016年，乳腺癌死亡率每年下降1.8％。中国女性乳腺癌发病率和死亡率均呈上升趋势。2003~2007年女性乳腺癌发病率为23.27/10万，死亡率为4.93/10万；2015年发病率为31.54/10万，死亡率6.67/10万。
乳腺癌的主要危险因素是年龄的增长。30岁的女性在未来10年中被诊断为乳腺癌的几率是1/250，而70岁的女性为1/27。
乳腺癌的发病率和死亡率也因地理、文化、人种、种族和社会经济状况的不同而不同。与其他人种相比，白人女性乳腺癌的发病率较高，这可能部分归因于筛查。然而，从2005年到2014年，黑人女性的乳腺癌发病率略有增加，为每年0.3%，导致黑人与白人的发病率趋同。
乳腺X线筛查可以早期诊断从而早期治疗乳腺癌，进而降低乳腺癌的死亡率。 但是，筛查还发现了一生中不会出现症状的病例，因此筛查会增加乳腺癌的发病率。 （有关更多信息，请参阅PDQ总结中关于乳腺癌筛查的“过度诊断”部分。）
乳腺癌的发展伴随着一系列基因突变的发生。
最初，突变不会改变组织学形态，但是随着突变的累积，会导致增生、非典型性增生、原位癌、最终导致浸润性癌。
随着年龄的增长，发生突变的体细胞数量会越多，这些突变产生的细胞群就越有可能演变成恶性肿瘤。雌激素和孕激素可能通过生长因子如转化生长因子（TGF）-α引起乳腺细胞的生长和增殖。
这些激素无论是内源性还是外源性，都可能促进乳腺癌细胞的发育和增殖。
乳腺癌发病率在全球范围内的不同可以通过遗传学、生育因素、饮食、运动和筛查的差异来解释。 这些因素中的有些因素是可改变的，有观察研究结果证明，日本人移民到美国后在两代人内罹患乳腺癌的风险从较低的日本人风险水平增加到较高的美国人风险水平。
乳腺癌的许多危险因素表明，长期暴露于内源性雌激素在该疾病的发展中起作用。 与初潮年龄在14岁或14岁以上的女性相比，初潮年龄在11岁或以下的女性患乳腺癌的几率高出约20％。
绝经较晚的女性也有更高的患病风险。 患乳腺癌的妇女往往具有较高的内源性雌激素和雄激素水平。
相反，过早绝经的女性患乳腺癌的风险较低。 在接受卵巢去势术后，根据年龄，体重和分娩次数的不同，乳腺癌风险可能降低高达75％，而年轻，偏瘦，未生育女性的风险减少幅度最大。
单侧卵巢切除也能降低乳腺癌风险，但程度比双侧切除小。
其他激素的变化对乳腺癌风险也有影响。（有关更多信息，请参阅本总结“有充分证据表明可降低乳腺癌风险的因素”一节中的早孕和母乳喂养部分。）
内源性雌激素水平，胰岛素水平和肥胖之间的相互作用（均会影响乳腺癌风险）了解较少，但建议采取干预措施降低该风险。 生育危险因素可能与易感基因型相互作用。 例如，在“护士健康研究”中所得到的研究结果，
仅在没有母亲或姐妹患有乳腺癌的家族史的女性中观察到首次分娩年龄，初潮和绝经与乳腺癌发展之间的关联。
有家族史的女性（尤其一级亲属受累时）患乳腺癌的风险增加。
从数据库，队列研究和病例对照研究得出的以下风险评估模型对这种风险进行了量化：
大约5%的乳腺癌与特定的异常等位基因有关。 （相关更多信息，请参阅PDQ关于乳腺癌和妇科癌症遗传学的总结。）BRCA基因的突变为常染色体显性遗传，并且在致癌方面具有高度外显率，常见在较年轻的女性。
在具有乳腺癌遗传易感性的人群中，BRCA1或BRCA2基因突变和具有癌症家族史可能会增加患癌风险。
BRCA1基因突变携带者罹患乳腺癌的终生风险为55%-65%，BRCA2基因突变携带者罹患乳腺癌的终生风险为45%-47%。
相比之下，在普通人群中，罹患乳腺癌的终生风险为12.4%。
有些女性遗传了对致突变剂或生长因子的易感性，这也会增加患乳腺癌的风险。
（有关更多信息，请参阅此总结的“有充分证据表明可增加乳腺癌风险的因素”一节中的“电离辐射暴露”部分。）
乳腺X线筛查广泛应用后，揭示乳腺密度存在差异性，且致密乳腺的女性乳腺癌发病率更高。同时乳腺密度也会影响乳腺X线筛查乳腺癌的结果。在由1112对配对的病例对照组成的筛查人群，三项巢式病例对照研究描述了相应风险增加的程度。与乳腺密度不到10%的女性相比，乳腺密度在75%或以上的女性患乳腺癌的风险增加（优势比[OR]，4.7；95%置信区间[CI]，3.0-7.4），无论癌症是筛查当时发现的（OR，3.5；95%CI，2.0-6.2），还是筛查阴性12个月内检出的（OR，17.8；95%CI，4.8-65.9），都能检测到乳腺癌的风险增加。乳腺癌风险的增加，无论是筛查还是其他方法检测到的乳腺癌风险，都有一定的增加，而且至少持续到研究开始后8年，年轻女性的风险高于年龄大的女性。对于中位年龄在56岁以下的女性，乳腺X线检查显示为乳腺密度为50%或以上的女性中，现场检出的乳腺癌风险增加26%，筛查阴性12个月内检出的乳腺癌增加50%。
乳腺致密的女性患乳腺癌的风险增加，患乳腺癌的风险与乳房的致密程度成正比。与乳腺密度最低比较，乳腺密度从较高到最高，患乳腺癌的相对风险（RR）从1.79上升至4.64。
乳腺致密的女性乳腺癌死亡率没有增加。
1997年对纳入超过150000名女性的51项流行病学研究再分析发现，绝经后激素治疗（HT）与乳腺癌风险增加有关。
2002年进行的心脏和雌孕激素替代治疗研究结果一致。
该研究引入2763名平均年龄67岁的绝经后冠心病妇女，随机分为激素替代组和安慰剂组。平均随访6.8年后发现乳腺癌的相对危险度（RR）为1.27（95%CI=0.84-1.94）。尽管无显著统计学意义，但RR估值与2002年发表的美国妇女健康倡议（WHI）报告相一致。
WHI研究了激素和膳食干预对心脏病和乳腺癌患病风险的影响。
50-79岁具有完整子宫的女性被随机分配为接受结合雌激素和持续孕激素联合治疗组（n=8506）或安慰剂（n=8102）治疗组。因为HT联合治疗并未降低患冠心病风险，反而增加了卒中和乳腺癌风险,该研究提前终止。所有亚组结果都显示浸润性乳腺癌风险增加（风险比HR=1.24；95%CI=1.02–1.50），但原位乳腺癌风险未增加。与HT联合治疗相关的肿瘤，具有相似的分级、组织学、雌激素受体（ER）、孕激素受体（PR）和HER2/neu的表达，HT联合治疗组淋巴结转移的发生率较高且转移范围较大。
平均11年的长期随访显示，HT治疗组的乳腺癌特异死亡率较高（分别为25例和12例，每年0.03%和0.01%；HR=1.95；95%CI=1.0-4.04；P=0.049）。HT联合治疗也与乳腺X线检查异常结果的高发生率有关。
WHI观察性研究与WHI随机对照试验（RCT）平行开展，其招募研究对象为50-79岁的绝经后女性。WHI观察性研究分析评估了已诊断乳腺癌患者接受联合HR治疗的预后，以及从绝经到开始HT治疗之间的时间对乳腺癌风险的影响。经过平均11.3年的随访，雌激素联合孕激素治疗组的女性乳腺癌的年发病率为0.60%，而对照组的发病率为0.42%（HR=1.55；95%CI=1.41-1.70）。HT治疗组和对照组诊断乳腺癌后的生存率相似。HT治疗组的乳腺癌死亡率高于对照，但该差异不具有统计学意义（HR=1.3；94%CI=0.90–1.93）。绝经后立即接受HT治疗的女性患乳腺癌风险最高，随着绝经与开始接受HT联合治疗之间的间期延长，风险降低但持续存在。在乳腺癌确诊后，HT联合治疗组的全因死亡率显著高于对照（HR=1.87；95%CI=1.37-2.54）。总体而言，这些结果与RCT结果一致。
子宫切除术后的女性无患子宫内膜癌的风险。WHI招募了10739名子宫切除术后、年龄在50-79岁的女性作为研究对象， 随机分组后分别接受马结合雌激素（CEE）或安慰剂治疗。这项试验也因卒中风险增加和风险获益指数无改善而提前终止。
平均随访6.8年后，CEE组乳腺癌发病率低于安慰剂组（发病率分别为0.26%和0.33%每年；HR=0.77；95%CI=0.59-1.01）。CEE组的总体风险获益指数稍差。
78%试验参与者接受了长期随访，中位随访时间为11.8年，初步结果保持不变，CEE组乳腺癌发病率同样较低（HR=0.77；95%CI=0.62-0.95），乳腺癌死亡率下降（死亡例数分别为6和16；HR=0.37；95%CI=0.13-0.91）。CEE组的全因死亡率也较低（分别为0.046%和0.076%每年；HR=0.62；95%CI=0.39-0.97）。停止CEE干预后，卒中风险降低。在整个随访期间，冠心病、深静脉血栓形成、卒中、髋部骨折或结直肠癌的发病率均无差异。
绝经后的前五年内开始接受CEE或安慰剂治疗的女性乳腺癌发病率相近（HR=1.06；95%CI=0.74–1.51）。
丹麦对1006名绝经早期妇女进行了HT试验，旨在评估其心血管事件结局。407例具有完整子宫的女性接受了联合HT（三相雌二醇和炔诺酮）治疗，95名子宫切除术后的女性接受了雌二醇治疗。对照组（包含407名子宫完整和97名子宫切除的女性）未接受处理。研究10年时，发现可能存在较大偏倚。被分配到HT组的女性中只有一半仍在服用规定的药物，而22%的对照组女性已经开始服用HT。接受HT治疗的女性和对照组乳腺癌的发病率并无差异。
观察性研究对随机对照试验（RCT）中获得的信息进行了补充。
英国百万女性研究
在1996年至2001年间，英国共招募了1084110名50至64岁的女性，并获得了有关HT使用的资料和其他个人资料。对这些女性进行了乳腺癌发病率和死亡率的随访。一半的女性使用过HT。随访2.6年，发生浸润性乳腺癌患者为9364名；随访4.1年，637名死于乳腺癌。招募阶段正使用HT的患者比从未使用HT的患者有较高的风险患乳腺癌（校正后的RR=1.66；95%CI=1.58-1.75；P<0.0001）并死于该疾病（校正后的RR=1.22；95%CI=1.00-1.48；P=0.05）。然而，过去使用过HT的患者，其患乳腺癌的风险并没有增加（分别为1.01[95%CI=0.94–1.09]和1.05[95%CI=0.82–1.34]）。仅目前使用雌激素（RR=1.30；95%CI=1.21-1.40；P<0.0001）、联合HT（RR=2.00；95%CI=1.88-2.12；P<0.0001）和替勃龙（RR=1.45；95%CI=1.25-1.68；P<0.0001）的患者发病率显著增加。联合HT治疗组和乳腺癌发生的关联强度显著大于其他类型的HT组（P<0.0001）。
