Breast Cancer Risk Factors
24/03/2015 Breast Cancer Risk Factors Breast Cancer Risk Factors Author: Alison T Stopeck, MD; Chief Editor: Jules E Harris, MD more... Updated: Jul 21, 2014 Practice Essentials Numerous risk factors have been found to increase a woman’s risk of developing breast cancer The common denominator for many of them is their effect on the level and duration of exposure to endogenous estrogen. Evidence from the Cancer Genome Atlas Network showed that the 4 main breast cancer subtypes (hER2enriched, luminal A, luminal B and basallike) are caused by different subsets of genetic and epigenetic aberrations. [1] See the image below. Intrinsic subtypes of breast cancer. Essential update: Potential link between hyperlipidemia and elevated breast cancer risk In a retrospective analysis of data on 664,159 women in the United Kingdom, Potluri et al found that the incidence of breast cancer was higher in those with elevated cholesterol levels than in those with than normal cholesterol levels (2.3% vs 1.4%) and that hyperlipidemia increased the risk of developing breast cancer by 1.64 times (95% confidence interval, 1.501.79). [2, 3] The researchers cautioned, however, that these results are preliminary and that the study did not control for obesity, which is a known risk factor for breast cancer. Risk factors Factors that increase the risk of breast cancer include the following: Advanced age Family history of cancer in a firstdegree relative – Family history of ovarian cancer at < 50 years, 1 first degree relative with breast cancer, ≥2 firstdegreerelatives with breast cancer Personal history – Positive BRCA1/BRCA2 mutation, breast biopsy with atypical hyperplasia, breast biopsy with lobular or ductal carcinoma in situ Reproductive history – Early menarche (< 12 years), late menopause, late age of first term pregnancy (>30 years) or nulliparity Use of estrogenprogesterone hormone replacement therapy (HRT) Current or recent oral contraceptive use Lifestyle factors – Adult weight gain, sedentary lifestyle, alcohol consumption Risk models used in breast cancer include (1) BRCA probability tools and (2) models for predicting absolute risk of developing breast cancer over time. BRCA probability tools include the following: BRCAPRO model Myriad I and II Manchester Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) Ontario Family History Assessment Tool (FHAT) Breast cancer risk prediction tools include the following: Gail model Gail model 2 (used as the basis for eligibility for a number of the breast cancer prevention trials) Women’s Contraceptive and Reproductive Experiences (CARE) model (developed to address concerns regarding applicability of the Gail model to black women) Overview Epidemiologic studies have identified many risk factors that increase the chance of a woman developing breast cancer (see Table 1, below). Many of these factors form the basis of breast cancer risk assessment tools. The common denominator for many of these risk factors is their effect on the level and duration of exposure to endogenous estrogen. For example, early menarche, nulliparity, and late menopause increase lifetime exposure to estrogen in premenopausal women, whereas obesity and hormone replacement therapy (HRT) increase estrogen levels in postmenopausal women. The increased risk in obese women is probably due to adipose conversion of androgens to estrogens. A study by Goss et al found that exemestane significantly reduced invasive breast cancers among postmenopausal women who had a moderately increased risk of breast cancer. [4] A study by Bouchardy et al examined the risk of second breast cancer after a first primary estrogen receptor (ER) negative breast cancer. The results indicated that the risk of second ERnegative breast cancer is high after a first http://emedicine.medscape.com/article/1945957overview 1/6 24/03/2015 Breast Cancer Risk Factors ERnegative tumor; this is particular the case among women with a strong family history. [5] Table 1. Risk Factors for Breast Cancer (Open Table in a new window) Risk Factors Advanced age Estimated Relative Risk >4 Family history Family history of ovarian cancer in women < 50y One firstdegree relative Two or more relatives (mother, sister) >5 >2 >2 Personal history Personal history Positive BRCA1/BRCA2 mutation Breast biopsy with atypical hyperplasia Breast biopsy with LCIS or DCIS Reproductive history Early age at menarche (< 12 y) Late age of menopause Late age of first term pregnancy (>30 y)/nulliparity 34 >4 45 810 2 1.52 2 Use of combined estrogen/progesterone HRT 1.52 Current or recent use of oral contraceptives 1.25 Lifestyle factors Adult weight gain Sedentary lifestyle Alcohol consumption 1.52 1.31.5 1.5 DCIS = ductal carcinoma in situ; HRT = hormone replacement therapy; LCIS = lobular carcinoma in situ. For more information, see Breast Cancer, as well as Breast Cancer Screening and the figure below. Intrinsic subtypes of breast cancer. Increasing Age Age is the most significant risk factor for breast cancer, with breast cancer being rare in women younger than 25 years. Incidence increases with increasing age, with a plateau in women aged 5055 years. Family History A family history of breast cancer in a firstdegree relative is the most