Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations.

Stephanie Jean,Chiara Benedetto,Bradley Wubbenhorst,Michael W Mclane,Dionyssios Katsaros,Kara N Maxwell,Janos L Tanyi,Jiaqi Li,Nandita Mitra,Emilie Marion Canuto,Lauren Fishbein,Lin Zhang,Katherine L Nathanson

doi:10.18632/oncotarget.9373

Stephanie Jean, Chiara Benedetto + Show 11 more

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https://doi.org/10.18632/oncotarget.9373

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PURPOSETo investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC).EXPERIMENTAL DESIGNWe performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins.RESULTSHR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs. 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/− cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs. 29.5 months (95% CI 17.7-50.5), p = 0.0005).CONCLUSIONSPrevious studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel.

Highlights

Epithelial ovarian cancer (EOC) remains the most deadly gynecologic cancer in the United States, and the fifth leading cause of cancer deaths in women [1]
We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had homologous recombination (HR) mutations compared to those without (median OS of 49.6 months vs. 43.3 months, p = 0.87)
When stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/- cyclophosphamide (median OS of 90 months vs. 29.5 months, p = 0.0005)

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Introduction

Epithelial ovarian cancer (EOC) remains the most deadly gynecologic cancer in the United States, and the fifth leading cause of cancer deaths in women [1]. Several studies suggest that sporadic ovarian carcinomas with somatic mutations in BRCA1/2 display differential response to platinum treatment with improved survival [5,6,7]. Given this differential response, there is ongoing interest in expanding on the original concept of phenotype “BRCAness” [8], and identifying sporadic ovarian cancers with defects in the HR pathway that may benefit from platinum and PARP-inhibitor therapy [9, 10]. All recent studies examining genetic/genomic correlates of survival of EOC patients are comprised of patients treated with both adjuvant platinum and paclitaxel [3, 5, 7, 9]

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