普吉特海峡癌症监测系统开展了一项基于人群的研究，纳入了965名乳腺癌患者和1007名对照。结果显示，联合HT使用者患浸润性乳腺癌的风险是相应对照的1.7倍，而仅使用雌激素者相关风险未见增高。
在所有的试验中，联合使用HT和乳腺癌风险增加之间的关系是一致的。而单纯雌激素HT治疗与乳腺癌发病率之间的关系尚不明确，部分研究显示其导致乳腺癌风险增加，但也有研究显示其为保护作用。可能的原因包括：雌激素治疗时间与绝经开始年龄有关，观察性研究中激素用药者和非用药者的常规筛查率不均衡。
WHI结果发表后，HT治疗在美国等地的使用量急剧下降。对联合HT组参与者进行后续随访，发现在同样的乳腺钼靶筛查率下，治疗后2年内原本升高的乳腺癌风险快速降低。
美国乳腺癌发病率数据显示，从2002年到2003年，50岁及以上女性的乳腺癌，尤其是ER阳性乳腺癌发病率急剧下降。
同样，在HT治疗方案使用率较高的多个国家，乳腺癌发病率在相近时间范围内下降，同时处方模式和/或报告的使用率也有所下降。
一项在接受定期乳腺X线筛查的女性中进行的研究表明，2002年至2003年乳腺癌发病率急剧下降的主要原因是HT方案的使用减少，而不是乳腺X线钼靶检查率下降。
在2002年至2003年乳腺癌发病率下降之后，美国的乳腺癌发病率趋于稳定。
电离辐射与其后罹患乳腺癌之间存在明确的相关性。
原子弹暴露，结核病导致的频繁X线检查，痤疮、癣、胸腺增大、产后乳腺炎和淋巴瘤导致的放射性治疗等因素导致乳腺癌风险增高。年轻人，特别是青春期阶段的风险更高。据估计，医用射线相关的乳腺癌占所有乳腺癌的比例不足1%。
但有一些理论提出，对于特定人群，例如AT杂合子人群，更易受到辐射增加乳腺癌风险的影响。
在携带BRCA1或BRCA2突变的女性中开展的一项大型队列研究显示，胸部X线检查会增加乳腺癌风险（RR=1.54；95%CI=1.1-2.1），特别是在20岁之前曾接受X线检查的女性。
16岁前接受霍奇金淋巴瘤治疗的女性，在40岁之前罹患乳腺癌的风险高达35%。
较高放射剂量（对乳腺癌患者剂量中位值为40Gy），且在10-16岁期间接受放疗者的乳腺癌风险较高。
与继发性白血病的风险不同，随着随访时间的延长，治疗相关乳腺癌的风险并未降低，增高的风险在放疗后可持续超过25年。
这些研究中，多数患者（85%-100%）在放射野内或放射野边界发生乳腺癌。
荷兰的一项研究对霍奇金淋巴瘤放疗后至少5年发生乳腺癌的48例女性进行评估，将她们与175例配对的未发生乳腺癌的霍奇金淋巴瘤女性进行比较。发现接受化疗和斗篷野放疗的患者比单独接受斗篷野放疗的患者更不易患乳腺癌，可能是由于化疗可诱导卵巢抑制（RR=0.06；95%CI=0.01–0.45）。
另一项研究对比了105例放疗相关乳腺癌患者和266例对照，两组之间通过年龄和放疗配对，发现类似的卵巢照射会产生保护作用。
这些研究提示卵巢激素可能促进了放疗诱导突变后乳腺组织的增生。
随之而来的另一个问题是，乳腺癌患者行肿瘤切除术和放疗（L-RT）后，再次患乳腺癌或其他恶性肿瘤的风险是否高于乳房切除术后患者？一项研究对比了1029例L-RT患者和1387例乳房切除术后患者，经过中位时间为15年的随访，两组患者的二次恶性肿瘤发病率无差异。
三项RCT的证据也支持这一结论。一项研究报道了1851例女性随机分组分别接受全乳房切除术、仅肿瘤切除术和L-RT治疗，对侧乳腺癌的发生率分别为8.5%、8.8%和9.4%。
另一项研究将701例女性患者随机分组，行根治性乳房切除术或保乳术联合术后放疗，发现两组女性的对侧乳腺癌发病率分别为每百人年10.2例和8.7例。
第三项研究中，1665例女性被随机分配为根治性乳房切除术、全乳房切除术或全乳房切除术联合化疗组，对比三组女性25年结局发现，不同治疗组的对侧乳腺癌发病率无显著差异，总发病率为6%。
肥胖与乳腺癌风险增高相关，尤其是绝经后未用HT治疗的女性。WHI观察了85917例50-79岁女性，收集了体重和乳腺癌相关危险因素的信息。
该研究测量了这些女性的身高、体重、腰围和臀围。经过中位时间为34.8个月的随访，共有1030例女性发生浸润性乳腺癌。在从未用过HT的女性中，乳腺癌风险升高与入组时体重和体重指数（BMI）、50岁时BMI、最大BMI、成年和绝经后的体重变化及腰围与臀围相关。体重是最强的预测因素，体重超过82.2kg的女性与体重低于58.6kg的女性相比，RR为2.85（95%CI=1.81-4.49）。
肥胖、糖尿病和胰岛素水平与乳腺癌风险之间的关联尚未有明确的结果。英国女性心脏与健康研究对60至79岁的151名乳腺癌患者和3690名女性对照进行了研究，发现在非糖尿病女性中，每增加1个单位的log（e）胰岛素水平，年龄校正后的乳腺癌OR为1.34（95%CI=1.02-1.77）。控制可能的混杂因素后，血糖与绝经前/后乳腺癌的关联仍然存在。此外，空腹血糖水平、稳态模型评分（空腹血糖值和胰岛素水平值的乘积除以22.5）、糖尿病、妊娠期糖耐量异常或糖尿病史也与乳腺癌有关。
饮酒会增加患乳腺癌的风险。一项英国的荟萃分析纳入了53项病例对照和队列研究的数据。
研究显示，与无饮酒史女性相比，每天饮酒35g至44g的女性患乳腺癌的RR为1.32（95%CI=1.19-1.45；P<0.001），每天饮酒45g以上的女性患乳腺癌的RR为1.46（95%CI=1.33-1.61；P<0.001）。每天酒精摄入量增加10g（即一杯酒），乳腺癌的RR增加约7%（95%CI=5.5%-8.7%；P<0.001）。在经过人种、教育、家族史、初潮年龄、身高、体重、BMI、哺乳、口服避孕药、绝经后激素治疗及激素类型、绝经年龄等因素校正后依然得到类似结果。
分娩后几年内患乳腺癌的风险增加，但之后患乳腺癌的风险长期降低，对较年轻的女性更加明显。
研究发现，在20岁以前经历足月妊娠的女性患乳腺癌的风险是未生产或35岁以上经历首次足月妊娠女性的一半。
国际绝经前乳腺癌协作组对来自15项前瞻性队列研究的约890000名女性的数据进行了汇总分析，证实了分娩与乳腺癌风险的相关性。与未生产女性相比，女性在分娩后20年内患ER阳性和ER阴性乳腺癌的风险增加。然而，分娩约24年后，ER阳性乳腺癌的发病风险降低，但ER阴性乳腺癌的发病风险仍然增加。因此，分娩与乳腺癌风险之间的关系是复杂的，受到分娩后的时间长度影响，与不同肿瘤特征相关。
母乳喂养可以降低患乳腺癌的风险。
对来自30个国家的47项流行病学研究（含50302名乳腺癌女性和96973名对照）的数据再分析后发现，进行过母乳喂养的生育后女性的乳腺癌发病率低于未母乳喂养过的生育后女性。母乳喂养的持续时间与风险降低的程度成正比。
每分娩一次乳腺癌风险降低7.0%（95%CI=5.0%-9.0%；P<0.0001）；此外，每增加12个月的母乳喂养时间，乳腺癌的RR降低4.3%（95%CI=2.9%-5.8%；P<0.0001）。
积极的锻炼可以降低患乳腺癌的风险，尤其是对年轻的生育后女性。
大量关于体力活动水平与乳腺癌风险之间关系的观察性研究显示，两者呈负相关。
运动锻炼的RR平均能降低30%至40%，但饮食或乳腺癌遗传易感性等混杂因素的影响未纳入考虑。在挪威开展的一项前瞻性队列纳入了25000多名女性，发现繁重的体力劳动或每周至少4小时的运动与乳腺癌风险降低有关，尤其是在绝经前女性以及等于或低于正常体重的女性中。
一项非裔美国女性的病例对照研究发现，每周7小时以上剧烈的娱乐性体育活动与乳腺癌发病率的降低有关。
乳腺癌辅助治疗临床试验发现他莫昔芬不仅能降低乳腺癌复发率，而且能预防对侧新发的原发性乳腺癌。
他莫昔芬还能够帮助预防绝经后乳腺癌患者的骨密度降低。
不良反应包括潮热、静脉血栓栓塞事件和子宫内膜癌等。
根据这些辅助治疗试验的结果，乳腺癌预防试验（BCPT）将13388例乳腺癌高危患者随机分组，分别接受他莫昔芬或安慰剂治疗。
由于他莫昔芬组乳腺癌发病率比安慰剂组低49%，该研究提前终止。经过4年随访，他莫昔芬和安慰剂组分别发生了85例和154例浸润性乳腺癌，原位乳腺癌分别为31和59例。他莫昔芬的另一获益为骨折发生率降低，他莫昔芬组和安慰剂组分别为47例和71例。但他莫昔芬组子宫内膜癌的发生较高（分别为33例和14例），血栓事件发生率也较高(分别为99例和70例，其中肺栓塞分别为17例和6例）。
经过7年随访之后，BCPT更新结果与初步报告相似。
安慰剂组中有部分女性退出；其中一部分参加了随后的试验，因此有新的女性加入安慰剂组。他莫昔芬的获益和风险与原报告中的并无显著差异，持续的获益是骨折率较低，而子宫内膜癌、血栓形成和白内障手术的风险持续增加。随访7年后，未观察到总死亡率方面的获益（RR=1.10；95%CI=0.85-1.43）。
另有3项他莫昔芬在乳腺癌一级预防方面的研究已完成。
对他莫昔芬一级预防试验的荟萃分析显示，乳腺癌的发病率降低了38%，各研究间并无明显的异质性。
ER阳性乳腺癌降低了48%。子宫内膜癌（总RR=2.4；95%CI=1.5-4.0）和血栓栓塞事件（RR=1.9；95%CI=1.4-2.6）发生率升高。这些一级预防试验均未检测乳腺癌死亡率的变化。
有导管原位癌（DCIS）病史的女性患对侧乳腺癌的风险增加。美国国家外科辅助乳腺和肠道项目（NSABP）试验B-24评估了他莫昔芬联合L-RT对DCIS患者的益处。接受LR-T治疗的女性被随机分配是否进行他莫昔芬辅助治疗。随访6年后，接受他莫昔芬治疗的女性相较对照组浸润性和原位乳腺癌发生率较低(分别为8.2% 和13.4%；RR=0.63；95%CI=0.47-0.83）。接受他莫昔芬治疗的女性患对侧乳腺癌的风险也较低（RR=0.49；95%CI=0.26-0.87）。
