Implications of BRCA mutations on recurrent ovarian cancer outcome treated with pegylated liposomal doxorubicin (PLD)

Introduction: Tumors deficient in homologous recombination (HR) DNA repair are exquisitively sensitive to platinums. In this study we are evaluating BRCA status effect on outcome in patients with recurrent ovarian cancer (reflecting some platinum resistance) treated with PLD. Recent case control studies have confirmed such sensitivity in BRCA mutation carriers with epithelial ovarian cancer (EOC) in comparison to staged and histology matched controls with ‘non‐hereditary’ ovarian cancer. We set out to perform a similar retrospective analysis in such patient population with recurrent disease treated with PLD. In this setting, the tumors have likely acquired some elements of platinum resistance, perhaps indicative of recovering BRCA function (as demonstrated in preclinical studies). However, if overexpression of platinum exporters plays a role in acquiring resistance, sensitivity to agents such as PLD or topotecan might be retained. Material and Methods: We compare outcome in BRCA1/2 mutation carriers with recurrence stages III/IV carcinomas treated in 4 institutions (now from 3; 4th awaiting for data) with PLD as a 2nd or 3rd line. One hundred and eighteen patients with papillary serous, endometrioid, and poorly differentiated carcinoma have been evaluated so far, 32 BRCA mutation carriers and 86 non‐hereditary (67 tested negative). Results: Median age is 59 years (31–83); 64 (54.2%) of patients have a platinum free interval of 1 year. Seventy two patients (61.0%) received PLD as 2 nd line and 46 (39.0%) as 3rd line. PLD and platinums regimens were used in 81 cases (68.6%) and PLD alone in 37 (31.4%). Patients with BRCA1/2 mutations have an estimated median TTP (time to progression) and OS (overall survival) of 10.23 (CI 95% 9.12–11.42) and 100.7 (CI indeterminate) months, respectively, after onset of treatment with PLD, versus 6.53 (CI 95% 4.69–8.38) and 24.96 (CI 95% 12.47–37.46) months, respectively, for the control group. Matching of known BRCA mutation patients with controls will be used to confirm that this difference is not attributed to other prognostic factors. Age, year of diagnosis, platinum‐free interval, 2nd or 3rd line PLD treatment as well as stage and histology match will be the bases for matching in future analysis. In addition, we are seeking information on response to regimens of PLD alone or with platinum in BRCA mutated patients. Conclusions: BRCA mutations in recurrent EOC patients might predict an improved response to PLD. This suggests persistent defects in HR even in patients who have acquired platinum resistance. Pooling our data may allow for additional analyses by type of mutation and contribution by other drugs. The potential role for PARP inhibitors in the treatment of these patients after chemotherapy induced remission is reinforced by these findings. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B200.