BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin.

ABSTRACT

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI) 11.4-21.6] versus 8.1 months (95% CI 6.1-10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI 32.5-indeterminate) versus 22.6 months (95% CI 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.