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

• Published in: Clinical cancer research Vol. 20; no. 3; pp. 764 - 775
• Main Authors: Pennington, Kathryn P., Walsh, Tom, Harrell, Maria I., Lee, Ming K., Pennil, Christopher C., Rendi, Mara H., Thornton, Anne, Norquist, Barbara M., Casadei, Silvia, Nord, Alexander S., Agnew, Kathy J., Pritchard, Colin C., Scroggins, Sheena, Garcia, Rochelle L., King, Mary-Claire, Swisher, Elizabeth M.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2014
• Subjects: Abdomen; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma - genetics; Carcinoma - mortality; Drug Resistance, Neoplasm - genetics; Fallopian Tube Neoplasms - drug therapy; Fallopian Tube Neoplasms - genetics; Fallopian Tube Neoplasms - mortality; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Homologous Recombination - drug effects; Homologous Recombination - genetics; Humans; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - mortality; Pharmacology. Drug treatments; Platinum Compounds - therapeutic use; Tumors; Peritoneal carcinoma; Homologous recombination; Malignant tumor; Fallopian tube; Survival; Genetic disease; Somatic mutation; Ovary; Platinum; Abdominal disease; Female genital system; Gene rearrangement; Predictive factor; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-2287

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: 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 BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: 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: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 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. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. Clin Cancer Res; 20(3); 764–75. ©2013 AACR.