widely recognized breast cancer risk factor. The lifetime risk is up to 4 times higher if a mother and sister are affected; the risk is approximately 5 times greater in women with 2 or more firstdegree relatives with breast cancer; and it is also greater among women with a single firstdegree relative, particularly if they were diagnosed at an early age (50 y or younger). A family history of ovarian cancer in a firstdegree relative, especially if the disease occurred at an early age (< 50 y), has been associated with a doubling of breast cancer risk. The family history characteristics that suggest increased risk of cancer are summarized as follows: One or more relatives with breast or ovarian cancer Breast cancer occurring in an affected relative younger than 50 years http://emedicine.medscape.com/article/1945957overview 2/6 24/03/2015 Breast Cancer Risk Factors Male relatives with breast cancer BRCA1 and BRCA2 mutations Ataxiatelangiectasia heterozygotes (4 times’ increased risk) Ashkenazi Jewish descent (2 times’ greater risk) Genetic Factors Although 2030% of women with breast cancer have at least one relative with a history of breast cancer, only 510% of women with breast cancer have an identifiable hereditary predisposition. BRCA1 and BRCA2 mutations are responsible for 38% of all cases of breast cancer and 1520% of familial cases. Rare mutations are seen in the PTEN, TP53, MLH1, MLH2, and STK11 genes. Evidence from the Cancer Genome Atlas Network showed that the 4 main breast cancer subtypes (hER2enriched, luminal A, luminal B and basallike) are caused by different subsets of genetic and epigenetic aberrations. Interestingly, breast basallike tumors shared a number of molecular characteristics common to ovarian cancer such as the types and frequencies of genomic mutations, suggesting a related etiology and potentially similar responsiveness to some of the same therapies. The BRCA1 and BRCA2 gene mutations, on chromosomes 17 and 13, respectively, account for the majority of autosomal dominant inherited breast cancers. Both genes are believed to be tumor suppressor genes whose products are involved with maintaining DNA integrity and transcriptional regulation. Mutation rates may vary by ethnic and racial groups. For BRCA1 mutations, the highest rates occur among Ashkenazi Jewish women (8.3%), followed by Hispanic women (3.5%), nonHispanic white women (2.2%), black women (1.3%), and Asian women (0.5%). Moreover, 95% of Ashkenazi Jews with a BRCA gene mutation will have 1 of the 3 founder mutations (185delAG, 538insC in BRCA1; 6174delT in BRCA2). Women who inherit a mutation in the BRCA1 or BRCA2 gene have an estimated 50 80% lifetime risk of developing breast cancer. Specifically, BRCA1 mutations are seen in 7% of families with multiple breast cancers and 40% of families with breast and ovarian cancer. Women with a BRCA1 mutation have a 40% lifetime risk of developing ovarian cancer. Breast cancers that develop in BRCA1 mutation carriers are more likely to be high grade, as well as estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2negative (triple negative) or basallike subtype. BRCA1 mutations are also associated with a higher risk of colon cancer and prostate cancer. BRCA2 mutations are identified in 1020% of families at high risk for breast and ovarian cancers and in only 2.7% of women with earlyonset breast cancer. Women with a BRCA2 mutation have an approximately 10% lifetime risk of ovarian cancer. BRCA2 mutation carriers who develop breast cancer are more likely to have a highgrade, ERpositive, PRpositive, and HER2negative cancer (luminal type). BRCA2 is also a risk factor for male breast cancer. Other cancers associated with BRCA2 mutations include prostate, pancreatic, fallopian tube, bladder, nonHodgkin lymphoma, and basal cell carcinoma. LiFraumeni syndrome, caused by TP53 mutations , is responsible for approximately 1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. LiFraumeni syndrome is also associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with a 90% lifetime risk of breast cancer. Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with intestinal hamartoma, cutaneous lesions, and thyroid cancer. There is about a 30% prevalence rate of breast cancer in women with this disease. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic lesions, ductal epithelial hyperplasia, and nipple malformations) are also common. Other rare genetic disorders, such as PeutzJeghers syndrome and hereditary nonpolyposis colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer. The table below lists genetically determined breast cancer syndromes. A study by Mangoni et al found an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in patients with breast cancer. The authors propose a hypothesis that mismatch repair mechanisms may be involved in the cellular response to radiotherapy and that genetic polymorphisms warrant further study as candidates for predicting acute radiosensitivity. [6] Table 2. Genetic Breast Cancer Syndromes (Open Table in a new window) Syndrome Gene Inheritance Cancers Other Features Breast/ovarian BRCA1 AD Breast, ovarian Cancer syndrome BRCA2 AD Breast, ovarian, prostate, pancreatic LiFraumeni syndrome TP53 AD Breast, brain, softtissue