Genetics and Prevention

Genetic Risk Factors

The National Cancer Care Network (NCCN) guidelines for genetic assessment in patients without a history of breast cancer recommends consideration for genetic counseling and possible testing for patients with a close relative, meaning a first- or second-degree relative, with one of the following: breast cancer diagnosed before the age of 45, two breast cancer primaries in a single individual, two individuals with breast cancer primaries on the same side of the family with one of those individuals being diagnosed before the age of 50, ovarian cancer, male breast cancer, pancreatic cancer, or metastatic prostate cancer. Individuals should also be considered for genetic counseling and testing if they have a personal or family history of three or more of the following cancers: breast cancer, sarcoma, adrenal corticoid carcinoma, brain tumor, leukemia, colon, endometrial, thyroid, or kidney cancer, macrocephaly, hamartomatous gastrointestinal (GI) polyps, lobular breast cancer, diffuse gastric cancer, gastrointestinal cancer, pancreatic cancer, ovarian sex cord of testicular Sertoli cell tumors, or childhood skin pigmentation. Individuals that meet the above criteria should be referred for formal genetic assessment and counseling.

Most hereditary breast cancer is caused by pathogenic variants in the BRCA1 and BRCA2 genes (BReast CAncer gene 1 and BReast CAncer gene 2). These genes are an important component in a deoxyribonucleic acid (DNA) repair pathway called homologous recombination (HR). HR is a process in which a strand of DNA is repaired using the homologous strand as a template. Loss of function of one of the copies of either of the BRCA genes leads to a defect in HR. The resulting inability of the cell to repair the DNA leaves it open to further damage, thus increasing the risk for cancer.

Over a woman’s lifetime, the cumulative risk for breast cancer in a BRCA1 pathogenic variant carrier is 55% to 72%. BRCA2 pathogenic variant carriers have a lifetime risk of 45% to 69%. The range in risk has not yet been fully explained. Currently, polygenic risk scores are in development attempting to determine if otherwise benign variants in other genes modify the risk of pathogenic variants in the BRCA genes. It is likely that other nongenetic factors also influence this risk.

Women with pathogenic variants in one of the BRCA genes also have an increased risk of developing a second primary breast cancer. This risk is dependent upon the age at which the woman was when her first breast cancer was diagnosed, as well as which BRCA gene is altered. The risk for a second primary breast cancer is thought to be 21.1% within 10 years and up to 83% by age 70 in BRCA1 carriers. For BRCA2 carriers, 10.8% within 10 years and 62% by age 70. Still, the ability to further stratify breast cancer risk by age for BRCA pathogenic variant carriers can be useful in surgical decision making. Patients can use more narrow risk assessments in determining whether they are comfortable with breast-conserving therapy versus bilateral mastectomy. Tables such as the one in Fig. 15.2 can be used as counseling aids in this decision-making process.

It is important to note that pathogenic variants in the BRCA genes also increase the risk for other cancers by the same HR deficiency mechanism. For women, the risk for ovarian cancer is between 39% and 44% for BRCA1 carriers and 11% to 17% for BRCA2 carriers. Additionally, there are increased risks for fallopian tube cancer, primary peritoneal cancer, and pancreatic cancers. Men have an increased risk for prostate cancer.

Although the BRCA genes cause the majority of hereditary breast cancer, there are other genes in which pathogenic variants can cause varying degrees of breast cancer risk. These genes are often categorized by their lifetime risk for breast or other cancers, also known as penetrance. The genes with the highest penetrance in addition to the BRCA genes are tumor protein p53 (TP53), Cadherin 1 (CDH1), Partner and Localizer of BRCA1 (PALB2), phosphatase and tensin homolog deleted (PTEN), and serine/threonine kinase 11 (STK11). Pathogenic variants in these genes are associated with lifetime risks for breast cancer that can reach 50% or higher. The moderate penetrance genes have been more recently described, and our understanding of them is likely incomplete. Additionally, management recommendations vary for the moderate penetrance genes. For example, ataxia telangiectasia mutated (ATM), BRCA1 Associated Ring Domain 1 (BARD1), Checkpoint Kinase 2 (CHEK2), and Neurofibromatosis type 1 (NF1) all have an absolute risk for breast cancer of 15% to 40%, and the NCCN makes recommendations for high-risk screening for breast cancer in individuals with pathogenic variants in these genes. Still, other moderate penetrance genes such as Restriction Site Associated DNA Paralog C and Paralog D (RAD51C and RAD51D) also have a lifetime risk for breast cancer in the range of 15% to 40% ; however, the NCCN recommends that screening for breast cancer be based on other factors such as family history.

