Breast Cancer Review | Risk Factors

Knowing about risk factors is important for helping to identify women whose chances of developing breast cancer are higher than average, and to determine who may benefit from increased observation or referrals to specialists. Similarly, women with average risk can be helped to improve their chances against developing the disease by learning which lifestyle factors are associated with increased risk and by modifying their behaviors. In either case, it is important that a woman's risk of breast cancer is routinely assessed and that risk reduction strategies are recommended.

Understanding Risk

A risk factor is any characteristic or behavior that increases the chances of developing a disease. Several basic measures of risk may be used for describing a woman's chances for developing breast cancer. The most common measures are those of absolute and relative risk.

Absolute Risk describes the percentage chance that a person will develop a disease during a given period of time. It is a useful measure for helping to determine what proportion of the population is at risk for a specific disease. In the case of breast cancer, the most recent estimate of absolute risk during the period of a lifetime is 13.32 percent, or roughly 1 in 8 women.¹ However, the absolute risk during any given decade of life is lower. The accompanying table shows the changes in absolute risk when estimating risk over a 10 year period for different age groups. Because rates of breast cancer increase with age, age-specific estimates are generally more meaningful than an estimate of lifetime risk.²

Relative Risk describes the percentage chance of developing a disease for persons having a certain characteristic (or a behavior) compared with those not having that same characteristic. Relative risk is often expressed as a percentage (e.g., 50% increase in risk). It is also often expressed as a ratio, preceded by the abbreviation RR (e.g., RR 1.5).

While familiar to most healthcare professionals, measures of risk can be a source of confusion for patients. In a study where women were asked to estimate their risk of breast cancer, researchers found that 89 percent overestimated their lifetime risk by more than three times the actual risk (i.e., 46% vs. 13%).³ Overestimating risk can cause undo stress and anxiety, both of which can lead to an avoidance of screening and risk-reducing strategies. When discussing risk with patients, healthcare providers are encouraged to use the opportunity to correct any potential misunderstanding. The use of examples that compare expressions of relative risk (e.g., 100% increase, or RR 2.0) with absolute risk (2 in 100 vs. 1 in 100) may be helpful when reviewing with patients the types of risk factors associated with the development of breast cancer.

Types of Risk Factors

With breast cancer, there are many established risk factors, including those that cannot be modified, such as family history, and those that can, like diet and exercise. Different factors are associated with varying increases in relative risk. Although a number of risk factors for breast cancer have been identified, known risk factors account for only a small percentage of women who actually develop breast cancer.

Gender and Age: Female gender is the most important risk factor for breast cancer. The risk for females is 100 times that of males. The second most important risk factor is age. The older a woman, the greater her chances of developing the disease. More than 80% of breast cancers occur in women aged 50 and older.⁴

Genetic Factors: Women with an inherited BRCA1 or BRCA2 mutation have a greatly increased risk of developing breast cancer. According to The National Cancer Institute (NCI), estimates range from 3 to 7 times that of women without these gene mutations.⁵ While BRCA1 and BRCA2 are the most common genes related to hereditary breast cancer, other genes associated with breast cancer risk include ATM, CHEK2, RAD51, AR, DIRAS3, ERBB2, and TP53. Additional breast cancer susceptibility genes that have not yet been identified are likely.⁶

Family History: Breast cancer risk is increased for women having a first-degree biological relative (mother, sister, daughter) or a second-degree relative (grandmother, aunt, niece) with the disease. Having one first-degree relative with breast cancer approximately doubles a woman's risk; having two or more first-degree relatives with breast cancer diagnosed at an early age can increase risk by as much as 5-fold.⁷ In general, the more biological relatives with breast cancer, especially relatives who were diagnosed before age 50, the higher a woman's breast cancer risk.

Personal History of Breast Cancer: A personal history of breast cancer increases a woman's risk of a second primary breast cancer either in the opposite breast, or the same breast if there is remaining tissue. The amount of risk depends on the presence of other factors, such as a BRCA mutations. Likewise, carcinoma in situ (LCIS and DCIS) increases a woman's risk for developing invasive breast cancer. Again, the magnitude of risk is modified by other factors, such as menopausal status, family history, time since biopsy, and treatment. Generally, a woman with cancer in one breast has a 3- to 4-fold increased risk of developing a new cancer in the opposite breast or in another part of the same breast.⁸

Breast Density: Women with mammographically dense breast tissue have an increased risk of developing breast cancer. Studies using quantitative methods for defining breast density report a 4 to 6 times increase in relative risk.⁹