sarcomas, leukemia, adrenocortical, others Cowden disease PTEN AD Breast, ovary, follicular thyroid, colon Adenomas of thyroid, fibroids, GI polyps PeutzJeghers STKII/LKB1 AD syndrome GI, breast Hamartomas of bowel, pigmentation of buccal mucosa Ataxia ATM telangiectasia AD Breast Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias Sitespecific CHEK2 AD Breast Low penetrance MuirTorre syndrome MSH2/MLH1 AD Fanconi anemia in homozygotes Colorectal, breast AD = autosomal dominant; GI = gastrointestinal. Neoplastic and Benign Risk Factors Neoplastic conditions that increase the risk of breast cancer include the following: Previous breast cancer Ovarian cancer http://emedicine.medscape.com/article/1945957overview 3/6 24/03/2015 Breast Cancer Risk Factors Endometrial cancer Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS) Benign breast conditions that increase the risk of breast cancer include the following: Hyperplasia (unless mild) Complex fibroadenoma Radial scar Papillomatosis Sclerosing adenosis Microglandular adenosis Cervical cancer is associated with a decreased risk of breast cancer. Exogenous Hormones One of the most widely studied risk factors in breast cancer is the use of exogenous hormones in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT). The overall evidence suggests a modest increased risk among current users of oral contraceptives. Risk is increased 1.24 times for 10 years’ use, normalizing 10 years after discontinuation; the progesteroneonly pill is not associated with increased risk. [7] Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT. Risk is increased 1.35 times for 5 or more years of HRT use, normalizing 5 years from discontinuing. [8] Risk is directly associated with length of exposure, with the greatest risk observed for the development of hormonally responsive lobular, mixed ductallobular, and tubular cancers. [9] In the Women’s Health Initiative (WHI), the incidence of breast cancer was greater in women taking combination estrogen plus progestin formulations than in those taking estrogenonly formulations, and the cancers in women taking combination HRT were more commonly nodepositive. Combination HRT also appears to be associated with increased mortality. [10] Published results of the WHI of estrogenonly and combinationHRT for the prevention of chronic disease indicate that the adverse outcomes associated with longterm use outweigh the potential disease prevention benefits, particularly for women older than 65 years. Menstrual and Obstetric History Factors that increase the number of menstrual cycles also increase the risk of breast cancer, probably due to increased endogenous estrogen exposure. Such factors include nulliparity, first full pregnancy when older than 30 years, menarche when younger than 13 years (2 times the risk), menopause when older than 50 years, and not breastfeeding. Conversely, late menarche, anovulation, and early menopause (spontaneous or induced) are protective, owing to their effect on lowering endogenous estrogen levels or shortening the duration of estrogenic exposure. Other Exogenous Factors Other exogenous factors affecting the risk of breast cancer include the following: Diethylstilbestrol use Alcohol consumption, probably through increasing estrogen levels Irradiation, particularly in the first decade of life Exposure to dichlorodiphenyldichloroethylene (DDE), a metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT) A study by Chen et al found that low levels of alcohol consumption were associated with a small increase in breast cancer risk; cumulative alcohol intake throughout adult life was the most consistent measure. Alcohol intake that occurred early and late in adult life was independently associated with risk. [11] In addition, the incidence of breast cancer is increased in individuals in higher socioeconomic classes. However, breast cancer survival rates are lower in women from lower socioeconomic classes. Breast Cancer Risk Assessment Models Several groups have made concerted efforts to develop multivariate methods to derive a breast cancer risk assessment tool using sets of risk factors (genetic and other) that are informative for estimating the risk of breast cancer. Two types of risk models have been developed that are clinically relevant: those that estimate a woman’s absolute risk of developing breast cancer over time and those that determine the likelihood that an individual is a carrier of a BRCA1, BRCA2, or an unknown gene mutation (ie, BRCA1/2 probability models). The BRCAPRO model, the most commonly used BRCA probability tool, identifies approximately 50% of mutation negative families but fails to screen 10% of mutation carriers. Other probability tools include the following: Myriad I and II Manchester Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) Ontario Family History Assessment Tool (FHAT) All these tools were developed by using mutation rates in Ashkenazi Jewish families and families of European descent. However, they have been validated in black and Hispanic populations. The US Preventive Services Task Force (USPSTF) does not specifically endorse any of these genetic risk assessment models because of insufficient data to evaluate their applicability to asymptomatic, cancerfree women. However, the