Pegylated liposomal doxorubicin (PLD) treatment for recurrent epithelial ovarian cancer (rEOC): Implications of BRCA mutations.

Abstract

5043 Background: Does BRCA status affect outcome of rEOC patients treated with PLD? Tumors deficient in homologous recombination (HR) DNA repair are sensitive to platinums. Recurrences likely reflect acquired platinum resistance, perhaps from recovering BRCA function (as suggested in preclinical studies). We now investigate whether sensitivity to PLD and other DNA damaging agents is retained in BRCA mutation carriers (BRCA+) with rEOC. Methods: We retrospectively analyzed rEOC patients treated with PLD as second- or third-line from 1998 to 2009 in 4 institutions (Israel, Italy, NY):155 rEOC patients have been evaluated of which 38 (24.5%) are BRCA+ and 117 (75.5%) non-hereditary consisting of 35 (22.5%) who tested negative and 82 (53%) untested, (excluding 10 patients with a family history in a first-degree relative). Results: Median age is 59 (31-83) years; 44 (28%) patients have a platinum free interval (PFI) of < 6 months and 111 (72 %) of > 6 months; 104 (67%) received PLD as second-line and 55 (33%) as third-line. PLD with a platinum was used in 90 (58%) and PLD alone in 65 (42%). BRCA+ vs. non-hereditary comparisons show: response rate 68.4% vs. 49%; median TTF (time to failure) 11.4 (CI 95% 5.9-18.1) vs. 9.4 (CI 95% 7.7-11.9) m; OS (overall survival) 56.8 (CI 95% 32.5-87.9) vs. 22.6 (CI 95% 16.0-34.1) m this last comparison (p = 0.005). Cox survival models showed OS to be associated with BRCA status when adjusting for age and PFI (p = 0.02; hazard ratio, BRCA- vs. BRCA+ = 3.5); PFI was significantly associated with overall survival (p = 0.04). BRCA+are being further analyzed for role of subsequent platinums and other drugs. Conclusions: BRCA mutation carriers rEOC have improved outcome, suggesting persistent defects in HR, accounting for responses to other DNA damaging agents even after acquired platinum resistance. The potential role for PARP inhibitors after chemotherapy induced-remission is reinforced by these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Yissum-Hadasit Doxil Royalties