Previous Breast Pathology: Women with different types of noncancerous breast lesions have different levels of relative risk of developing subsequent breast cancer. Proliferative changes without atypia are associated with an increased relative risk of 1.5 to 2.0. Proliferative changes with atypia affect a higher increase, ranging from 4.0 to 5.0. Additionally, recent research suggests that nonproliferative changes may be associated with a slight increase in relative risk (RR 1.27).¹⁰

Previous Radiation Therapy: The risk of breast cancer is significantly increased for women who have had therapeutic radiation to the upper torso (e.g., treatment of Hodgkin’s lymphoma). Radiation treatment received at younger ages is associated with higher risk. However, risk may be lowered for patients who were also treated with chemotherapy and the chemotherapy stopped ovarian hormone production.¹¹

Hormonal Factors: The longer a woman has been exposed to estrogen, the greater the breast cancer risk. Estrogen exposure is increased for women with early onset of menses (prior to age 12) and late menopause (after 55). Similarly, women who have had no children or their first child after age 30 have a slightly higher risk due to increased estrogen exposure. Hormone replacement therapy is associated with an increased risk of heart disease, heart attacks, stroke, blood clots, and breast cancer.¹² Findings from studies of oral contraceptives have suggested that risk is slightly increased for women who currently use oral contraceptives, but risk may not be increased for women who have stopped using them more than 10 years ago.¹³

Weight and Diet: Obesity is a risk factor for breast cancer, possibly associated with higher levels of estrogen production. Excess fat in the waist or upper body area, and weight gained as an adult, especially near menopause, may increase risk more than the same amount of fat in the hips and thighs, or weight gained in childhood. With regard to dietary fat, study findings have been inconclusive.¹⁴

Personal History of Other Cancers: The risk of developing breast cancer is greater in women who have been diagnosed with cancer of the endometrium, ovary, or colon.¹⁵ The association of other cancers with increased risk may be due to genetic factors.

Alcohol: Alcohol consumption has been shown to increase a woman's risk of breast cancer, perhaps by raising the level of estrogen in the body. Most studies suggest that the risk of breast cancer increases as the amount of alcohol consumed increases. One alcoholic drink a day confers only a slight increase in risk while 2 to 5 drinks daily increases risk by about 1.5 times.¹⁶

Race/Ethnicity/Socioeconomic Status: In the U.S., breast cancer risk is highest for White women, followed by African-American, Asian/Pacific Island women, Hispanic women and lastly, American Indian and Alaskan Native women. In general, women from lower socioeconomic groups, regardless of their race/ethnicity, have a lower risk of developing breast cancer but higher death rates.¹⁷

DES: Women who took diethylstilbestrol (DES), a synthetic form of estrogen hormone previously prescribed to prevent miscarriage (from 1940 to 1971), may have a slightly increased risk of breast cancer.¹⁸

Smoking: Research on the relationship between cigarette smoking and breast cancer risk has produced mixed results. Some studies have found increased risk (both for smokers and for passive smoke exposure) while others have failed to establish an association. In 2005, however, The California Environmental Protection Agency concluded that the evidence regarding secondhand smoke and breast cancer suggests a causal relationship in younger, premenopausal women.¹⁹

Environmental Chemicals: Because established risk factors for breast cancer account for a minority of all cases, some believe that environmental chemicals may play an important role in risk. Although studies on humans have been inconclusive, the list of chemicals known to cause breast tumors in laboratory animals lends support to this position. Examples fall within the categories of chemical solvents; chemicals used with the manufacturing of dyes; chemicals used in the manufacturing of rubber, vinyl, polyurethane foams or neoprene; fumigants and pesticides; gasoline additives; and pharmaceuticals, among others.²⁰

Risk Assessment

Assessing a woman's individual risk for breast cancer engages the primary care provider and the patient in a discussion about breast cancer prevention, educates a woman about risk factors, and helps guide a personalized plan for risk reduction and early detection. A risk assessment should be made at each routine screening visit since a patient's personal risk factors will change over time. The most frequently used models for estimating breast cancer risk are the Gail and Claus Models.

The Gail Model incorporates a number of established risk factors to estimate a woman's lifetime and 5-year risk for invasive breast cancer. A 5-year risk of 1.7% or higher is considered elevated and meets criteria for certain breast cancer prevention trials. While an excellent assessment tool for most patients, this model is not recommended for use with patients having a strong family history since it excludes some well-established factors associated with hereditary breast cancer.²¹ The Gail model is the basis for the Breast Cancer Risk Assessment Tool available Online from the National Cancer Institute.