USPSTF does support the use of a greater than 10% risk probability for recommending further evaluation with an experienced genetic counselor for decisions on genetic testing. [12] Gail model In contrast to BRCA probability tools, risk prediction models are designed to derive individual risk estimates for the http://emedicine.medscape.com/article/1945957overview 4/6 24/03/2015 Breast Cancer Risk Factors development of breast cancer over time. The Gail model, developed in 1989 from data derived from the Breast Cancer Detection and Demonstration Project (BCDDP), was developed to estimate the probability of developing breast cancer over a defined age interval; it was also intended to improve screening guidelines. However, the model was subsequently revised (Gail Model 2) and validated to predict risk of invasive breast cancer, including information on the history of firstdegree affected family members. The Gail Model 2 has been used extensively in clinical practice and has served as the basis for eligibility for a number of the breast cancer prevention trials. The US Food and Drug Administration (FDA) guidelines use the National Surgical Adjuvant Breast and Bowel Project’s (NSABP) modified Gail model as the basis for eligibility for the prophylactic use of tamoxifen (Soltamox). Tamoxifen, a selective estrogen receptor (SERM), is approved for women aged 35 years and older who have a 5 year Gail risk of breast cancer of 1.67% or more. The Gail Model 2 also forms the basis of the National Cancer Institute’s Breast Cancer Risk Assessment Tool. The Gail Model 2 is most accurate for nonHispanic white women who receive annual mammograms, but the model tends to overestimate risk in younger women who do not receive annual mammograms. The model also demonstrates reduced accuracy in populations with demographics (ie, age, race, screening habits) that differ from the population on which it was built. At the individual level, the model lacks adequate discrimination in predicting risk and has been challenged on its generalizability across populations. To address concerns regarding applicability of the Gail model to black women, Gail and colleagues derived a model using data from a large casecontrol study of black women participating in the Women’s Contraceptive and Reproductive Experiences (CARE) Study. The CARE model demonstrated high concordance between the numbers of breast cancer predicted and the number of breast cancers observed among black women when validated in the WHI cohort. Future Improvements in Risk Prediction Improvements in risk prediction and clinical tools are likely to emerge in the next few years with the addition of factors such as the following: Breast density Mammographic density change across examinations Use of HRT Weight Age at birth of first live child Number of firstdegree relatives with breast cancer Going forward, it is likely that there will be specific models for risks of premenopausal versus postmenopausal cancers and for specific breast cancer subtypes (luminal vs basal). Contributor Information and Disclosures Author Alison T Stopeck, MD Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center Alison T Stopeck, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Hemophilia and Thrombosis Research Society, and Southwest Oncology Group Disclosure: Genentech Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; AstraZeneca Grant/research funds Other Coauthor(s) Leona Downey, MD Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center Leona Downey, MD is a member of the following medical societies: American Geriatrics Society, American Society of Clinical Oncology, and Southwest Oncology Group Disclosure: Nothing to disclose. Robert B Livingston, MD Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center Robert B Livingston, MD is a member of the following medical societies: American Association for Cancer Research, American Federation for Clinical Research, and American Society of Clinical Oncology Disclosure: Nothing to disclose. Patricia A Thompson, PhD Assistant Professor, Department of Pathology, University of Arizona College of Medicine Disclosure: Nothing to disclose. Specialty Editor Board Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; EditorinChief, Medscape Drug Reference Disclosure: Medscape Salary Employment http://emedicine.medscape.com/article/1945957overview 5/6 24/03/2015 Breast Cancer Risk Factors Chief Editor Jules E Harris, MD Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research Disclosure: Nothing to disclose. Additional Contributors Julie Lang, MD Associate Professor of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California Julie Lang, MD is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology Disclosure: Genomic Health, Grant/research funds, Speaking and teaching; Agendia, Grant/research funds, Speaking and teaching; Surgical Tools, Grant/research funds, Research; Sysmex, Grant/research funds, Research Rachel Swart, MD, PhD Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona Rachel Swart, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Arizona Medical Association, and Southwest Oncology Group Disclosure: Roche Grant/research funds Other References 1. 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