Genetic testing for breast cancer allows for personalized treatment that can improve patient outcomes. According to experts, it can be challenging to implement genetic testing in practice.^1-5

Genetic testing results can inform decisions about the extent of breast surgery, the optimal systemic treatment, and whether a patient should avoid radiation.^2-4

At the same time, it can be challenging for health care providers to ensure that patients undergo appropriate and timely genetic testing, receive adequate genetic counseling, and understand the implications of their test results.^1,5

Who Should Undergo Genetic Testing for Breast Cancer?

The criteria for genetic testing for breast cancer patients vary between guidelines.^4,6,7

NCCN Guidelines

The National Comprehensive Cancer Network (NCCN), on the other hand, does not recommend universal genetic testing for breast cancer patients.⁷ NCCN guidelines recommend testing for high-penetrance breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) in all male patients and certain female patients with breast cancer.

The guidelines recommend genetic testing for women who are 50 years of age or younger as well as those who have Ashkenazi Jewish ancestry, triple-negative breast cancer, multiple primary breast cancers (synchronous or metachronous), lobular breast cancer and a personal or family history of diffuse gastric cancer, or a family history of breast, ovarian, pancreatic, or prostate cancer (with additional stipulations).

The NCCN guidelines also recommend using genetic testing to guide the use of PARP inhibitors in the metastatic setting and to guide adjuvant treatment with olaparib in high-risk, HER2-negative breast cancer.

Another factor to consider when deciding which patients should undergo genetic testing is that research on this topic has often focused on younger patients, but the median age at breast cancer diagnosis is 63 years in the United States.^8-10

Older Population

Recent evidence suggests that pathogenic variants have a substantial clinical impact in the older population.^9,10 In an analysis of data from the Women’s Health Initiative, 3.55% of breast cancer patients aged 50-79 years were found to have pathogenic variants in breast cancer-associated genes.⁹

A study of women older than 65 years with and without breast cancer quantified the risk of breast cancer according to the presence of certain pathogenic variants.¹⁰ The researchers found that the remaining lifetime risk of breast cancer from ages 66 to 85 years was approximately 20% for women with pathogenic variants in BRCA1/2 and about 15% for women with pathogenic variants in CHEK2 and PALB2.

Read more: Breast Cancer Survivor

The findings, when considered in the context of tumor type, led the investigators to advise consideration of genetic testing for all women with triple-negative or estrogen receptor-negative breast cancer, regardless of age.

Genetic Testing for Breast Cancer Is Underused

Recent studies have suggested that genetic testing is underused in patients with breast cancer.²

In a study of more than 2500 women with breast cancer, 52.9% of those who were high risk underwent genetic testing.¹¹ The leading reason for not being tested was that the patient’s physician did not recommend it (56.1%). Patients also cited the high cost of testing (13.7%) and not wanting to undergo testing (10.7%).

In another study that included nearly 1.4 million cancer patients, 50% of male breast cancer patients and 26% of female breast cancer patients underwent genetic testing.¹²

Read more: Breast Cancer Statistics

Authors of a related editorial suggested that the underuse of genetic testing seen in this study may be the result of barriers related to the health care system, such as a lack of timely access to genetic counseling.¹³ The authors also suggested that underuse of testing could be a result of patient-related factors, such as being preoccupied with treatment, a lack of breast cancer awareness or interest, mistrust, or fear of the possible consequences of testing.

Genetic Counseling and Communicating Test Results

Guidelines recommend that patients who are eligible for genetic testing receive counseling from a genetic counselor, clinical geneticist, oncologist, surgeon, oncology nurse, or other health care professional with expertise and experience in cancer genetics.^3,4,6,7

Research has suggested that there is room for improvement in the provision of genetic counseling.^1,5 For example, in a study of breast cancer patients and their surgeons, 26% to 37% of patients underwent testing without seeing a genetic counselor.⁵

Clinicians’ skill in explaining test results to patients is essential for enabling patients to make appropriately informed decisions and can determine whether testing ultimately improves care and outcomes, experts say.^1,5