盐酸雷洛昔芬（易维特）是一种SERM, 它对乳腺有抗雌激素作用，对骨、脂代谢和凝血有雌激素作用。与他莫昔芬不同，它对子宫内膜有抗雌激素作用。
雷洛昔芬多重结果评估（MORE）试验为一项随机、双盲临床试验，共纳入1994年-1998年间美国180个临床中心的7705例绝经后骨质疏松患者。 研究发现雷洛昔芬可降低椎体骨折的发生。乳腺癌的发生为次要终点。经过中位时间为47个月的随访，接受雷洛昔芬治疗的女性相较对照组患浸润性乳腺癌的风险降低（RR=0.25；95%CI=0.17-0.45）。
雷洛昔芬与他莫昔芬相似，主要降低ER阳性乳腺癌的风险，而不降低ER阴性乳腺癌风险。雷洛昔芬与他莫昔芬均增加潮热和血栓栓塞事件的发生。但随访47个月后，未发现子宫内膜癌风险增加。
MORE研究衍生研究，即易维特相关性持续转归（CORE）研究对80%的MORE参与者继续进行评估，在原分组基础之上继续增加4年时间。虽然两项研究之间相差中位时间为10个月的间隔，仅有55%的患者依然按原分组要求服药，但雷洛昔芬组的浸润性乳腺癌发病率仍然较低。与MORE相似，CORE研究的结果主要见于ER阳性浸润性乳腺癌发病风险降低。在MORE联合CORE的8年研究之中，浸润性乳腺癌发病率总体降低66%（HR=0.34；95%CI=0.22-0.50）；ER阳性浸润性乳腺癌发病率降低76%（HR=0.24；95%CI=0.15-0.40）。
雷洛昔芬心脏应用试验为一项随机、安慰剂对照试验，以评估雷洛昔芬对冠状动脉事件和浸润性乳腺癌发病率的影响。与MORE和CORE试验的结果相似，雷洛昔芬可降低浸润性乳腺癌的风险（HR=0.56；95%CI=0.38–0.83）。
他莫昔芬和雷洛昔芬（STAR）研究（NSABP P-2）在19747例高危女性中对比了他莫昔芬与雷洛昔芬的作用，经过平均3.9年随访，发现2组的浸润性乳腺癌发病率相似，但他莫昔芬组非浸润性乳腺癌发病率低于雷洛昔芬组。子宫癌、静脉栓塞事件、白内障等不良反应的发生率在他莫昔芬组更高，两组缺血性心脏病、卒中或骨折事件的发生无差异。
接受他莫昔芬治疗的女性中，与治疗相关的性交困难、肌肉骨骼问题和体重增加的症状发生率较低，而接受雷洛昔芬治疗的女性中，血管舒缩、膀胱控制症状、妇科症状和腿部痉挛的发生率较低。
| 他莫昔芬 | 雷洛昔芬 | RR，95%CI | |
|---|---|---|---|
| 浸润性乳腺癌 | 4.3 | 4.41 | 1.02，0.82-1.28 |
| 非浸润性乳腺癌 | 1.51 | 2.11 | 1.4，0.98-2.00 |
| 子宫癌 | 2 | 1.25 | 0.62，0.35–1.08 |
| 静脉血栓栓塞(VTE) | 3.8 | 2.6 | 0.7, 0.68–0.99 |
| 白内障 | 12.3 | 9.72 | 0.79，0.68–0.92 |
| 症状发生率（0-4级） | |||
| 首选他莫西芬 | |||
| 性交困难 | 0.68 | 0.78 | P<0.001 |
| 肌肉及骨骼问题 | 1.1 | 1.15 | P=0.002 |
| 体重增加 | 0.76 | 0.82 | P<0.001 |
| 首选雷洛昔芬 | |||
| 血管舒缩症状 | 0.96 | 0.85 | P<0.001 |
| 尿失禁 | 0.88 | 0.73 | P<0.001 |
| 腿部抽筋 | 1.1 | 0.91 | P<0.001 |
| 妇科问题 | 0.29 | 0.19 | P<0.001 |
| CI=置信区间；RR=相对风险；VTE=静脉血栓栓塞。 | |||
市场上另一大类用于治疗激素敏感性乳腺癌的药物也可能有预防乳腺癌的作用。这些药物干扰肾上腺酶芳香化酶，阻止绝经后女性产生雌激素。阿那曲唑与来曲唑抑制芳香化酶活性，而依西美坦则灭活该酶。这些药物的不良反应包括乏力、关节痛、肌痛和骨密度下降，因此骨折发生率可能升高。
既往诊断为乳腺癌的妇女在接受AI治疗时复发和新发乳腺癌的风险较低，如下研究显示:
芳香化酶抑制剂或失活剂也被证明可以用于乳腺癌高风险女性的预防作用，如下研究所示：
一项回顾性队列研究评估了双侧预防性乳房切除术对后续乳腺癌发生率的影响，纳入的患者为家族史评估提示有高-中度乳腺癌风险的女性。
在BRCA突变状况未知的情况下，90%的女性接受了皮下而非全乳切除术。经过中位时间为14年的随访，425名中危女性的发病风险降低了89%；214名高危女性的风险降低了90%至94%，风险的降低程度也受乳腺癌预期发病率计算方法的影响。中危女性乳腺癌死亡率降低100%，高危女性死亡风险降低81%。由于该研究使用家族史而非基因检测作为风险指标，乳腺癌的风险有可能被高估。
根据美国国家癌症数据库的数据，患有单侧乳腺疾病（DCIS和早期浸润性乳腺癌）的女性双侧乳腺切除率从1998年的1.9%上升到2011年的11.2%。
在中等风险人群中，尚无研究评估预防性乳房切除术对于单侧乳腺癌患者的对侧新发乳腺癌的预防效果。
卵巢去势和卵巢切除术可降低正常女性和胸部照射导致风险增加的女性患乳腺癌的风险。（更多信息请参阅本总结证据描述部分中的内源性雌激素部分。）观察性研究发现，通过预防性卵巢切除术预防卵巢癌发生的BRCA1或BRCA2突变女性中，乳腺癌风险比未行预防性卵巢切除术的突变携带者降低50%。
但这些观察性研究都受到选择偏倚、患者与对照者的家族关系、卵巢切除术适应证、激素使用信息不全面的影响。一项前瞻性队列研究也有类似的发现，BRCA2突变携带者比BRCA1携带者乳腺癌风险降低的幅度更大。
口服避孕药会导致使用期间的乳腺癌风险小幅增加，但随着时间推移，风险逐渐降低。
一项设计较佳的病例对照研究发现乳腺癌风险与口服避孕药的规律服用、持续时间和是否近期使用无关。
另一项病例对照研究发现，在35至64岁的女性中，使用注射或植入式含孕激素的避孕药不会增加患乳腺癌的风险。
丹麦的一项全国前瞻性队列研究发现，目前正使用或近期使用激素类避孕药的女性比从未使用激素类避孕药的女性患乳腺癌的风险更高。此外，随着药物使用持续时间的延长，患乳腺癌的风险增加。然而，就绝对数量而言，口服避孕药对乳腺癌风险的影响非常小。每7690名使用药物避孕1年的女性中仅新增1例乳腺癌。
职业、环境或化学暴露都被认为是乳腺癌病因之一。多项荟萃分析描述了多达134种环境化学物质的来源和暴露指标，提示其可能与癌症发生有关。
一些研究表明，有机氯暴露，如与杀虫剂有关的有机氯暴露，可能与乳腺癌风险增加有关，
但其他病例对照和巢式病例对照研究未得到类似的结论。
报道两者之间存在正相关性的一些研究中提到的有机氯的鉴定标准并不一致。其中一些物质有微弱的雌激素效应，但其对乳腺癌风险的影响未得到证实。美国1972年开始禁用双对氯苯基三氯乙烷，1977年开始停止生产多氯联苯。总的来说，支持乳腺癌与特定环境暴露相关性的流行病学和动物研究证据通常较微弱。由于需要考虑的因素较多，任何与乳腺癌或其他癌症的关联结果都可能被诸如多样性、测量误差、回忆和报告偏倚等所混淆。
曾有研究提出流产是乳腺癌发病因素之一。但观察性研究的结果并不一致；阳性和阴性的结果均存在。但阳性结果的观察性研究往往缺乏严谨性，且女性对社会敏感问题的回应上可能存在偏倚。
例如，一项研究比较了对流产有不同社会态度的地区中其回忆或报告偏倚的影响。
美国妇产科医师学会妇科实践委员会的结论是，“最近更严谨的研究表明流产与随后的乳腺癌风险增加之间无因果关系。”
研究使用了关于流产的前瞻性记录的数据从而避免回忆偏倚的研究，基本显示流产与随后的乳腺癌发生无关。
膳食改变对乳腺癌的影响可能和改变的情况有关。然而，几乎没有证据表明任何形式的饮食改变会影响乳腺癌的发病率。
很少有随机试验比较不同膳食因素的癌症发病率。相关研究均为观察性，包括随机试验的事后分析。这些分析可能受很多偏倚影响，使得观察结果难以被解释。尤其要注意的是，这里P值和置信区间CI的解释与随机试验中主要终点的计算结果是不同的。
1975年以前发表的一份生态研究摘要显示，世界范围内，年龄校正后乳腺癌死亡率与人均膳食脂肪消耗量之间存在正相关关系。
病例对照研究结果并不一致。经过20年后，一份对7项队列研究结果的综合分析发现，饮食脂肪摄入总量与乳腺癌风险之间无关。
在纳入WHI研究的48835名50-79岁的绝经后女性中进行了一项随机、对照、饮食调整研究。这项干预措施通过增加蔬菜、水果和谷物的摄入，以达到总脂肪摄入量减少20%的目标。经过中位时间为8.1年以上随访，干预组的脂肪摄入量减少了约10%，使得雌二醇和γ-生育酚水平降低，但体重下降未持续。饮食干预组的浸润性乳腺癌发病率较低但无统计学差异，HR为0.91（95%CI=0.83-1.01）。
在全因死亡率、总死亡率或心血管事件发病率方面干预和对照组无差异。
为研究水果蔬菜摄入对乳腺癌发生的影响，一项荟萃分析纳入了8项队列研究，包含350000名女性，新发乳腺癌7377名，多种统计模型分析结果均显示二者之间不存在相关性。
女性健康饮食和生活随机试验
研究了膳食因素对既往诊断为乳腺癌女性的新发乳腺癌发病率的影响。研究纳入了超过3000名女性并随机分配到两组，一组为增加水果和蔬菜摄入量，增加纤维摄入量，减少脂肪摄入量的强化组，另一组接受“每天5份”膳食指南的对照组。经过平均7.3年的随访，新发原发乳腺癌发生率未见降低、无病生存时间和总生存时间在两组间也未见差异。
一项在西班牙开展的随机试验
将心血管病高风险的参与者分配至三种饮食组：添加特级初榨橄榄油的地中海饮食、添加混合坚果的地中海饮食或限制性地中海饮食（经咨询后减少膳食脂肪含量）。主要心血管事件作为该试验项目的主要终点，经膳食调整后发生率降低。
研究人员还分析了其他终点事件，包括乳腺癌发病率，未报告接受检查的人数的情况下，发生35例浸润性乳腺癌（主要心血管事件发生288例），经过平均时间为4.8年、4.3年和4.2年的随访后，乳腺癌发病率分别为8/1476（0.54%）、10/1285（0.78%）和17/1391（1.22%）。但由于其研究背景，很难确定这些差异的统计意义。
