Data from Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas

Abstract

<div>Abstract<p><b>Purpose:</b> Hallmarks of germline <i>BRCA1/2</i>-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic <i>BRCA1/2</i> mutations and mutations in other homologous recombination DNA repair genes is uncertain.</p><p><b>Experimental Design:</b> Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including <i>BRCA1</i>, <i>BRCA2</i>, and 11 other genes in the homologous recombination pathway.</p><p><b>Results:</b> Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: <i>BRCA1</i>, <i>BRCA2</i>, <i>ATM</i>, <i>BARD1</i>, <i>BRIP1</i>, <i>CHEK1</i>, <i>CHEK2</i>, <i>FAM175A</i>, <i>MRE11A</i>, <i>NBN, PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i>. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, <i>P</i> = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (<i>P</i> = 0.0002) and improved overall survival (<i>P</i> = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.</p><p><b>Conclusions:</b> Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic <i>BRCA1/2</i> mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline <i>BRCA1/2</i> mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. <i>Clin Cancer Res; 20(3); 764–75. ©2013 AACR</i>.</p></div>