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Breast cancer susceptibility panel testing rarely found actionable mutations
Few BRCA1/BRCA2-negative women with early onset breast cancer who underwent massively parallel genomic sequencing harbored clinically actionable mutations, according to study results presented at the ASCO Annual Meeting.
“We’re in a time where the testing technology has outpaced what we know from a clinical standpoint,” Kara Maxwell, MD, PhD, fellow in the division of hematology-oncology at Perelman School of Medicine at the University of Pennsylvania, said in a press release. “There’s going to be a lot of unknown variants that we’re going to have to deal with as more patients undergo large gene panel testing. 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 really know what it means.’”
Maxwell and colleagues evaluated germline sequencing data on 22 genes from 278 patients with early onset breast cancer. All patients were BRCA1 and BRCA2 negative, and none had a personal or family history of ovarian cancer.
Sixty percent of patients harbored at least one rare variant, and 30% of patients harbored a clinically reportable variant — either a deleterious variant, likely deleterious variant or a variant of uncertain significance — in known cancer susceptibility genes. Eleven percent of patients had a deleterious or likely deleterious variant.
Only seven patients (2.5%) harbored a deleterious or likely deleterious genetic variant for which clinical management guidelines exist. They included four patients with mutated TP53, one with mutated CDKN2A, one with mutated MSH2 and one biallelic MUTYH carrier.
Researchers observed six patients (2.2%) who were heterozygous carriers of a deleterious or likely deleterious MUTYH variant.
Twenty-four patients (8.6%) had a deleterious or likely deleterious variant in a moderate penetrance cancer susceptibility gene for which no clinical guidelines exist.
An additional 49 patients (18%) harbored a variant of unknown significance in a high or moderate penetrance gene. In total, 19% of patients were found to have a variant of uncertain significance.
“Our results point to a critical need for large-scale cooperative studies to determine how to use the findings of multiplex panel testing for breast cancer susceptibility,” Maxwell said during a panel discussion.
The Prospective Registry of Multiplex Testing (PROMPT) study — led by investigators Mark E. Robson, MD, and Kenneth Offit, MD, MPH, at Memorial Sloan Kettering Cancer Center, Fergus J. Couch, PhD, at Mayo Clinic and Susan M. Domchek, MD, of the Abramson Cancer Center of the University of Pennsylvania — is one such study currently underway, Maxwell said.
For more information:
Maxwell KN. Abstract #1510. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: One researcher reports research funding from Myriad Genetics.