一些临床试验评估了某些微量营养元素对降低乳腺癌风险的作用，其主要结局事件包括心血管疾病和癌症发生。女性健康研究纳入39876例女性，随机分组服用β胡萝卜素或安慰剂，经过2年观察，发现乳腺癌发病率没有差异。
在该研究中，隔天服用600IU维生素E未见与癌症发生具有关联。
女性抗氧化心血管研究在8171名女性中，评估了维生素C、维生素E或β-胡萝卜素的摄入与癌症和浸润性乳腺癌发生的关系，发现并无关联。
两年后，其中5442名女性被随机分配为联合服用1.5mg叶酸、50mg维生素B6和1mg维生素B12或服用安慰剂组。经过7.3年的随访，乳腺癌和各类浸润性癌症的发病率在两组间无明显差异。
芬维A胺
是一种维生素A类似物，在之前的临床研究中已被证明可以减少乳腺癌的发生。意大利一项III期临床试验在2972名年龄在30至70岁的女性中比较了接受5年芬维A胺干预治疗与不干预的人群结局，这些女性既往均接受I期乳腺癌切除术或DCIS切除术。经过中位时间为97个月的随访，其对侧乳腺癌（P=0.642）、同侧乳腺癌（P=0.177）、远处转移、非乳腺恶性肿瘤的发生率和和全因死亡率在统计学上无显著差异。
主动吸烟在乳腺癌病因学中的潜在作用已被研究了30多年，没有明确的证据表明两者之间存在相关性。
自20世纪90年代中期以来，吸烟与乳腺癌的相关性研究更多关注被动吸烟。
最近的一项荟萃分析表明，被动吸烟与乳腺癌之间的总体不存在相关性，一些研究中的阳性结果可能是由于方法学的缺陷（如乳腺癌确诊后评估暴露因素）所导致。
尽管在非专业出版物上警告女性腋下除臭剂和止汗剂会导致乳腺癌，但没有证据支持这些观点。一项访谈式研究纳入813名乳腺癌患者和793名对照，发现使用止汗剂、除臭剂或刮胡刀与乳腺癌风险之间没有关联。
与之相反，一项对437名乳腺癌幸存者的研究发现，使用止汗剂/除臭剂并更频繁地刮腋毛的女性癌症诊断的年龄更轻。但其可能的原因之一是，这些女性月经初潮较早或内源性激素水平较高，而这两者是乳腺癌和体毛增加的共同风险因素。
两项设计较佳的RCT试验荟萃分析
以及RCT加上观察性研究
未发现他汀类药物增加或降低乳腺癌风险的证据。
有研究关注口服和静脉注射双膦酸盐治疗高钙血症和骨质疏松症对预防乳腺癌的潜在收益。初步观察性研究表明，使用这些药物大约1至4年的女性乳腺癌发病率较低。
但患骨质疏松症女性会比骨密度正常的女性患乳腺癌的风险更低，这一情况可能对上述研究结果造成混淆。其他证据来源于在乳腺癌女性病例中开展的研究：这些药物的使用与对侧新发乳腺癌的降低有关。
在此背景下，开展了两项大型随机安慰剂对照试验。骨折干预试验（FIT）使用阿仑膦酸钠或安慰剂治疗6194名绝经后骨质疏松症女性，经过3.8年后，两组间乳腺癌发病率无差异，分别为1.8%和1.5%（HR=1.24；CI=0.84-1.83）。另一项实验为每年使用1 次唑来膦酸的临床结果和发病率降低试验的关键部位骨折试验（HORIZON-PRT），其对7580名绝经后骨质疏松症女性给予唑来膦酸钠静脉注射治疗或安慰剂治疗，结果发现，在2.8年时，乳腺癌的发病率在两组间无差异，分别为0.8%和0.9%（HR=1.15；CI=0.7-1.89）。
2007年，世界卫生组织（WHO）下属的国际癌症研究机构（IARC）将涉及昼夜节律紊乱的轮班工作列为可能的乳腺癌致癌因素。主要证据来自动物研究。当时人类研究的证据有限。
2013年，一项纳入15项流行病学研究的荟萃分析发现，在曾经上过夜班的女性中，乳腺癌发病率增加的证据并不充分。
2016年，合并3项新近在英国开展的前瞻性研究（涉及近80万名女性）和其他7项前瞻性研究的结果发现，乳腺癌发病率与夜班工作不存在相关性。即使是长达20年以上的夜间轮班工作，其发病风险比值的置信区间也很窄，（RR=1.01；95%CI=0.93-1.10）。这些结果表明乳腺癌与长期夜间轮班工作不存在任何程度的相关性。
2003年在英国的亲代研究强调了乳腺癌的风险因素和致病因素。在105000名女性的前瞻性队列中，通过问卷调查获得了基线和20岁时卧室光线水平的信息。经过平均6.1年的随访，观察到1775例乳腺癌。校正包括夜班工作等混杂因素后，发现无证据表明夜间卧室光线亮度与乳腺癌风险有关。夜间光线最亮组相对于最暗组，乳腺癌发病率的HR为1.01（95%CI=0.88–1.15）。
With an estimated 268,600 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2019.
Also in 2019, breast cancer will kill an estimated 41,760 women, second only to lung cancer as a cause of cancer mortality in women. Breast cancer also occurs in men, and it is estimated that 2,670 new cases will be diagnosed in 2019.
Despite a prior long-term trend of gradually increasing breast cancer incidence in women, data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.8% per year from 2007 to 2016.
The major risk factor for breast cancer is advancing age. A 30-year-old woman has a 1 in 250 chance of being diagnosed with breast cancer in the next 10 years, whereas a 70-year-old woman has a 1 in 27 chance.
Breast cancer incidence and mortality risk also vary on the basis of geography, culture, race, ethnicity, and socioeconomic status. Compared with other races, white women have a higher incidence of breast cancer that may be attributable, in part, to screening behavior. However, breast cancer incidence rates increased slightly in black women by 0.3% per year between 2005 and 2014, resulting in the convergence of rates in blacks with those in whites.
Screening by mammography decreases breast cancer mortality by identifying cases for treatment at an earlier stage. However, screening also identifies more cases than would become symptomatic in a woman’s lifetime, so screening increases breast cancer incidence. (Refer to the Overdiagnosis section in the PDQ summary on Breast Cancer Screening for more information.)
Breast cancer develops when a series of genetic mutations occurs.
Initially, mutations do not change the histologic appearance of the tissue, but accumulated mutations will result in hyperplasia, dysplasia, carcinoma in situ, and eventually, invasive cancer.
The longer a woman lives, the more somatic mutations occur, and the more likely it is that these mutations will produce populations of cells that will evolve into malignancies. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha.
These hormones, whether endogenous or exogenous, may promote the development and proliferation of breast cancer cells.
International variation in breast cancer rates may be explained by differences in genetics, reproductive factors, diet, exercise and screening behavior. Some of these factors are modifiable, as evidenced by the observation that Japanese immigrants to the United States increase their breast cancer risk from lower Japanese levels to higher American levels within two generations.
