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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
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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
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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
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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
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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
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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. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature.
Oct 4 2012;490(7418):61­70. [Medline]. [Full Text].
2. Lowry F. High cholesterol may boost breast cancer risk. Medscape Medical News [serial online]. July 10,
2014;Accessed July 14, 2014. Available at http://www.medscape.com/viewarticle/828084.
3. Potluri R, Lavu D, Uppal H, Chandran S. Hyperlipidaemia as a risk factor for breast cancer? (abstract
P740). Cardiovasc Res. 2014;103(suppl 1):S102­43. [Full Text].
4. Goss PE, Ingle JN, Ales­Martinez JE, et al. Exemestane for breast­cancer prevention in postmenopausal
women. N Engl J Med. Jun 23 2011;364(25):2381­91. [Medline].
5. Bouchardy C, Benhamou S, Fioretta G, et al. Risk of second breast cancer according to estrogen receptor
status and family history. Breast Cancer Res Treat. May 2011;127(1):233­41. [Medline].
6. Ellis RJ, Kaminsky DA, Zhou EH, et al. Ten­year outcomes: the clinical utility of single photon emission
computed tomography/computed tomography capromab pendetide (Prostascint) in a cohort diagnosed with
localized prostate cancer. Int J Radiat Oncol Biol Phys. Sep 1 2011;81(1):29­34. [Medline].
7. Collaborative Group on Hormonal Factors in Breast Cancer. Collaborative Group on Hormonal Factors in
Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53
297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.
Lancet. Jun 22 1996;347(9017):1713­27.
8. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement
therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast
cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast
Cancer. Lancet. Oct 11 1997;350(9084):1047­59.
9. Reeves GK, Beral V, Green J, Gathani T, Bull D; Million Women Study Collaborators. Hormonal therapy
for menopause and breast­cancer risk by histological type: a cohort study and meta­analysis. Lancet Oncol.
Nov 2006;7(11):910­8.
10. [Best Evidence] Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen
plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. Oct 20
2010;304(15):1684­92. [Medline].
11. Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult
life, drinking patterns, and breast cancer risk. JAMA. Nov 2 2011;306(17):1884­90. [Medline].
12. U.S. Preventive Services Task Force. Genetic Risk Assessment and BRCA Mutation Testing for Breast
and Ovarian Cancer Susceptibility. Available at
http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrgen.htm. Accessed December 22, 2010.
13. Coogan PF. Calcium­Channel Blockers and Breast Cancer: A Hypothesis Revived. JAMA Intern Med. Aug
5 2013;[Medline].
14. Kelly JC. Some antihypertensives linked to breast cancer risk. August 5, 2013. Medscape Medical News
[serial online]. Available at http://www.medscape.com/viewarticle/808935. Accessed August 16, 2013.
15. Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of Antihypertensive Medications and
Breast Cancer Risk Among Women Aged 55 to 74 Years. JAMA Intern Med. Aug 5 2013;[Medline].
Medscape Reference © 2011 WebMD, LLC
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