Using Genetic Test Results to Guide Treatment Decisions

Guidelines and experts recommend that genetic test results be used to guide treatment decisions. Testing should occur before the start of treatment, though that does not always happen in practice.^1,3,4,6,14 Guidelines also note that treatment approaches should be similar for women and men.^3,4

Decisions About Surgery

Waiting for genetic test results to start treatment is considered particularly important with regard to surgery, as the test results may influence decisions between lumpectomy and mastectomy in the affected breast or both breasts.^1,3,4,6,14

However, research suggests that genetic testing is sometimes performed after surgery. In the aforementioned study of breast cancer patients and their surgeons, 27% of patients who had a higher risk of genetic variants did not undergo genetic testing until after surgery.⁵ In addition, 17% to 38% of surgeons reported that they never postponed surgery to wait for test results.

Guidelines from the American Society of Clinical Oncology (ASCO), American Society for Radiation Oncology (ASTRO), and Society of Surgical Oncology (SSO) recommend offering breast-conserving therapy to patients with newly diagnosed breast cancer who have mutations in moderate-risk breast cancer genes.³

The guidelines also state that patients with newly diagnosed breast cancer who have mutations in BRCA1/2 may be considered for breast-conserving therapy. However, bilateral mastectomy should be discussed with these patients due to the risk of contralateral breast cancer or new cancer in the ipsilateral breast.

For patients with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, the guidelines state that nipple-sparing mastectomy is “a reasonable approach in appropriately-selected patients.”

Decisions About Radiation

The ASCO/ASTRO/SSO guidelines state that radiation should not be withheld because of a patient’s mutations status, except for patients who have TP53 mutations.³

In general, radiation is not recommended for patients with germline TP53 mutations. These patients should undergo mastectomy instead. However, these patients may receive radiation if they have a significant risk of locoregional recurrence.

There is no evidence to suggest that radiation increases toxicity or the risk of contralateral breast cancer in patients with mutations in other breast cancer-associated genes, according to the guidelines.

Decisions About Systemic Therapy

The ASCO/ASTRO/SSO guidelines recommend platinum chemotherapy (rather than taxanes) to treat patients with advanced breast cancer who have BRCA1/2 mutations and have not previously received platinum chemotherapy.³

The guidelines also state that PARP inhibitors (olaparib and talazoparib) are preferable to non-platinum chemotherapy for the treatment of metastatic, HER2-negative breast cancers in patients with mutations in BRCA1/2.

There are no data to support the routine addition of platinum chemotherapy to anthracycline- and taxane-based chemotherapy in the adjuvant or neoadjuvant setting, according to the guidelines.

A recent update to these guidelines recommends that patients with early-stage, HER2-negative breast cancer with a high risk of recurrence and BRCA1/2 pathogenic or likely pathogenic variants should be offered 1 year of adjuvant olaparib after the completion of (neo)adjuvant chemotherapy and local treatment, including radiation.¹⁵

Genetic Testing for Breast Cancer May Lead to Inappropriate Treatment

Genetic testing can sometimes result in patients receiving treatment that deviates from guidelines, research suggests.^1,5,14,16,17

In a study of more than 20,000 women with breast cancer, patients who had pathogenic variants in BRCA1/2 and other breast cancer-associated genes had patterns of treatment that potentially deviated from guidelines.¹⁶

Specifically, patients with mutations in breast cancer-associated genes were more likely to undergo bilateral mastectomy, despite eligibility for unilateral mastectomy. They were also less likely to receive radiation after lumpectomy, despite an indication for radiation. And they were more likely to receive chemotherapy for early-stage hormone receptor-positive disease, despite potentially being eligible to skip chemotherapy.

Another issue is that genetic testing can reveal variants of uncertain significance (VUS), which have an unknown clinical impact.¹ For example, studies have suggested that an estimated 5% to 10% of patients with breast cancer have a VUS in a BRCA gene. Management of these patients (as well as those found to have negative genetic testing results) should be guided by their family history and the presence of any other predisposing factors, not by the variant.^1,14

Most VUSs are eventually reclassified as benign. However, finding VUSs can generate the same sort of patient anxiety as a positive test result and may alter clinical management.^1,14,17

In the study of breast cancer patients and their surgeons, 51% of average-risk patients found to have a VUS underwent bilateral mastectomy, compared to 42% of those with no mutations, suggesting that clinicians and/or patients possibly misunderstood the VUS finding.⁵

This article originally appeared on Cancer Therapy Advisor.