Many of the risk factors for breast cancer suggest that longer exposure to endogenous estrogen plays a role in the development of the disease. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than do those who experienced menarche at age 14 years or older.
Women who experience late menopause also have an increased risk. Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.
Conversely, women who experience premature menopause have a lower risk of breast cancer. Following ovarian ablation, breast cancer risk may be reduced as much as 75% depending on age, weight, and parity, with the greatest reduction for young, thin, nulliparous women.
The removal of one ovary also reduces the risk of breast cancer but to a lesser degree than does the removal of both ovaries.
Other hormonal changes also influence breast cancer risk. (Refer to the Early pregnancy and Breast-feeding sections in the Factors With Adequate Evidence of Decreased Risk of Breast Cancer section of this summary for more information.)
The interaction of endogenous estrogen levels, insulin levels, and obesity—all of which affect breast cancer risk—are poorly understood but suggest strategies for interventions to decrease that risk. It is likely that reproductive risk factors interact with predisposing genotypes. For example, in the Nurses’ Health Study,
the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only among women without a family history of breast cancer in a mother or sister.
Breast cancer risk increases in women with a positive family history, particularly if first-degree relatives are affected.
The following risk assessment models, derived from databases, cohort, and case-control studies, quantitate this risk:
Specific abnormal alleles are associated with approximately 5% of breast cancers. (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.) Mutations in BRCA genes are inherited in an autosomal dominant fashion and are highly penetrant in causing cancer, often at a younger age.
Family history and mutation location within the BRCA1 or BRCA2 gene may contribute to the risk of cancer development among those with an inherited predisposition to breast cancer.
The lifetime risk of breast cancer is 55% to 65% for BRCA1 mutation carriers and 45% to 47% for BRCA2 mutation carriers.
In comparison, the lifetime risk of breast cancer is 12.4% in the general population.
Some women inherit a susceptibility to mutagens or growth factors, which increase breast cancer risk.
(Refer to the Ionizing radiation exposure section in the Factors With Adequate Evidence of Increased Risk of Breast Cancer section of this summary for more information.)
Widespread use of screening mammograms has revealed varying amounts of mammographically dense tissue and that women with a greater proportion of dense tissue have a higher incidence of breast cancer. Mammographic density also confounds the identification of cancers by that technology. The extent of increased risk was described in a report of three nested case-control studies in screened populations with 1,112 matched case-control pairs. Compared with women with density comprising less than 10% of breast tissue, women with density in 75% or more of their breast had an increased risk of breast cancer (odds ratio [OR], 4.7; 95% confidence interval [CI], 3.0–7.4), whether the cancer was detected by screening (OR, 3.5; 95% CI, 2.0–6.2) or detected less than 12 months after a negative screening examination (OR, 17.8; 95% CI, 4.8–65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger women than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were identified in women with mammographic breast density of 50% or more.
Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased breast density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.
There is no increased risk of breast cancer mortality among women with dense breast tissue.
Based on a 1997 reanalysis of 51 epidemiological studies encompassing more than 150,000 women, hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk.
