Genetic Testing and Risk Intervention Based on Family History of Early-Onset Breast Cancer

Genetic Testing and Risk Intervention Based on Family History of Early-Onset Breast Cancer

Mia is a 35-year-old healthy Black woman with a family history of breast cancer. Her mother died from breast cancer at age 38, and her maternal aunt died from breast cancer at age 45. Mia reports her cancer family history on the intake forms that she completes during routine annual visits to her primary care physician (PCP). After reading a news article about familial breast cancer and germline BRCA1/BRCA2 genetic testing, she sends a message to her PCP requesting BRCA1/BRCA2 genetic testing, but she receives a response saying that genetic testing is not necessary and that “the only people who ever come back positive for that test are women of Ashkenazi Jewish descent.”

In this case example, Mia is at an ideal age to begin breast cancer risk interventions. Although breast cancer screening for the general population begins at age 40, National Comprehensive Cancer Network (NCCN) guidelines indicate that Mia should begin screening now, given her mother’s early-onset breast cancer diagnosis. At this risk level, breast magnetic resonance imaging (MRI) in addition to annual mammography is recommended.¹ Because Mia has more than one close blood relative with a history of breast cancer diagnosis at an age younger than 50, she meets the criteria for genetic testing for high-risk breast cancer genes including BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53.²

Mia meets with a genetic counselor and decides to undergo genetic testing. Her test results reveal that Mia does carry a BRCA1 mutation. Mia and the geneticist weigh all options and, given that her absolute risk of developing breast cancer with a BRCA1 mutation is approximately 60% to72%,^3,4 she opts for a prophylactic bilateral mastectomy. She chooses no reconstruction so that she can have easy access to her chest wall for self-examinations. Bilateral breast tissue is negative for any abnormal breast cancer cells.

Mia and the geneticist also discuss options including prophylactic bilateral salpingo-oophorectomy given her high-level risk of developing ovarian cancer with a BRCA1 mutation. She is referred to a fertility specialist, where they discuss the safety implications of having children while carrying a BRCA mutation. They also discuss various preservation options. In the end, Mia decides she does not want to have any children. She undergoes a bilateral salpingo-oophorectomy, ensuring that the surgery is completed while she is between the age of 35 and 40, per the NCCN Guideline’s recommendations.¹ Her team recommends monthly self-checks as well as clinical chest wall examination every 6 to 12 months. They advise her to be familiar with her body and to report any changes.

Genetic, Environment, and Lifestyle Factors

Approximately 5% to 10% of breast cancers are hereditary, 15% to 20% are familial, and 70% are sporadic breast cancers.⁵ Hereditary cancers are caused by a mutation in a gene that is passed down from a parent to a child. Familial cancers are cancers that occur more often in families than in the general population. These cancers can occur at an early age, may or may not have the presence of a gene mutation, and/or may be attributed to a shared environmental or lifestyle exposure. Sporadic cancers are cancers that are of an unknown etiology and are not linked to a family history or a high-risk variant that is known to increase the risk of cancer. High-risk genes, which increase an individual’s risk of breast cancer by 50% or more, include BRCA1, BRCA2, PALB2, PTEN and TP53.^6,7 Moderate-risk genes, which increase an individual’s risk by 20% to 40%, include ATM, CHEK2, CDH1, and NF1.⁸ Hallmark signs of hereditary cancers include early-age onset, multiple family members affected, bilateral cancers, multiple synchronous cancers, or unusual presentations of common cancers. Personal, lifestyle, and environmental factors such as work environments, smoking, heavy drinking, older age, and hormone exposure can also contribute to cancer development.

Genetic testing is now an integral part of cancer care, partly due to the Precision Medicine Initiative launched by former President Barack Obama and the National Institutes of Health. The Precision Medicine Initiative looked to understand how a person’s genetics, environment, and lifestyle can help determine the best approach to prevent or treat disease.⁹ However, despite these great strides, we continue to see a substantial number of individuals who, like Mia, should be offered genetic testing but are not. Lack of knowledge about genetic testing among professionals and patients is still an issue.

Who Should Receive Genetic Testing?

Family history that is suggestive of an underlying genetic risk for breast cancer includes having two or more relatives who develop breast cancer prior to age 50, having multiple relatives who developed breast or ovarian cancer, having a relative who at a young age developed cancer in both breasts, having a male relative with breast cancer, or being of Ashkenazi Jewish decent. These individuals are at a high risk, and health care providers should be familiar and able to distinguish those individuals who may have an underlying genetic mutation such as a BRCA mutation.

