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Epithelial ovarian cancer patients with the gene mutation BRCA1 or BRCA2 were more likely to reach five-year survival than those without the mutation, according to the largest such observational study to date, published in the Journal of the American Medical Association (2012;307:335-421).

BRCA1... - Click to enlarge in new windowBRCA1

"It's an important step in really showing that there are important differences in the ways tumors behave," said corresponding author Paul Pharoah, PhD, Senior Clinical Research Fellow in the Department of Oncology and Public Health and Primary Care at the University of Cambridge. "And, it's important to start to reclassify tumors by their molecular differences in order to understand the molecular reasons for the differences in how they respond to therapy."


The researchers, from EMBRACE (Epidemiological Study of Familial Breast Cancer), kConFab (Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer), and The Cancer Genome Atlas Research Network, compared the five-year survival rates in a pooled analysis of 26 observational studies, which included data from 1213 epithelial ovarian cases with pathogenic germline mutations in BRCA1 (909 patients) or BRCA2 (304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).


The five-year survival rate for non-carriers was 36%, while the rate for BRCA1 carriers was 44% and for BRCA2 carriers was 52%.


Additional clinical testing is needed to pinpoint what causes tumors in BRCA1 and BRCA2 carriers to behave differently than tumors in non-carriers, Pharaoh noted in a telephone interview. But, the different prognoses could be a result of the defective molecular pathways-homologous recombination-in BRCA1 and BRCA2 carriers causing the tumors to be more sensitive to standard platinum-based chemotherapy.


The next step is further clinical trials that focus on the effects of more targeted therapies on BRCA1 and BRCA2 carriers to eventually find more targeted treatments.


"What we really want to know is how they [epithelial ovarian cancer patients with BRCA1 or BRCA2] respond differently to different therapies-because then you can target those therapies to those people most likely to respond," he said.

PAUL PHARAOH, PHD, a... - Click to enlarge in new windowPAUL PHARAOH, PHD, and his colleagues concluded that the results have potentially important implications for the clinical management of patients with epithelial ovarian cancer (EOCs): "Most immediately, our findings can be used by health care professionals for patient counseling regarding expected survival. BRCA1 and BRCA2 carriers with EOC respond better than noncarriers to platinum-based chemotherapies and have improved survival despite the fact that the disease is generally diagnosed at a later stage and higher grade....Our data provide further support that there may be different functional mechanisms involved in the etiology of different subtypes of EOCs and, therefore, different therapeutic targets based on germline and somatic genetic variation."