References

Ahn S, Port ER. Genetic testing in patients with newly diagnosed breast cancer: Room for improvement. J Clin Oncol. 2017;35(20):2221-2223. doi:10.1200/JCO.2017.72.8816
Tung N, Desai N. Germline genetic testing for women with breast cancer: Shifting the paradigm from whom to test to whom NOT to test. J Clin Oncol. 2021;39(31):3415-3418. doi:10.1200/JCO.21.01761
Tung NM, Boughey JC, Pierce LJ, et al. Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline. J Clin Oncol. 2020;38(18):2080-2106. doi:10.1200/JCO.20.00299
Hassett MJ, Somerfield MR, Baker ER, et al. Management of male breast cancer: ASCO guideline. J Clin Oncol. 2020;38(16):1849-1863. doi:10.1200/JCO.19.03120
Kurian AW, Li Y, Hamilton AS, et al. Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. J Clin Oncol. 2017;35(20):2232-2239. doi:10.1200/JCO.2016.71.6480
Manahan ER, Kuerer HM, Sebastian M, et al. Consensus guidelines on genetic testing for hereditary breast cancer from the American Society of Breast Surgeons. Ann Surg Oncol. 2019;26(10):3025-3031. doi:10.1245/s10434-019-07549-8
NCCN Clinical Practice Guidelines: Genetic/familial high-risk assessment: Breast, ovarian and pancreatic: Version 2.2024. National Comprehensive Cancer Network. Published September 27, 2023. Accessed October 14, 2023.
Cancer Stat Facts: Female Breast Cancer. National Cancer Institute Surveillance, Epidemiology & End Results Program. Accessed October 14, 2023.
Kurian AW, Bernhisel R, Larson K, et al. Prevalence of pathogenic variants in cancer susceptibility genes among women with postmenopausal breast cancer. JAMA. 2020;323(10):995-997. doi:10.1001/jama.2020.0229
Boddicker NJ, Hu C, Weitzel JN, et al. Risk of late-onset breast cancer in genetically predisposed women. J Clin Oncol. 2021;39(31):3430-3440. doi:10.1200/JCO.21.00531
Kurian AW, Griffith KA, Hamilton AS, et al. Genetic testing and counseling among patients with newly diagnosed breast cancer. JAMA. 2017;317(5):531-534. doi:10.1001/jama.2016.16918
Kurian AW, Abrahamse P, Furgal A, et al. Germline genetic testing after cancer diagnosis. JAMA. 2023;330(1):43-51. doi:10.1001/jama.2023.9526
Stadler ZK, Schrag D. Genetic testing for cancer susceptibility. JAMA. 2023;330(1):30-32. doi:10.1001/jama.2023.9474
Yadav S, Couch FJ. Germline genetic testing for breast cancer risk: The past, present, and future. Am Soc Clin Oncol Educ Book. 2019;39:61-74. doi:10.1200/EDBK_238987
Tung NM, Zakalik D, Somerfield MR; Hereditary Breast Cancer Guideline Expert Panel. Adjuvant PARP inhibitors in patients with high-risk early-stage HER2-negative breast cancer and germline BRCA mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update. J Clin Oncol. 2021;39(26):2959-2961. doi:10.1200/JCO.21.01532
Kurian AW, Ward KC, Abrahamse P, et al. Association of germline genetic testing results with locoregional and systemic therapy in patients with breast cancer. JAMA Oncol. 2020;6(4):e196400. doi:10.1001/jamaoncol.2019.6400
Mighton C, Shickh S, Uleryk E, Pechlivanoglou P, Bombard Y. Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: A systematic review and meta-analysis. Genet Med. 2021;23(1):22-33. doi:10.1038/s41436

Genetic Testing for Breast Cancer: Who Should Receive It and How Results Should Inform Treatment