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

PurposeHallmarks 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 designUsing 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.ResultsThirty-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.ConclusionsGermline 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

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

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 (HR) 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 HR pathway. RESULTS: 31% of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous ovarian carcinomas had similar rates of HR mutations to serous carcinomas (28% vs. 31%, p=0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic HR mutations was highly predictive of primary platinum sensitivity (p=0.0002) and improved overall survival (p=0.0006), with median overall survival 66 months in germline HR mutation carriers, 59 months in cases with a somatic HR mutation, and 41 months for cases without an HR mutation. CONCLUSIONS: Germline or somatic mutations in HR genes are present in almost one-third of ovarian carcinomas, including both serous and non-serous histologies. Somatic BRCA1/2 mutations and mutations in other HR genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of HR mutations in non-serous carcinomas supports their inclusion in PARP inhibitor clinical trials

Systematic review of knowledge translation strategies in the allied health professions

<p>Abstract</p> <p>Background</p> <p>Knowledge translation (KT) aims to close the research-practice gap in order to realize and maximize the benefits of research within the practice setting. Previous studies have investigated KT strategies in nursing and medicine; however, the present study is the first systematic review of the effectiveness of a variety of KT interventions in five allied health disciplines: dietetics, occupational therapy, pharmacy, physiotherapy, and speech-language pathology.</p> <p>Methods</p> <p>A health research librarian developed and implemented search strategies in eight electronic databases (MEDLINE, CINAHL, ERIC, PASCAL, EMBASE, IPA, Scopus, CENTRAL) using language (English) and date restrictions (1985 to March 2010). Other relevant sources were manually searched. Two reviewers independently screened the titles and abstracts, reviewed full-text articles, performed data extraction, and performed quality assessment. Within each profession, evidence tables were created, grouping and analyzing data by research design, KT strategy, targeted behaviour, and primary outcome. The published descriptions of the KT interventions were compared to the Workgroup for Intervention Development and Evaluation Research (WIDER) Recommendations to Improve the Reporting of the Content of Behaviour Change Interventions.</p> <p>Results</p> <p>A total of 2,638 articles were located and the titles and abstracts were screened. Of those, 1,172 full-text articles were reviewed and subsequently 32 studies were included in the systematic review. A variety of single (n = 15) and multiple (n = 17) KT interventions were identified, with educational meetings being the predominant KT strategy (n = 11). The majority of primary outcomes were identified as professional/process outcomes (n = 25); however, patient outcomes (n = 4), economic outcomes (n = 2), and multiple primary outcomes (n = 1) were also represented. Generally, the studies were of low methodological quality. Outcome reporting bias was common and precluded clear determination of intervention effectiveness. In the majority of studies, the interventions demonstrated mixed effects on primary outcomes, and only four studies demonstrated statistically significant, positive effects on primary outcomes. None of the studies satisfied the four WIDER Recommendations.</p> <p>Conclusions</p> <p>Across five allied health professions, equivocal results, low methodological quality, and outcome reporting bias limited our ability to recommend one KT strategy over another. Further research employing the WIDER Recommendations is needed to inform the development and implementation of effective KT interventions in allied health.</p