The Heart and Estrogen/Progestin Replacement Study supported this finding in 2002.
In this study, 2,763 women with coronary heart disease at a mean age of 67 years were randomly assigned to receive either estrogen and progestin therapy or placebo. After a mean follow-up of 6.8 years, the RR for breast cancer was 1.27 (95% CI, 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women’s Health Initiative (WHI), also published in 2002.
The WHI investigated the effect of hormones and dietary interventions on heart disease and breast cancer risk.
Women aged 50 to 79 years with intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). The trial was terminated early because combined HT did not decrease coronary heart disease risk but did increase the risk of stroke and breast cancer. An increased rate of invasive breast cancer risk (hazard ratio [HR], 1.24; 95% CI, 1.02–1.50), but not for in situ breast cancer, was observed in all subgroups of women. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu, with a trend toward larger size and higher incidence of lymph node metastases in the combined HT group.
Extended follow-up of a mean of 11 years showed higher breast cancer–specific mortality for the HT group (25 vs. 12 deaths, 0.03% vs. 0.01% per year; HR, 1.95; 95% CI, 1.0–4.04; P = .049). Combined HT was also associated with a higher percentage of abnormal mammograms.
The WHI observational study was conducted in parallel with the WHI randomized controlled trial (RCT), recruiting postmenopausal women aged 50 to 79 years. An analysis was conducted in the observational study of the WHI to further examine the prognosis of women taking combination HT who were diagnosed with breast cancer and the risks based on time between menopause and initiation of HT. After a mean follow-up of 11.3 years, the annualized incidence of breast cancer among women using estrogen plus progestin was 0.60%, compared with 0.42% among nonusers (HR, 1.55; 95% CI, 1.41–1.70). Survival after the diagnosis of breast cancer was similar for combined HT users and nonusers. Death from breast cancer was higher among combined HT users than among nonusers, but the difference was not statistically significant (HR, 1.3; 94% CI, 0.90–1.93). Risks were highest among women initiating HT at the time of menopause, and risks diminished but persisted with increasing time between menopause and starting combination HT. All-cause mortality after the diagnosis of breast cancer was statistically significantly higher among combined HT users than among nonusers (HR, 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT.
The WHI also studied women who had previously undergone a hysterectomy and thus were not at risk for endometrial cancer, which is associated with unopposed estrogen therapy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive conjugated equine estrogen (CEE) or placebo. This trial was also stopped early because of an increased risk of stroke and no improvement in a global risk-benefit index.
After an average 6.8 years of follow-up, breast cancer incidence was lower in the group receiving CEE (0.26% per year vs. 0.33%; HR, 0.77; 95% CI, 0.59–1.01). The global risk-benefit index was slightly worse for CEE.
An extended follow-up for a median of 11.8 years included 78% of the trial participants. Results seen in the initial study persisted, with a similar risk reduction for breast cancer in CEE recipients (HR, 0.77; 95% CI, 0.62–0.95) and a decrease in breast cancer mortality (6 vs. 16 deaths; HR, 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% vs. 0.076% per year; HR, 0.62; 95% CI, 0.39–0.97). After CEE was discontinued, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no difference in the incidence of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer.
Breast cancer incidence was similar for women who initiated CEE or placebo within the first 5 years after onset of menopause (HR, 1.06; 95% CI, 0.74–1.51).
A Danish trial of HT for 1,006 women entering menopause was designed to evaluate cardiovascular outcomes. Combined HT (triphasic estradiol and norethisterone) was given to 407 women with intact uteri, and estradiol was given to 95 women who had undergone hysterectomy. Controls (407 with intact uteri and 97 with hysterectomy) were not treated. At 10 years, there was considerable contamination. Only one-half of the women assigned to the HT group were still taking the prescribed HT, and 22% of the control women had begun HT. Cardiovascular outcomes favored HT-treated women, and there was no difference in breast cancer incidence.
Observational studies augment the information obtained in RCTs.
The Million Women Study
recruited 1,084,110 women aged 50 to 64 years in the United Kingdom between 1996 and 2001 and obtained information about HT use and other personal details. The women were followed for breast cancer incidence and death. One-half of the women had used HT. At 2.6 years of follow up, there were 9,364 invasive breast cancers; at 4.1 years, there were 637 breast cancer deaths. Current users of HT at recruitment were more likely than never-users to develop breast cancer (adjusted RR = 1.66; 95% CI, 1.58–1.75; P < .0001) and to die from the disease (adjusted RR, 1.22; 95% CI, 1.00–1.48; P = .05). Past users of HT were, however, not at an increased risk of incident or fatal breast cancer (1.01 [95% CI, 0.94–1.09] and 1.05 [95% CI, 0.82–1.34], respectively). Incidence was significantly increased for current users of estrogen only (RR, 1.30; 95% CI, 1.21–1.40; P < .0001), combined HT (RR, 2.00; 95% CI, 1.88–2.12; P < .0001), and tibolone (RR, 1.45; 95% CI, 1.25–1.68; P < .0001). The magnitude of the associated risk was substantially greater for combined HT than for other types of HT (P < .0001).
A population-based survey of 965 women with breast cancer and 1,007 controls was conducted by the Cancer Surveillance System of Puget Sound. It showed that combined HT users had a 1.7-fold increased risk of invasive breast cancer, whereas estrogen-only users did not.
The association between the use of combined HT and increased breast cancer risk is consistent throughout all the trials. In contrast, the association between estrogen-only HT and breast cancer incidence is confusing because some studies show increased risk and some show protection. It is possible that the timing of estrogen-only HT in relation to the onset of menopause is critical. Furthermore, observational studies may not account for different screening behavior between HT users and nonusers, whereas RCTs, by design, will control that variable.
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of WHI participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening.
Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003 among women aged 50 years and older, especially for ER–positive cancers.
Similarly, in multiple countries where HT use was high, breast cancer rates decreased in a similar time frame, coincident with decreases in prescribing patterns and/or reported prevalence of use.
A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates.
After the decline in breast cancer incidence from 2002 to 2003, rates in the United States stabilized.
A well-established relationship exists between exposure to ionizing radiation and subsequent breast cancer.
Excess breast cancer risk has been observed in association with atomic bomb exposure, frequent fluoroscopy for tuberculosis, and radiation therapy for acne, tinea, thymic enlargement, postpartum mastitis, and lymphoma. Risk is higher for the young, especially around puberty. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total.
However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure.
A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer even more (RR, 1.54; 95% CI, 1.1–2.1), especially for women who had x-rays before age 20 years.
Women treated for Hodgkin lymphoma by age 16 years have a subsequent risk up to 35% of developing breast cancer by age 40 years.
Higher radiation doses (median dose, 40 Gy in breast cancer cases) and treatment between the ages of 10 and 16 years are associated with higher risk.
Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer does not abate with duration of follow-up, persisting more than 25 years after treatment.
In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.
A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than were those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR, 0.06; 95% CI, 0.01–0.45).
Another study of 105 radiation-associated breast cancer patients and 266 age-matched and radiation-matched controls showed a similar protective effect for ovarian radiation.
These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.
The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at higher risk for second breast malignancies or other malignancies than are those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with outcomes of 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies.
Further evidence from three RCTs is also reassuring. One report of 1,851 women randomly assigned to undergo total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively.
Another study of 701 women randomly assigned to undergo radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas per 100 woman-years to be 10.2 versus 8.7, respectively.
The third study compared 25-year outcomes of 1,665 women randomly assigned to undergo radical mastectomy, total mastectomy, or total mastectomy with radiation. There was no significant difference in the rate of contralateral breast cancer according to treatment group, and the overall rate was 6%.
Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observed 85,917 women aged 50 to 79 years and collected information on weight history and known risk factors for breast cancer.
Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.81–4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.
The association between obesity, diabetes, and insulin levels with breast cancer risk have been studied but not clearly defined. The British Women’s Heart and Health Study of women aged 60 to 79 years compared 151 women who had a diagnosis of breast cancer with 3,690 women who did not. The age-adjusted OR was 1.34 (95% CI, 1.02–1.77) for each unit increase in log(e) insulin level among nondiabetic women. The association was observed, after adjustment for confounders and for potential mediating factors, for both pre- and postmenopausal breast cancers. In addition, fasting glucose level, homeostatic model assessment score (the product of fasting glucose and insulin levels divided by 22.5), diabetes, and a history of gestational glycosuria or diabetes were also associated with breast cancer.
Alcohol consumption increases the risk of breast cancer. A British meta-analysis included individual data from 53 case-control and cohort studies.
Compared with the RR of breast cancer for women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.19–1.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%–8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. These findings persist after stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.
Childbirth is followed by an increase in risk of breast cancer for several years, and then a long-term reduction in risk, which is greater for younger women.
In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women whose first full-term pregnancy occurred at age 35 years or older.
