ASCO in partnership with the Society of Surgical Oncology (SSO) has released a new guideline addressing recommendations in germline testing in patients with breast cancer.1 The guideline provides oncologists with a framework for how to approach germline testing and recommendations for who should be tested and what genes should be tested to support risk assessment and treatment decision-making.
Guideline Recommendations
According to the guideline, BRCA1/2 testing should be offered to all women younger than age 65 at the time of a new stage I to III or de novo stage IV or metastatic breast cancer. The guideline also recommends offering such testing to women older than age 65 if they are candidates for PARP inhibitor therapy, have triple-negative breast cancer, were assigned male sex at birth, or have a personal or family history suggestive of a pathogenic variant. BRCA1/2 testing is also recommended for all patients with either local or metastatic recurrent breast cancer who are candidates for PARP inhibitor therapy. Additionally, the guideline Expert Panel recommends offering BRCA1/2 testing to patients with a second primary cancer either in the contralateral or ipsilateral breast.
The guideline suggests that tests for high-penetrance genes beyond BRCA1/2, such as PALB2, TP53, PTEN, STK11, and CDH1, may inform management decisions and family risk assessment. Testing for these high-penetrance genes should therefore be offered to appropriate patients. In contrast, the guideline states that tests for moderate-penetrance breast cancer genes offer no benefits for treatment of the index breast cancer; however, such testing may inform risks of second primary cancer or family risk assessment.
Individualized posttest genetic counseling is recommended for patients with pathogenic variants. In patients without a pathogenic variant on testing, the guideline suggests counseling may still provide benefit if the patient has a significant family history of cancer. The guideline also states that a specific multigene panel, when ordered, should consider the patient’s personal as well as family history.
Variants of uncertain significance (VUS), according to the guideline, should not change treatment. The guideline noted that patients should know that VUS may be reclassified as pathogenic. These patients should also understand the necessity of periodic follow-up.
Recommendations in Context
Isabelle Bedrosian, MD
Guideline Co-Chair Isabelle Bedrosian, MD, of The University of Texas MD Anderson Cancer Center, said that there are two important goals for germline testing: guiding treatment decision-making and helping patients and clinicians better understand future risk.
In germline BRCA1/2 mutation carriers, for instance, PARP inhibitors are an important component of care, so the identification of women who carry BRCA1/2 alterations could potentially impact the treatment offered, Dr. Bedrosian said. She noted that germline testing is used to help better understand the risk of future cancer for the patient as well as for family members, and “understanding these risks is important, so mitigation strategies can be implemented.”
Dr. Bedrosian added that the ability to test for the presence of germline mutations is “very exciting” and provides insights into biology, etiology, and potential new therapies. “However, the field of clinical cancer genetics is also rapidly evolving, and our ability to test for mutations is being outpaced by our ability to fully understand the implications of finding a positive test result,” she said.
Mark E. Robson, MD
Mark E. Robson, MD, of the Memorial Sloan Kettering Cancer Center, who also served as a Guideline Co-Chair, said that although germline testing was initially focused on risk assessment and prediction of secondary cancers, it has become increasingly relevant for surgical treatment planning and selection of therapy. “We’ve evolved from something that was personal utility, something that people just wanted to know for their own reasons, into something that has much more [to offer] in the way of clinical utility and therapeutic relevance,” he said.
Dr. Robson noted the concept behind the new guideline is to expand the pool of patients who might potentially benefit from testing. Additionally, the guideline creates “an age criterion rather than a strong family history criterion to make it easier for those with limited access to genetics professionals to get their testing done,” he added.
The guideline communicates the ongoing important role of cancer genetics professionals in interpreting results. “There’s also a role for cancer genetics professionals in making sure that the correct genes are tested,” Dr. Robson explained, “and that people who have a need for testing beyond breast cancer susceptibility genes get the appropriate evaluation.”
According to Dr. Bedrosian, there are several areas in clinical cancer genetics that remain unknown. “They include a better understanding of the cancer risks associated with many of the genes that are currently included in germline panels [and] how penetrance of germline mutations may be modified by factors such as age, family, and reproductive history,” she said.
In addition, Dr. Bedrosian said, more research is needed to better determine the clinical relevance of VUS, how best to implement testing to ensure equitable access, and how to ensure patients undergoing testing fully understand the significance of testing as well as test results.
REFERENCE
1. Bedrosian I, Somerfield MR, Achatz MI, et al: Germline testing in patients with breast cancer: ASCO-SSO guideline. J Clin Oncol. January 4, 2024 (early release online).
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, January 5, 2024. All rights reserved.