The Claus Model provides a more accurate estimate of risk for women with a family history of breast cancer by taking into account both maternal and paternal family history, second-degree relatives, and their ages at diagnosis. It also factors within the model a family history of ovarian cancer. However, unlike the Gail Model, the Claus Model does not include risk factors other than family history.²²

In addition to these, The Assessment of Risk Algorithm, developed by the State of California, Department of Health Services, provides a basic guide for primary care providers to follow and can help identify women at greater risk of breast cancer than the general population. The algorithm attempts to incorporate risk factors that have epidemiologic evidence of significant risk. It does not include all possible risk factors nor does it assess absolute risk for combinations of risk factors. In summary, the algorithm provides a qualitative assessment of risk based on personal history, family history, medical/pathological/genetic factors, with the outcome of either normal or increased risk for breast cancer. The Assessment of Risk Algorithm is available on this web site.

A complete breast cancer risk assessment includes an evaluation for known risk factors using a reliable risk assessment tool and obtaining a thorough personal and family history. The Breast Cancer History and Risk Assessment Form, also developed by the California Department of Health Services, can be used with the Assessment of Risk Algorithm to help identify women who may be at increased risk of developing breast cancer. For the woman with high risk, a referral to a risk assessment counselor can be helpful in further defining her risk, identifying possible genetic risks, and recommending appropriate risk reduction strategies.

Gene Testing

Inherited breast cancer accounts for 5% to 10% of all breast cancers.²³ Of these, only a small percent of cases will be linked to BRCA1 and BRCA2 mutations. Even among women with these mutations, not all will develop breast cancer. For this reason, The U.S. Preventive Services Task Force cautions against routine testing for genetic risk of breast cancer. However, if a patient's family history is strongly suggestive of BRCA mutations, the Task Force recommends that her primary care physician suggest genetic counseling and possible gene testing.²⁴

For helping to identify patients with increased risk for BRCA mutations, the Mayo Clinic lists the following: ²⁵

According to The National Cancer Institute, women with an altered BRCA1 or BRCA2 gene are 3 to 7 times more likely to develop breast cancer than women without alterations in these genes.²⁶ In addition, these women have an increased risk of ovarian cancer, and of developing these cancers at a young age (i.e., before menopause). It is therefore essential that women with these gene mutations be identified and referred for thorough evaluation. If gene testing is indicated, the genetic counselor will advise the woman of the benefits, limitations, and risks of testing - including those that have potential impact for a woman's emotions, social relationships, finances and employment. If gene testing is not indicated, or if the patient chooses not to be tested, she should nevertheless be provided with a thorough cancer risk management plan.

Professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others) can be located using NCI's Cancer Genetics Services Directory. A genetic counselor can also be located through the The National Society of Genetic Counselors web site. Genetic tests may be ordered by the genetic counselor or by the primary care provider. GeneTests, an NIH-funded educational project to help healthcare providers understand the appropriate use of genetic counseling and testing, is an excellent Online source for learning more about this topic. Additionally, the National Human Genome Research Institute (NHGRI) offers a thorough review of related ethical, policy and legislative issues.

Risk Reduction Strategies

Risk reduction strategies should be tailored to each woman's level of risk, balance of risk and benefits, and personal preference.

Strategies for Women at Average Risk

For women at average risk, the emphasis is on healthy lifestyle habits. The American Cancer Society recommends that women avoid alcohol, exercise regularly, and maintain a healthy body weight. Women who give birth to several children might wish to consider breast-feeding for longer periods (reduces number of lifetime menstrual cycles). Avoiding hormone replacement therapy after menopause will keep a woman from increasing her risk. Low-fat diets may also help to reduce risk, although study findings on the relationship between dietary fat and breast cancer are inconclusive. At minimum, a low-fat diet can help to reduce risk indirectly by helping to prevent obesity - one of the established risk factors for breast cancer. Likewise, patients wishing to decrease their risk of breast cancer should avoid smoking. While the research in this area is inconclusive, most recent studies appear to suggest a linkage.

Woman Shopping for Produce. Source: Adapted from NCI Visuals Online. AV-8712-3446.

Patients who modify their lifestyle choices toward reducing their risk of breast cancer will be taking constructive steps toward better overall health. But even with best efforts, changes in modifiable risk factors still leave a woman vulnerable. Other than behavioral changes, the most important action a woman can take to decrease her chances of dying from breast cancer is to follow early detection guidelines. The earlier breast cancer is found, the better the chances for successful treatment.

