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BRCA1/2 somatic, germline mutations, expression loss may help predict benefit of PARP1 inhibitors

-- Eric Metcalf

Thursday, July 8, 2010 (Last Updated: 07/09/2010)

THURSDAY, July 8 (HealthDay News) -- Somatic and germline mutations and expression loss in BRCA1 and BRCA2 are common enough in ovarian cancer to warrant assessment in trials for predicting the benefit of poly(ADP ribose) polymerase-1 (PARP1) inhibitors, according to research published online July 6 in the Journal of Clinical Oncology.

Bryan T.J. Hennessy, M.D., of the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues analyzed data from samples of 235 ovarian cancers. BRCA1/2 was sequenced in all; it was assessed by copy number analysis in 95 and by tiling assays in 65. Germline DNA was sequenced when available for cancers with BRCA1/2 mutations.

The researchers found BRCA1 mutations in 31 tumors and BRCA2 mutations in 13; one was determined to be a homozygous BRCA1 intragenic deletion. Mutations were especially common in high-grade serous cancers, occurring in 23 percent. In 28 patients with available germline DNA, nine of 21 BRCA1 mutations were somatic, as were two of seven BRCA2 mutations. Mutations were associated with improved progression-free survival after platinum-based chemotherapy. BRCA1/2 deficiency -- defined as mutations or expression loss -- was also associated with progression-free survival.

"In summary, loss of BRCA function due to frequent somatic aberrations in ovarian cancers likely deregulates homologous recombination and thereby increases sensitivity to platinum drugs and possibly also to PARP1 inhibitors. This is consistent with prior studies of germline BRCA1/2 mutations. The novel observation that somatic BRCA1/2 aberrations occur frequently could significantly increase the ability to identify patients who will benefit from PARP1 inhibitors in ovarian cancer clinical trials," the authors conclude.

Several authors disclosed financial relationships with Myriad Genetics.

Abstract
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Specialties Gastroenterology
Hematology & Oncology
Pathology

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