How to spot heritable breast cancer: A primary care physician’s guide

WHAT HAPPENS WHEN GENETIC TESTING IS NOT INDICATED?

Cancer genetic risk assessment and counseling provides benefits even when genetic testing is not indicated. In some situations genetic testing is not warranted, but referral for heightened surveillance for breast cancer is deemed necessary. Patients who have a personal or family history of cancer can still gain from a detailed assessment of their personal and family history and may come away relieved after learning that they or their family members are not at high risk of developing cancer. Such patients or families may be classified as demonstrating either familial or sporadic breast cancer diagnoses.

Familial breast cancer

Familial breast cancers, believed to account for 15% to 20% of all cases of breast cancer, share features with hereditary breast cancer syndromes.⁴ In affected families, the frequency of breast cancer is higher than in the general population (multiple family members may be affected), and the age of onset tends to be close to that in the general population.

Members of a family with familial breast cancer who have not yet developed the disease may be at increased risk of it. Several risk-assessment tools (the Gail, Tyrer-Cuzick, Claus, and other models)^21–25 use personal and family history to estimate breast cancer risk.

Depending on the assessed risk, additional options for screening and surveillance are available. The American Cancer Society recommends magnetic resonance imaging (MRI) in addition to annual mammography for women whose lifetime risk of breast cancer is greater than 20%. They also recommend that women at moderately increased risk (ie, 15%–20% lifetime risk) talk to their doctor about the benefits and limitations of adding MRI screening to yearly mammography.¹

Sporadic breast cancer

Sporadic forms of breast cancer account for 70% to 80% of cases of breast cancer. Sporadic breast cancers are thought to have mainly nonhereditary causes, with environment and personal risk factors playing a large role.

Women with apparently sporadic breast cancers are diagnosed at or beyond the average age at diagnosis in the general population and do not have a family history that suggests either a hereditary cancer syndrome or familial breast cancer. If they undergo a cancer risk assessment, they may be relieved to learn that other women in their family do not have a high probability of being affected, and that they themselves do not appear to be at increased risk of other malignancies.

PATIENT 2: NEGATIVE TEST RESULTS ARE SOMETIMES ‘UNINFORMATIVE’

A healthy 35-year-old woman is referred for a genetics consultation by her gynecologist because her mother developed breast cancer at age 40 and died of the disease. A detailed personal and family history and risk assessment are done. After pretest genetic counseling, testing for BRCA1 and BRCA2 mutations (hereditary breast and ovarian cancer syndrome) is ordered, and the patient’s test results are negative. Risk assessment determines that no other hereditary cancer syndrome is likely. Therefore, no other genetic testing is offered at this time.

Genetic testing is most informative when performed first on the family member at highest risk of having a mutation. For families with breast cancer, this is typically the person with cancer diagnosed at the earliest age.

Unfortunately, sometimes these family members cannot be tested because they are deceased or otherwise unavailable. In such situations, it is acceptable to offer testing to a close, unaffected relative, such as your patient. Pretest genetic counseling in these circumstances is key, highlighting the fact that negative (normal) results would be uninformative. In your case, we cannot know whether the patient’s mother would have tested positive for a BRCA1 or BRCA2 mutation and your patient is a “true negative,” or whether her mother would have tested negative as well.

In unaffected patients with uninformative genetic testing results, medical management is based on the patient’s personal risk factors and family history of cancer. For your patient, statistical risk modeling tools (the Gail, Claus, Couch, and Tyrer-Cuzick models) determine that her risk of developing breast cancer is 22% to 28.5%, qualifying her for MRI along with yearly mammography per the American Cancer Society guidelines previously discussed.

KNOWLEDGE CONTINUES TO EXPAND

Major advances in the understanding of breast cancer susceptibility were made in the last decade through genetic linkage mapping in families that have an overabundance of members with breast cancer.^26–28 Additionally, as more information is acquired, other genes predisposing to cancer or modifying cancer risk may be identified and additional knowledge gained.

With the advent of gene-panel-based testing and exome sequencing, we will incidentally discover mutations that predispose to cancer in patients in whom we were not looking for these mutations. With improving technology and value-based health care delivery, providers must continue to embrace multidisciplinary care, and genetics will become central in guiding medical management. In the event of an incidental finding suggesting susceptibility to heritable cancer, a consult to genetic counseling is recommended.

Many studies of the genetics of breast cancer are now focusing on known hereditary breast cancer syndromes and on possibilities for risk reduction, lifestyle modification, and identification of genetic variations that may increase or decrease cancer risk for an individual patient. The Center for Personalized Genetic Healthcare at Cleveland Clinic is collaborating in one such study. Titled “Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Syndrome,” it is an international study led by a leading breast cancer researcher, Dr. Steven Narod from the Women’s College Research Institute in Toronto, ON. This study is focusing on women with a BRCA1 or BRCA2 mutation and their personal cancer risk factors, lifestyle choices, and overall development of cancer. This research group and others are also focusing on identifying genetic “modifiers” of cancer risk in these high-risk women.²⁹

For patients who do not have a hereditary cancer syndrome, research is further exploring novel genes and their relation to breast cancer risk. One such study in our laboratory has found that several genes once thought only to cause an increased risk of hereditary paraganglioma may also predispose to breast and thyroid cancer.^29,31 Additional research in this area is under way to clarify these risks.

GOOD SCIENCE, BAD MEDICINE?

Other research studies have identified a number of genes currently thought to be “moderately penetrant” for breast cancer risk, meaning that they may confer a risk of breast cancer slightly greater than that in the general population, but in some instances the risk has not been proven to be high enough to alter a patient’s management.^32,33

Although a few clinical laboratories currently offer testing for these kinds of genes, the clinical utility of this testing is questionable. Before offering testing on a clinical basis, we need clear, consistent data on the types of cancers associated with these genes and on the lifetime percentage risk of acquiring these cancers. Currently, it is difficult to understand whether a variant in a moderately penetrant gene is the true explanation behind a patient’s breast cancer diagnosis. If such a variant is identified and family members pursue testing for it, should those family members who test negative be considered to have the same risk of cancer as the general population? And should family members testing positive be offered prophylactic surgical options?

Without more data these questions cannot be answered, and until such data are gathered, we believe that testing for moderately penetrant genes should not be performed outside of a research study. The Center for Personalized Genetic Healthcare in Cleveland Clinic’s Genomic Medicine Institute can assist in educating and coordinating patients’ enrollment in such research studies.

PUTTING IT ALL TOGETHER

Primary care physicians are the first-line providers to individuals and families, many of whom have a personal or family history of breast cancer. Identifying patients at risk of breast cancer and hereditary cancer syndromes can be challenging in this era of shortened appointment times and patients with complex medical histories.

Reviewing an individual’s personal and cancer family history is a necessary first step in considering appropriate medical management recommendations for cancer screening and prevention, the cornerstone of personalized health care. Patients with hereditary breast cancer syndromes and those with familial breast cancer can benefit from high-risk breast cancer surveillance.

Cancer genetics risk assessment ensures that the correct genetic testing is offered to the most appropriate patients, with personalized interpretation of results and provision of future management recommendations based on the individual patient’s personal and family history. Genetic counselors empower patients to make educated and informed decisions about genetic testing, cancer screening, and prevention.

As health care continues to focus more on prevention in this new era of genomic medicine and value-based delivery of health care, genetic counselors will serve as powerful allies to physicians.³⁴

Acknowledgments: We would like to thank Dr. Colleen Clayton and Dr. Lynn Pattimakiel of the Medicine Institute, Cleveland Clinic, for their critical review of and thoughtful feedback on this manuscript.