Strategies for Women at Increased Risk

For women at increased risk, additional risk reduction strategies should be considered. At present, these strategies include increased surveillance; the use of additional imaging tests; chemoprevention (e.g., tamoxifen); and, for women with a strong family history or known genetic predisposition, prophylactic mastectomy. Enrollment in a breast cancer prevention trial may also be considered for women with higher than average risk. For more information about this topic, healthcare providers are referred to the National Comprehensive Cancer Network (NCCN) web site. NCCN's Clinical Practice Guidelines in Oncology™ are a recognized standard for clinical policy in the oncology community.

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Notes

¹National Cancer Institute. Probability of Breast Cancer in American Women (Apr. 15, 2005). Retrieved Jul. 9, 2006 at: http://www.cancer.gov/cancertopics/factsheet/Detection/probability- breast-cancer

²See note 1.

³Behind the Cancer Headlines. Women Overestimate Breast Cancer Risk (Jun. 7, 2005). Retrieved Apr. 2, 2006 at: http://www.mabcie.com/June_7,_2005_breast_cancer.html

⁴MedlinePlus. Breast Cancer (updated, Oct. 21, 2005). Retrieved Jul. 9, 2006 at: http://www.nlm.nih.gov/medlineplus/ency/article/000913.htm

⁵National Cancer Institute. Genetic Testing for BRCA1 and BRCA2: It's Your Choice (Feb. 6, 2002). Retrieved Jul. 9, 2006 at: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

⁶Genetics Home Reference. Breast Cancer (May, 2006). Retrieved Jul. 9, 2006 at: http://ghr.nlm.nih.gov/condition=breastcancer

⁷American Cancer Society. What Are the Risk Factors for Breast Cancer? (revised, Sep. 2, 2005). Retrieved Apr. 9, 2006 at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_2X_
What_are_ the_risk_ factors_for_ breast_cancer_5.asp

⁸See note 7.

⁹Korde LA, Calzone KA, Zujewski J. Assessing Breast Cancer Risk: Genetic Factors Are Not the Whole Story. Postgrad Med. 2004 Oct;116(4):6-8, 11-4, 19-20. Retrieved Apr. 13, 2006 at: http://www.postgradmed.com/issues/2004/10_04/korde.htm

¹⁰National Cancer Institute. Benign Breast Disease Indicates Relative Risk for Breast Cancer. NCI Bulletin. 2005 Jul;30(2). Retrieved Apr. 13, 2006 at:http://www.cancer.gov/ncicancerbulletin/
NCI_Cancer_Bulletin_072605/page5

¹¹See note 7.

¹²MedlinePlus. Hormone Replacement Therapy (updated, Feb. 9, 2006). Retrieved Jul. 9, 2006 at: http://www.nlm.nih.gov/medlineplus/ency/article/007111.htm

¹³See note 7.

¹⁴See note 7.

¹⁵Fletcher, SW. Risk Factors for Breast Cancer (May 11, 2006). Retrieved Jul. 9, 2006 at: http://patients.uptodate.com/topic.asp?title=breast+cancer+reduction&file=cancer/2174&
mark=1&submit=find

¹⁶See note 7.

¹⁷The Program on Breast Cancer Environmental Factors. Fact Sheet #47: Breast Cancer in Women from Different Racial/Ethnic Groups (Apr., 2003). Retrieved Apr. 13, 2006 at: http://envirocancer.cornell.edu /Factsheet/general/fs47. ethnicity.cfm

¹⁸See note 7.

¹⁹See note 7.

²⁰The Program on Breast Cancer Environmental Factors. Fact Sheet #45: Environmental Chemicals and Breast Cancer Risk Why is There Concern? (May, 2002). Retrieved Apr. 13, 2006 at: http://envirocancer .cornell.edu/factsheet/general/fs45.chemical.cfm

²¹National Cancer Institute. Models for Prediction of Breast Cancer Risk (last modified, Mar. 24, 2006). Retrieved Apr. 10, 2006 at: http://cancernet.nci.nih.gov/cancertopics/pdq/genetics/breast
-and-ovarian/healthprofessional#Section_66

²²See note 21.

²³See note 5.

²⁴National Human Genome Research Institute.Task Force Recommends Against Routine Testing for Genetic Risk of Breast or Ovarian Cancer in the General Population (Sept, 2005). Retrieved Apr. 10, 2006 at: http://www.genome.gov/16015415

²⁵Mayo Clinic. Genetic testing for breast and ovarian cancers: When family history places you at high risk (Jan. 24, 2005). Retrieved Jul. 9, 2006 at: http://www.mayoclinic.com/health/genetic-testing-
for-breast-cancer/HQ00350

²⁶See note 5.

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Risk Factors

Introduction

Understanding Risk

Types of Risk Factors

Risk Assessment

Gene Testing

Risk Reduction Strategies