Large panel genetic testing in breast cancer produces more questions than answers

While large genetic testing panels promise to uncover clues about patients' DNA, a team of researchers has found that those powerful tests tend to produce more questions than they answer. In a study of 278 women with early onset breast cancer who did not have the BRCA gene mutations, the researchers found that only 2.5% of the patients had inherited mutations that were actually clinically actionable. Experts do not yet know how to interpret most of the mutations discovered by the test—known as massively parallel gene sequencing.

Results of the study, led by author Kara Maxwell, MD, PhD, a fellow in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, were presented during the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Large genetic testing panels sometimes reveal mutations in genes that are associated with an increased risk in developing cancer. BRCA1 and BRCA2 genes are prime examples, where women can opt for mastectomies and ovary removal surgery—which research shows reduces their risk of developing those cancers. However, there is not yet guidance for clinicians on how to care for patients who exhibit other types of mutations, such as CHEK2 and ATM. These are known as variants of unknown significance (VUS).

"We're in a time where the testing technology has outpaced what we know from a clinical standpoint. There's going to be a lot of unknown variants that we're going to have to deal with as more patients undergo large genetic testing panels," said Maxwell. "It's crucial that we figure out the right way to counsel women on these issues, because it can really provoke a lot of anxiety for a patient when you tell them, 'We found a change in your DNA and we don't know what it means.'"

The team studied 278 patients who had a breast cancer diagnosis at younger than 40 years, were not carriers of the BRCA1 or BRCA2 mutations, and had no family history of ovarian cancer.

The researchers performed massively parallel gene sequencing to detect 22 known or proposed breast cancer susceptibility genes in each woman. Though the testing did reveal multiple variants of genes that are known to confer increased risk of breast cancer in patients who develop the disease young, only 2.5% of patients tested were found to have mutations that are actionable under current treatment guidelines, including TP53, CDKN2A, MSH2, and MUTYH.

In all, the sequencing revealed reportable variants in more than 30% of the patients.

"Knowing there is a mutation may not help us any more than knowing that the person has a positive family history—which we already know," Nathanson said. "We don't know yet what to do with the information on an individual basis, and there certainly are no clinical standards."

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