Having the information about an underlying genetic risk can make a big difference both in prevention and in ensuring that patients who have already been diagnosed have the most effective treatment options.

Prevention

Knowing that a person carries certain high-risk cancer genes enables them to receive more frequent screening earlier in life, preventative surgeries, and/or chemoprevention. Early detection measures include yearly mammogram and breast MRIs alternating every 6 months. MRI starts as early as age 20 for high-risk genetic carriers. Mammograms should start as early as age 30 with physical breast examinations by a licensed health care provider two times per year. If a high-risk genetic carrier qualifies for preventative surgery, they may consider risk-reducing bilateral mastectomy or salpingo-oophorectomy, with the aim of reducing as much tissue and cells as possible.

Precision treatment options

The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer recommend genetic testing for all patients with recurrent or metastatic disease to identify those with a BRCA1/2 mutation who would benefit from treatment with a PARP inhibitor. The two PARP inhibitors that are currently approved in the breast cancer setting by the U.S. Food and Drug Administration are olaparib and talazoparib. Unfortunately, many patients who meet the criteria do not receive genetic testing for a variety of reasons. Advanced practitioners (APs) can play an integral role in the care of these patients by familiarizing themselves with the criteria, guiding patients through the genetic testing process, and explaining how the results can affect their treatment choices.

The Genetic Testing Process

Patients who are considered high risk should be given a questionnaire at their initial visit that evaluates their personal and family history of cancer. Their responses will determine whether they meet the NCCN guidelines for genetic testing. If they do, pre-test education should be given, followed by referral to a geneticist. Here, they can individualize each treatment plan to their risk assessment. Pre-, peri-, and post-test counseling is critical.

Genetic testing can be performed by a blood or saliva test. It takes approximately 3 weeks to receive results. When results are available, a genetic counselor will see the patient back in the office to review the results. This is covered by most insurance companies for patients who meet the criteria based on their family or personal history.

The AP's Role

APs play a crucial role in the genetic testing process. By collecting a thorough family history during routine clinical encounters, carefully reviewing the information, listening to the patient’s concerns about their cancer risk, and sharing their knowledge about genetic testing guidelines, APs can help bridge the gap to ensure that individuals who could benefit from genetic testing can receive it. When identified, the AP should submit a patient referral to genetic services.

APs also serve an important role in educating patients about reducing their risk of breast cancer. Recommendations include:

• Maintaining a healthy weight;
• Staying active with regular physical exercise;
• Limiting or abstaining from alcohol intake;
• Avoiding smoking;
• Eating a nutritious diet rich in fruits, vegetables, and whole grains; and
• Breastfeeding, if possible.

In addition to these lifestyle habits, regular screenings are vital. Early detection of breast cancer is key: when it’s found early, the chances of successful treatment are much higher.¹⁰ APs are important advocates for encouraging regular mammograms/self-exams and ensuring that their patients know the importance of these life-saving screenings.

An important component of patient care, regardless of specialty, is genetic cancer risk assessment. Cancer risk is an important part of a patient assessment, and including genetic evaluation is essential when performing comprehensive cancer risk evaluation. Genetic testing can provide key information that can inform both prevention and treatment options. We still have a long way to go to educate our community—including both patients and health care professionals—on genetic consultation and testing when there is any family history of cancer.

References

1. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2024. Accessed November 9, 2023. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf.
2. Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(4):380-391.
3. Susan G. Komen. BRCA genes and genetic testing. Accessed January 13, 2025. https://www.komen.org/breast-cancer/risk-factor/gene-mutations-genetic-testing/brca-genes/.
4. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416.
5. Hereditary Breast Cancer Guide for Health Professionals. UT Southwestern Medical Center. Accessed December 30, 2024. https://utswmed.org/conditions-treatments/genetics-and-hereditary-cancers/guide-hereditary-cancer-health-pros/hereditary-breast-cancer-guide-health-pros/.
6. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26(7):1291-1299.
7. King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646.
8. Goldgar DE, Easton DF, Deffenbaugh AM, et al. Integrated evaluation of 13 breast cancer risk-associated genes. J Natl Cancer Inst. 2010;102(10):789-798.
9. The White House. Precision Medicine Initiative. Accessed November 24, 2024. https://obamawhitehouse.archives.gov/precision-medicine.
10. National Breast Cancer Organization. Breast cancer facts. Accessed November 25, 2024. https://www.nationalbreastcancer.org/breast-cancer-facts/.