No Clinical Benefit to Expanding Gene Panel Beyond Ovarian and Breast Cancer Genes in High-risk Women

Expanding a panel of tested genes beyond the known breast and ovarian cancer-specific genes in patients with breast and ovarian cancer did not confer any clinical benefit. Instead, such an expansion resulted in more questions than answers for patients with breast and ovarian cancer.1

Running large, multigene sequencing panels to evaluate risk of cancer is increasing in medicine as the price of sequencing technology decreases and more precise approaches to cancer care gain momentum. These tests are particularly common among patients with breast and ovarian cancers even though questions remained about the growing list of mutations that have suspected but unproven correlations with breast and ovarian cancer risk.

Sometimes genetic panels reveal mutations in genes with known associations for an increased risk of developing cancer, such as BRCA1 and BRCA2 mutations. These mutations might prompt women to elect for mastectomies and removal of ovaries to decrease risk of developing cancers. Revealing mutations in other genes, such as CHEK2 or ATM, does not yet have clinical guidance.

This study examined whether a benefit occurred when the gene panel expanded to include non-breast/ovarian cancer and even noncancer susceptibility genes. Whole exome sequencing and analysis of a 180-gene panel included 25 breast/ovarian cancer specific-susceptibility genes, 123 other cancer-susceptibility genes, and 32 genes related to cardiovascular disease risk. Researchers assessed this panel in 404 people from 253 families with breast and/or ovarian cancer.

Researchers also assessed the clinical utility of a classification methodology for mutational variants based on the American College of Medical Genetics and Genomics (ACMG) guidelines to help define mutations. ACMG recently published these guidelines to address inconsistent classification of mutations among clinical laboratories.

This study identified 1605 genetic variants using the ACMG guidelines, finding that 11% of patients without BRCA1/2 mutations had clinically actionable variants in other genes of cancer susceptibility. Most of these genes moderately increased the risk of developing breast or ovarian cancers.

In addition, 12% of patients had variants of uncertain significance (VUS) in well-established cancer susceptibility genes. When genes not known to be involved in breast or ovarian cancers were included, the VUS rate increased to 78%.

"Adding on the additional cancer susceptibility genes to the 'breast cancer susceptibility' genes opened up more questions than it answered," said Katherine Nathanson, MD, professor of medicine, Department of Medicine, Division of Translational Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and study leader.

"This study therefore adds to prior findings of ours, and demonstrates little incremental utility to testing non-breast cancer susceptibility genes in breast cancer families."

Reference

1. Maxwell KN, Hart SN, Vijai J. Evaluation of ACMG-guideline-based variant classification of cancer susceptibility and non-cancer-associated genes in families affected by breast cancer [published online ahead of print May 5, 2016]. Am J Hum Genet. doi:10.1016/j.ajhg.2016.02.024.

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