The association of childbirth with breast cancer risk was demonstrated by the International Premenopausal Breast Cancer Collaborative Group, which undertook a pooled analysis of individual-level data from about 890,000 women from 15 prospective cohort studies. When compared with nulliparous women, parous women had an increased risk of developing both ER–positive and ER–negative breast cancer for up to 20 years after childbirth. However, after about 24 years, the risk of developing ER–positive breast cancer decreased, but the risk of developing ER–negative breast cancer remained elevated. Thus, the association between parity and breast cancer risk is complex and appears to be influenced by the time period after childbirth and tumor phenotype.
Breast-feeding is associated with a decreased risk of breast cancer.
A reanalysis of individual data from 47 epidemiological studies in 30 countries of 50,302 women with breast cancer and 96,973 controls revealed that breast cancer incidence was lower in parous women who had ever breast-fed than in parous women who had not. It was also proportionate to duration of breast-feeding.
The RR of breast cancer decreased by 4.3% (95%, CI, 2.9%–5.8%; P < .0001) for every 12 months of breast-feeding in addition to a decrease of 7.0% (95% CI, 5.0%–9.0%; P < .0001) for each birth.
Active exercise may reduce breast cancer risk, particularly in young parous women.
Numerous observational studies on the relationship between the level of physical activity and breast cancer risk have shown an inverse relationship.
The average RR reduction is 30% to 40%, but confounding variables—such as diet or a genetic predisposition to breast cancer—have not been addressed. A prospective study of more than 25,000 Norwegian women found that heavy manual labor or at least 4 hours of exercise per week is associated with decreased breast cancer risk, especially in premenopausal women and those of normal or lower-than-normal body weight.
In a case-control study of African American women, strenuous recreational physical activity more than 7 hours per week was associated with decreased breast cancer incidence.
Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents new primary contralateral breast cancers.
Tamoxifen also maintains bone density among postmenopausal women with breast cancer.
Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.
These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 patients at elevated risk of breast cancer to receive tamoxifen or placebo.
The study was closed early because of a 49% reduction in the incidence of breast cancer for the tamoxifen group (85 vs. 154 invasive breast cancer cases and 31 vs. 59 in situ cases at 4 years). Tamoxifen-treated women also had fewer fractures (47 vs. 71) but more endometrial cancer (33 vs. 14 cases) and thrombotic events (99 vs. 70), including pulmonary emboli (17 vs. 6).
An update of the BCPT results after 7 years of follow-up demonstrated results similar to those in the initial report.
There were some dropouts among women in the placebo arm; some of them enrolled in a subsequent trial, so new women were added to the placebo group. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of fewer fractures and persistent increased risk of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR, 1.10; 95% CI, 0.85–1.43).
Three other trials of tamoxifen for primary prevention of breast cancer have been completed.
A meta-analysis of these primary prevention tamoxifen trials showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.
ER-positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR, 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR, 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for contralateral breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-24 addressed their management. Women were randomly assigned to receive L-RT either with or without adjuvant tamoxifen. At 6 years, the tamoxifen-treated women had fewer invasive and in situ breast cancers (8.2% vs. 13.4%; RR, 0.63; 95% CI, 0.47–0.83). The risk of contralateral breast cancer was also lower in women treated with tamoxifen (RR, 0.49; 95% CI, 0.26–0.87).
Raloxifene hydrochloride (Evista) is a SERM that has antiestrogenic effects on breast and estrogenic effects on bone, lipid metabolism, and blood clotting. Unlike tamoxifen, it has antiestrogenic effects on the endometrium.
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, double-blind trial that evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. Vertebral fractures were reduced. The effect on breast cancer incidence was a secondary endpoint. After a median follow-up of 47 months, the risk of invasive breast cancer decreased in the raloxifene-treated women (RR, 0.25; 95% CI, 0.17–0.45).
As with tamoxifen, raloxifene reduced the risk of ER-positive breast cancer but not ER-negative breast cancer and was associated with an excess risk of hot flashes and thromboembolic events. No excess risk of endometrial cancer or hyperplasia was observed after 47 months of follow-up.
An extension of the MORE trial was the Continuing Outcomes Relevant to Evista (CORE) trial, which studied about 80% of MORE participants in their randomly assigned groups for an additional 4 years. Although there was a median 10-month gap between the two studies, and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive ER-positive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR, 0.34; 95% CI, 0.22–0.50); the reduction for ER-positive invasive breast cancer was 76% (HR, 0.24; 95% CI, 0.15–0.40).
The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. As in the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR, 0.56; 95% CI, 0.38–0.83).
The Study of Tamoxifen and Raloxifene (STAR) (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women who were monitored for a mean of 3.9 years. Invasive breast cancer incidence was approximately the same for both drugs, but there were fewer noninvasive cancers in the tamoxifen group. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures.
Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain occurred less frequently in tamoxifen-treated women, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps occurred less frequently in those receiving raloxifene.
| Tamoxifen | Raloxifene | RR, 95% CI | |
|---|---|---|---|
| Invasive breast cancer | 4.3 | 4.41 | 1.02, 0.82–1.28 |
| Noninvasive breast cancer | 1.51 | 2.11 | 1.4, 0.98–2.00 |
| Uterine cancer | 2.0 | 1.25 | 0.62, 0.35–1.08 |
| VTE | 3.8 | 2.6 | 0.7, 0.68–0.99 |
| Cataracts | 12.3 | 9.72 | 0.79, 0.68–0.92 |
| Incidence of Symptoms (0–4 scale) | |||
| Favor Tamoxifen | |||
| Dyspareunia | 0.68 | 0.78 | P < .001 |
| Musculoskeletal problems | 1.10 | 1.15 | P = .002 |
| Weight gain | 0.76 | 0.82 | P < .001 |
| Favor Raloxifene | |||
| Vasomotor symptoms | 0.96 | 0.85 | P < .001 |
| Bladder control symptoms | 0.88 | 0.73 | P < .001 |
| Leg cramps | 1.10 | 0.91 | P < .001 |
| Gynecologic problems | 0.29 | 0.19 | P < .001 |
| CI = confidence interval; RR = relative risk; VTE = venous thromboembolism. | |||
Another class of agents that is commercially available for the treatment of women with hormone-sensitive breast cancer may also prevent breast cancer. These drugs interfere with aromatase, the adrenal enzyme that allows estrogen production in postmenopausal women. Anastrozole and letrozole inhibit aromatase activity, whereas exemestane inactivates the enzyme. Side effects for all three drugs include fatigue, arthralgia, myalgia, decreased bone mineral density, and increased fracture rate.
Women with a previous diagnosis of breast cancer have a lower risk of recurrence and of new breast cancers when treated with AIs, as shown in the following studies:
Aromatase inhibitors or inactivators also have been shown to prevent breast cancer in women at increased risk, as shown in the following studies:
A retrospective cohort study evaluated the impact of bilateral prophylactic mastectomy on breast cancer incidence among women at high and moderate risk on the basis of family history.
BRCA mutation status was not known. Subcutaneous, rather than total, mastectomy was performed in 90% of these women. After a median follow-up of 14 years postsurgery, the risk reduction for the 425 moderate-risk women was 89%; for the 214 high-risk women, it was 90% to 94%, depending on the method used to calculate expected rates of breast cancer. The risk reduction for breast cancer mortality was 100% for moderate-risk women and 81% for high-risk women. Because the study used family history as a risk indicator rather than genetic testing, breast cancer risk may be overestimated.
The rate of bilateral mastectomy among women with unilateral disease (DCIS and early-stage invasive breast cancer) was reported to have increased from 1.9% in 1998 to 11.2% in 2011 based on data from the U.S. National Cancer Data Base.
No studies have been done on the benefits of prophylactic mastectomy in the average-risk population to prevent contralateral breast cancer in women with an ipsilateral breast cancer.
Ovarian ablation and oophorectomy are associated with decreased breast cancer risk in normal women and in women with increased risk resulting from thoracic irradiation. (Refer to the Endogenous estrogen section in the Description of the Evidence section of this summary for more information.) Observational studies of women with high breast cancer risk resulting from BRCA1 or BRCA2 gene mutations showed that prophylactic oophorectomy to prevent ovarian cancer was also associated with a 50% decrease in breast cancer incidence.
These studies are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use. A prospective cohort study had similar findings, with a greater breast cancer risk reduction in BRCA2 mutation carriers than in BRCA1 carriers.
Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time.
A well-conducted case-control study did not observe an association between breast cancer risk and oral contraceptive use for every use, duration of use, or recency of use.
Another case-control study found no increased risk of breast cancer associated with the use of injectable or implantable progestin-only contraceptives in women aged 35 to 64 years.
A nationwide prospective cohort study in Denmark found that women who currently or recently used contemporary hormonal contraceptives had a higher risk of breast cancer than did women who had never used hormonal contraceptives. Moreover, the risk of breast cancer increased with longer duration of hormonal contraceptive use. However, in absolute terms, the effect of oral contraceptives on breast cancer risk was very small. Thus, approximately one extra case of breast cancer would be expected for every 7,690 women using hormonal contraception for 1 year.
