Abstract 4251: Paclitaxel is necessary for improved survival in epithelial ovarian cancers with somatic homologous recombination gene mutations
Authors: Jean Stephanie , Wubbenhorst Bradley , Li Jiaqi , Maxwell Kara N. , Fishbein Lauren , McLane Michael W. , Mitra Nandita , Zhang Lin , Nathanson Katherine L. , Tanyi Janos L. 
Published: August 2015

Abstract
The impact of somatic mutations and genomic alterations in determining the clinical outcome of sporadic epithelial ovarian cancer (EOC) remains uncertain. Our goal was to identify molecular markers of optimal cytoreduction, chemotherapeutic response, and survival. We focused on genes in the homologous recombination (HR) DNA repair pathway, as germline mutations in these genes confer improved survival, and data suggest that somatic mutations may similarly predict improved survival and chemosensitivity. One hundred fifty-eight patients were included with diagnoses of serous, endometrioid, or clear cell EOC and underwent primary cytoreduction followed by platinum-based chemotherapy. We performed targeted massively parallel sequencing of 53 genes in known genes from pathways such as HR and checkpoint inhibition in primary surgical samples. Patients were treated with platinum and cyclophosphamide (n = 24) or platinum and paclitaxel (n = 67). We detected 226 deleterious variants in 35 distinct genes. TP53 mutations were found in tumors from 90 subjects (56%) and deleterious mutations in HR genes in 45 (28%). Twenty-three patient tumors (15%) were found to have homozygous copy number loss of genes in the HR pathway. We did not detect an overall survival (OS) benefit in advanced stage patients treated with platinum whose tumors had HR mutations/loss as compared to those without HR defects. However, OS was significantly different between patients (p = 0.0028) whose tumors had HR mutations/loss if they received cyclophosphamide (median 24.1 months) as compared to paclitaxel (median 50.4 months). Furthermore, in patients with both TP53 and HR gene mutations or deletions, median OS improved to 76.6 months in the platinum and paclitaxel treated cohort (p = 0.0001). In this analysis by chemotherapy regimen and mutation status, the patients with TP53 and HR mutation/loss demonstrated worse median OS than those without such defects when treated with platinum and cyclophosphamide (24.1 months vs. 32.7 months respectively), but improved survival over patients without TP53 and HR defects when treated with platinum and paclitaxel (76.6 months vs. 44.4 months respectively, p = 0.0100). We also found that a somatic HR mutation was significantly associated with suboptimal debulking status (p = 0.012). Chances for optimal debulking and early stage were significantly increased in patients with PTEN mutations (p = 0.042), leading to OS benefit. The survival benefit attributed to platinum agents in HR deficient ovarian cancers may depend upon the use of paclitaxel in addition to platinum. This merits elucidation of the mechanism, and may be due to the mitosis cell cycle specificity of paclitaxel, and ensuing inhibition of HR deficient genomically unstable tumor subclones.
Citation Format: Stephanie Jean, Bradley Wubbenhorst, Jiaqi Li, Kara N. Maxwell, Lauren Fishbein, Michael W. McLane, Nandita Mitra, Lin Zhang, Katherine L. Nathanson, Janos L. Tanyi. Paclitaxel is necessary for improved survival in epithelial ovarian cancers with somatic homologous recombination gene mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4251. doi:10.1158/1538-7445.AM2015-4251