Genetic testing for genes related to increased risks for breast and other cancers is most commonly done via next-generation sequencing (NGS). This technology allows for the testing of multiple genes simultaneously, which renders results in a more timely manner than testing genes individually and sequentially. Still, testing multiple genes can result in complex results. Some patients may be found to have pathogenic variants in more than one gene. Patients can have variants within genes that are of unknown clinical significance. Even patients with single pathogenic variants in genes will need care beyond breast cancer risk management. It is imperative that patients understand the potential complexities of genetic testing. Because of this, the National Program of Breast Centers, the body that sets the standards and accredits breast cancer treatment centers in community care, has set a standard for genetic counseling and testing in breast cancer. Standard 2.16 says that pretest genetic counseling should be performed by a cancer genetics professional who has an educational background in genetics and cancer genetics, counseling, and hereditary cancer syndromes and can provide accurate risk assessment and empathetic genetic counseling to cancer patients and their families. The National Society of Genetic Counselors has a resource to find qualified genetic counselors who can provide this evaluation both in person and virtually ( https://findageneticcounselor.nsgc.org/ ).

Familial/Personal History/Lifestyle Risk Factors

If an individual does not meet the above criteria for genetic counseling and testing, they should then be assessed for breast cancer risk factors related to personal and family history. There are several different computer models that can be used to calculate a woman’s risk of breast cancer. One of the earliest computer models to look at breast cancer risk is the modified Gail model. This model is available at the National Cancer Institute website at http://www.cancer.gov/bcrisktool/Default.aspx . The modified Gail model is based on patient age, age at menarche, age of first live birth, number of biopsies, presence of atypia (but not lobular carcinoma in-situ [LCIS]), and the number of first-degree relatives with breast cancer. The modified Gail model is only validated to use in patients age 35 or older. The NCCN Risk Reduction Panel recommends that those individuals greater than age 35 with a 1.66% or greater 5-year risk of breast cancer be considered for risk reduction strategies such as lifestyle modification and risk-reducing medication. The Gail model is not without limitations. It should not be used in patients with a BRCA1 , BRCA2 , PTEN , or P53 mutation. It is not recommended for individuals with a strong family history of breast cancer, a history of thoracic radiation between the ages of 10 and 30, or those individuals with lobular carcinoma in situ.

The Tyrer-Cuzick model is a computer-based multivariant model that considers personal history, history of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and classical LCIS, family history of both the maternal and paternal sides and breast density. The Tyrer-Cuzick model can be found online at http://www.ems-trials.org/riskevaluator/ . Individuals with a lifetime risk for breast cancer of greater than 20% based on the results of the Tyrer-Cuzick calculation can be offered increased screening with breast magnetic resonance imaging (MRI), risk-reducing medication, and recommendations regarding lifestyle modification. Unlike the Gail model, the Tyrer-Cuzick risk model can be used in individuals less than 35 years of age. An analysis of the Mayo Clinic cohort demonstrated that the Gail model underestimated the risk of breast cancer in individuals with atypical hyperplasia, while the Tyrer-Cuzick risk model overestimated the risk of breast cancer in individuals with a personal history of ALH/ADH.

Other elements that can cause an increased breast cancer risk include being born female, increasing age, ethnicity, and race, and lifestyle factors including increased body mass index (BMI), alcohol consumption, current or prior estrogen-progesterone hormone therapy, and reproductive history. The two greatest risk factors for developing breast cancer are being born female and increasing age. While men can develop breast cancer, the incidence is much higher in women, and most breast cancers are diagnosed in women aged 55 and older. Ethnicity and race also play a factor in breast cancer risk. Caucasian women have a slightly higher risk of breast cancer than African American women. African American women have a higher incidence of breast cancer being diagnosed before the age of 45 and are more likely to die from breast cancer at any age. Asian, Native American, and Hispanic women have a lower incidence and mortality rate from breast cancer. While age, race/ethnicity, and family history are beyond the control of the individual, clinicians can educate and affect many of the breast cancer risk factors related to lifestyle.