Occupational, environmental, or chemical exposures have all been proposed as causes of breast cancer. Meta-analyses, describing up to 134 environmental chemicals, their sources, and biomarkers of their exposures, suggest that they may be associated with cancer.
Some studies suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk,
but other case-control and nested case-control studies do not.
Studies reporting positive associations have been inconsistent in the identification of responsible organochlorines. Some of these substances have weak estrogenic effects, but their effect on breast cancer risk remains unproven. The use of dichloro-diphenyl-trichloroethane was banned in the United States in 1972, and the production of polychlorinated biphenyls was stopped in 1977. Overall, the epidemiological and animal study evidence that support an association between breast cancer and specific environmental exposures is generally weak. Because so many factors must be considered, any associations with breast cancer or other cancers could be confounded by the analytical problems of multiplicities, measurement challenges, and recall and publication bias.
Abortion has been proposed as a risk factor for breast cancer. Findings from observational studies have varied; some studies showed an association, while other studies did not. Observational studies that support this association were less rigorous and potentially biased because of differential recall by women on a socially sensitive issue.
For example, the impact of recall or reporting bias was demonstrated in a study that compared regions with different social attitudes on abortion.
The Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists has concluded that “more rigorous recent studies demonstrate no causal relationship between induced abortion and a subsequent increase in breast cancer risk.”
Studies that used prospectively recorded data regarding abortion, thereby avoiding recall bias, largely showed no association with the subsequent development of breast cancer.
Any effect of dietary modifications on breast cancer would likely depend on the type of modification. However, there is little evidence that dietary modifications of any kind have an impact on the incidence of breast cancer.
There are very few randomized trials in humans comparing cancer incidence for different diets. Most studies are observational—including post hoc analyses of randomized trials—and are subject to biases that may be so large as to render the observation difficult to interpret. In particular, p-values and CIs do not have the same interpretation as when calculated for the primary endpoint in a randomized trial.
A summary of ecological studies published before 1975 showed a positive correlation between international age-adjusted breast cancer mortality rates and the estimated per capita consumption of dietary fat.
Results of case-control studies have been mixed. Twenty years later, a pooled analysis of results from seven cohort studies found no association between total dietary fat intake and breast cancer risk.
A randomized, controlled, dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20% by increasing vegetable, fruit, and grain consumption. The intervention group reduced fat intake by approximately 10% for more than 8.1 years of follow-up, resulting in lower estradiol and gamma-tocopherol levels, but no persistent weight loss. The incidence of invasive breast cancer was numerically, but not statistically lower in the intervention group, with an HR of 0.91 (95% CI, 0.83–1.01).
There was no difference in all-cause mortality, overall mortality, or the incidence of cardiovascular events.
With regard to fruit and vegetable intake, a pooled analysis of eight cohort studies including more than 350,000 women with 7,377 incident breast cancers showed little or no association for various assumed statistical models.
The Women's Healthy Eating and Living Randomized Trial
examined the effect of diet on the incidence of new primary breast cancers in women previously diagnosed with breast cancer. More than 3,000 women were enrolled and randomly assigned to an intense regimen of increased fruit and vegetable intake, increased fiber intake, and decreased fat intake, or a comparison group receiving printed materials on the “5-A-Day” dietary guidelines. After a mean of 7.3 years of follow-up, there was no reduction in new primary cancers, no difference in disease-free survival, and no difference in overall survival.
A randomized trial in Spain
assigned participants who were at high cardiovascular risk to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control Mediterranean diet (counseling to reduce dietary fat). The investigators reported a statistically significant reduction in major cardiovascular events, which was the trial’s primary endpoint.
The investigators also addressed other endpoints, including the incidence of breast cancer, although it is not specified how many were examined. Based on only 35 cases of invasive breast cancer (as compared with 288 major cardiovascular events), the respective rates of breast cancer were 8 of 1,476 (0.54%); 10 of 1,285 (0.78%); and 17 of 1,391 (1.22%) with respective average follow-up durations of 4.8, 4.3, and 4.2 years. The circumstances of the study make it difficult to determine the statistical significance of these differences.
The potential role of specific micronutrients for breast cancer risk reduction has been examined in clinical trials, with cardiovascular disease and cancer as outcomes. The Women’s Health Study, a randomized trial with 39,876 women, found no difference in breast cancer incidence at 2 years between women assigned to take either beta carotene or placebo.
In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day.
The Women’s Antioxidant Cardiovascular Study examined 8,171 women for incidence of total cancer and invasive breast cancer and found no effect for vitamin C, vitamin E, or beta carotene.
Two years later, a subset of 5,442 women were randomly assigned to take 1.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or placebo. After 7.3 years, there was no difference in the incidence of total invasive cancer or invasive breast cancer.
Fenretinide
is a vitamin A analog that has been shown to reduce breast carcinogenesis in preclinical studies. A phase III Italian trial compared the efficacy of a 5-year intervention with fenretinide versus no treatment in 2,972 women, aged 30 to 70 years, with surgically removed stage I breast cancer or DCIS. At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P = .642), ipsilateral breast cancer (P = .177), incidence of distant metastases, nonbreast malignancies, and all-cause mortality.
The potential role of active cigarette smoking in the etiology of breast cancer has been studied for more than three decades, with no clear-cut evidence of an association.
Since the mid-1990s, studies of cigarette smoking and breast cancer have more carefully accounted for secondhand smoke exposure.
A recent meta-analysis suggests that there is no overall association between passive smoking and breast cancer and that study methodology (ascertainment of exposure after breast cancer diagnosis) may be responsible for the apparent risk associations seen in some studies.
Despite warnings to women in lay publications that underarm deodorants and antiperspirants cause breast cancer, there is no evidence to support these concerns. A study based on interviews with 813 women who had breast cancer and 793 controls found no association between the risk of breast cancer and the use of antiperspirants, the use of deodorants, or the use of blade razors before these products were applied.
In contrast, a study of 437 breast cancer survivors found that women who used antiperspirants/deodorants and shaved their underarms more frequently had cancer diagnosed at a significantly younger age. A possible explanation for this finding is that these women had an earlier menarche or higher levels of endogenous hormones, both known to be risk factors for breast cancer and to increase body hair.
Two well-conducted meta-analyses of RCTs
and RCTs plus observational studies
found no evidence that statin use either increases or decreases the risk of breast cancer.
Oral and intravenous bisphosphonates for the treatment of hypercalcemia and osteoporosis have been studied for a possible beneficial effect on breast cancer prevention. Initial observational studies suggested that women who used these drugs for durations of approximately 1 to 4 years had a lower incidence of breast cancer.
These findings are confounded by the fact that women with osteoporosis have lower breast cancer risk than those with normal bone density. Additional evidence came from studies of women with a breast cancer diagnosis; the use of these drugs was associated with fewer new contralateral cancers.
With this background, two large randomized placebo-controlled trials were done. The Fracture Intervention Trial (FIT) treated 6,194 postmenopausal osteopenic women with either alendronate or placebo and found no difference at 3.8 years in breast cancer incidence, with incidence of 1.8% and 1.5%, respectively (HR, 1.24; CI, 0.84–1.83). The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PRT) examined 7,580 postmenopausal osteoporotic women with either intravenous zoledronate or placebo and found no difference at 2.8 years in breast cancer incidence, with incidence of 0.8% and 0.9%, respectively (HR, 1.15; CI, 0.7–1.89).
In 2007, the World Health Organization’s International Agency for Research on Cancer (IARC) classified shift work that involves circadian disruption as a probable breast carcinogen. The principal evidence was from animal studies. There was limited evidence from human studies at the time.
In 2013, a meta-analysis of 15 epidemiologic studies concluded that there was weak evidence of an increased incidence of breast cancer among women who had ever worked night shifts.
In 2016, the results from three recent prospective studies from the United Kingdom, involving nearly 800,000 women, were combined with results from seven other prospective studies and showed no evidence of any association between breast cancer incidence and night shift work. In particular, the confidence intervals for the incidence rate ratios were narrow, even for 20 years or more of night shift work (rate ratio, 1.01; 95% CI, 0.93–1.10). These results exclude a moderate association of breast cancer incidence with long duration of night shift work.
The U.K. Generations Study was established in 2003 to address risk factors and causes of breast cancer. In a prospective cohort of 105,000 women, information was obtained by questionnaire on bedroom light levels at night at the time of study recruitment and at age 20 years. They followed women for an average of 6.1 years and observed 1,775 breast cancers. Adjusting for potentially confounding factors, including night shift work, they found no evidence that the amount of bedroom light at night was associated with breast cancer risk. For the highest-to-lowest levels of light at night, the HR of breast cancer incidence was 1.01 (95% CI, 0.88–1.15).
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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PDQ® Screening and Prevention Editorial Board. PDQ Breast Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated
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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Breast Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.