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The Effect of Germline Mutations on Breast Cancer Treatment

Patients with breast cancer for whom germline genetic testing reveals pathogenic mutations often receive treatment that deviates from standard therapeutic guidelines, according to results of a population-based cohort study published today in JAMA Oncology.

The use and importance of germline genetic testing for patients with cancer has increased in recent years as our understanding has grown regarding mutations that increase cancer susceptibility and as targeted treatments such as poly ADP ribose polymerase (PARP) inhibitors have been indicated for specific mutations.

"The primary reason for testing breast cancer patients is to target prevention strategies for second cancers and for relatives who share an identified pathogenic variant," write the researchers in their publication, led by first author Allison W. Kurian, MD, MSc, Director of the Stanford Women's Clinical Cancer Genetics Program and Associate Professor of Medicine and of Health Research and Policy at Stanford University School of Medicine. "Integrating genetic testing into breast cancer care has been complex and challenging. There is wide variability in which clinician orders testing and discloses results; in the clinical significance of results; and in how clinicians interpret results to patients. Little is known about the association between germline testing results and treatment."

In order to answer the question of how germline testing results impact treatment, the researchers examined data from the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and California on women aged 20 or older diagnosed with stages 0 to III breast cancer between 2014 and 2016. Of 119,198 patients, the researchers analyzed treatment for the 20,568 women (17.3%) who underwent genetic testing within three months of their diagnosis.

"The results suggest that breast cancer treatment of pathogenic variant carriers is less concordant with practice guidelines, particularly for radiotherapy and chemotherapy," state Dr. Kurian and colleagues.

Carriers of pathogenic BRCA1 and BRCA2 mutations were more likely to receive bilateral mastectomy for a unilateral tumor (61.7% vs 24.3%), were less likely to receive postlumpectomy radiotherapy (50.2% vs 81.5%), and were more likely to receive chemotherapy for early-stage estrogen receptor (ER)/progesterone receptor (PR)-positive cancer (38.0% vs 30.3%). Similar treatment discrepancies were seen for carriers of pathogenic mutations in other genes associated with breast cancer, including ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53.

Based on evidence from observational studies and simulation modeling, current practice guidelines suggest discussing the option of bilateral mastectomy with patients who have pathogenic variants of BRCA1/2, PTEN, and TP53; however, the guidelines do not suggest bilateral mastectomy for carriers of ATM and CHECK2 variants, citing a lack of sufficient evidence.

Regarding the reduced rates of postlumpectomy radiotherapy for carriers of pathogenic variants, the investigators acknowledge the possibility that some patients had subsequent mastectomy as an alternative to radiotherapy. "We speculate, however, that lower postlumpectomy radiotherapy rates… might reflect concerns about whether radiotherapy is associated with increases in cancer risks or toxic effects in these patients," write the authors, noting that although the safety of radiation treatment in TP53 pathogenic variant carriers is considered doubtful, patients with TP53 mutations only constituted 0.1% of the patient sample; thus unanswered questions remain regarding the causes of the discrepancy in radiotherapy usage.

Even after adjustment for factors associated with chemotherapy decision making, such as age, cancer stage and grade, and 21-gene recurrence score, carriers of BRCA1/2 mutations and, to a lesser degree, carriers of other pathogenic mutations were more likely to receive chemotherapy. "There is a growing consensus that many women with stages I to II, ER/PR-positive, [human epidermal growth factor receptor 2 (HER2)]-negative breast cancer may safely forego chemotherapy," write Dr. Kurian and colleagues. Evidence has been mixed regarding the increased benefit from chemotherapy for patients with BRCA1/2 mutations, and a study of patients with CHEK2 mutations did not find greater benefit with chemotherapy; therefore guidelines do not recommend that germline testing results affect decision making regarding chemotherapy for ER/PR-positive, HER2-negative breast cancer.

"Multiplex sequencing for germline cancer susceptibility genes has quickly been adopted in oncology practice, sometimes outpacing the evidence base," conclude the investigators. "We believe more research is needed to confirm our results and to evaluate long-term outcomes of pathogenic variant carriers to understand treatment decision making and consequences."

For More Information

Kurian AW, Ward KC, Abrahamse P, et al (2020). Association of germline genetic testing results with locoregional and systemic therapy in patients with breast cancer. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamanetworkopen.2019.20471

Image Credit: National Human Genome Research Institute

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