The prevalence of obesity among adults in the United States in 2017 to 2018 was 42.4%. Among women, the prevalence of obesity was 39.7% among those aged 20 to 39, 43.3% among those aged 40 to 59, and 43.3% among those aged 60 and over. There is a substantial amount of evidence that overweight/obese women have a higher risk for postmenopausal breast cancer. The Nurses’ Health Study suggested that women experiencing a weight gain of 25 kg or more since the age of 18 have an increased risk of breast cancer compared to those who have maintained their weight. Most breast cancer diagnosed in post-menopausal individuals is hormone sensitive, specifically estrogen receptor and/or progesterone receptor sensitive. After menopause, once an individual’s ovaries have stopped producing estrogen, most of the estrogen production comes from the fat tissue. Having more fat tissue increases estrogen levels and increases the risk of hormone-positive breast cancer. In the same Nurses’ Health Study, women who never used postmenopausal hormone replacement therapy and lost 10 kg or more after menopause and were able to keep the weight off had a significantly lower risk for breast cancer compared to those who maintain that weight.

Exercise has been associated with decreased risk of breast cancer. A population, case-controlled study of 4538 patients with breast cancer and controlled patients grouped according to race demonstrated a 20% lower risk of breast cancer in both black and white women with annual lifetime activity levels greater than the median activity level when compared to inactive women. The American Cancer Society recommends that adults get between 150 and 300 minutes (about 5 hours) of moderate-intensity or 75 to 150 minutes of vigorous-intensity exercise per week, with reaching 300 minutes or more of exercise per week being the ideal.

There is a known correlation between alcohol intake and breast cancer risk. A population-based study of 51,847 women provided an association between alcohol consumption and an increased likelihood of developing hormone-positive breast cancer. Even one drink per day can increase breast cancer risk. In an analysis of two cohort studies, there was found to be a 10% increase in risk for breast cancer for every 10 g of alcohol consumed daily. The consensus from the NCCN risk reduction panel was to recommend less than one alcoholic beverage per day. One drink is defined as 1 oz of liquor, 6 oz of wine, or 12 oz of beer.

Hormone replacement therapy can also increase an individual’s risk of breast cancer. The Women’s Health Initiative enrolled 161,809 women between the ages of 50 and 79 into a set of clinical trials. Two of these trials involved the use of hormone therapy in primary disease prevention. The first trial of 16,608 involved women with an intact uterus were given estrogen plus progesterone or a placebo. The second trial involved 10,739 women who had undergone prior hysterectomy and were randomized to estrogen therapy alone versus a placebo. The first trial was closed early after a 26% increased incidence of breast cancer was identified in the hormone therapy treatment group. The use of hormone therapy was associated with a greater incidence of breast cancer as well as higher breast cancer mortality. However, the incidence of breast cancer rapidly declined in patients once they had stopped taking hormone therapy. While the second clinical trial looking at estrogen therapy alone did not demonstrate an increased risk for breast cancer, there was an increased incidence of abnormal mammograms associated with breast density, as well as an increase in the incidence of benign proliferative breast changes. Combined hormone replacement therapy as well as estrogen replacement therapy alone has been demonstrated to increase a postmenopausal individuals’ risk for cardiovascular disease (e.g., heart attack and stroke). Women with elevated risk for breast cancer should not be offered hormone replacement therapy. Other means of controlling menopausal symptoms should be attempted prior to resorting to hormone replacement therapy. However, if avoidance of hormone replacement therapy is not possible, patients should be given the lowest dose of hormone replacement for a limited time. Women who are offered hormone replacement therapy need to be counseled that hormone replacement therapy can increase the risk of breast cancer and can make breast cancer more difficult to detect on a mammogram due to changes in breast density.

An individual’s reproductive history can also affect breast cancer risk. Nulliparity as well as a prolonged interval between menarche and an individual’s first live birth, early onset of menarche, or late onset of menopause have been associated with increased risk of breast cancer. Numerous studies have demonstrated a protective effect from breastfeeding, with the relative risk for breast cancer decreasing by 4.3% for every 12 months of breastfeeding performed.

Risk-Reducing Interventions