Extreme drug resistance assay results do not influence survival in women with epithelial ovarian cancer.

OBJECTIVES: Extreme drug resistance (EDR) assays have been used to identify chemotherapy regimens that are least likely to be of clinical benefit in the treatment of epithelial ovarian cancer (EOC). We sought to examine the impact of EDR assay-guided therapy on the outcome of patients with EOC in the primary and recurrent settings. METHODS: We conducted a retrospective review of demographic, pathologic, EDR assay and clinical outcome data from 377 patients with EOC who had an assay sent at the time of their primary or subsequent cytoreductive surgeries. Multivariate analyses were performed using Cox proportional hazards method to identify and estimate the impact of independent prognostic factors on time to progression (TTP), overall survival (OS) and survival after recurrence (RS). RESULTS: Increasing age was associated with a worse OS and RS (HR=1.34; 95% CI, 1.14-1.58 and HR=1.14; 95% CI, 1.00-1.31, respectively for each decade increase in age). Surgical outcome in the setting of primary or secondary cytoreduction remained an important predictor of survival. Compared with patients with microscopic residual disease, patients who were left with 0.1 to 1.0 cm and >1.0 cm residual disease had an increased risk of recurrence (HR=1.94; 95% CI, 1.33 to 2.84 and HR=3.61; 95% CI; 2.07 to 6.39, respectively) and death (HR=1.59; 95% CI, 1.03 to 2.45; and HR=2.14; 95% CI, 1.09 to 4.20, respectively). For patients who recurred, those who did not undergo secondary cytoreductive surgery and patients who were left with >1.0 cm residual had an increased risk of death compared to patients with microscopic residual (HR=2.13; 95% CI, 1.28 to 3.54; and HR=2.84; 95% CI, 1.71 to 4.71, respectively). EDR assay results analyzed for single agents or combinations of chemotherapies failed to independently predict patient outcomes no matter if the assay was performed at the time of the primary surgery or recurrence. CONCLUSION: EDR assay results do not independently predict or alter the outcomes of patients with EOC who are treated with the current standards of primary cytoreductive surgery followed by platinum and taxane combination chemotherapy.

BRCA1 promoter methylation predicts adverse ovarian cancer prognosis.

OBJECTIVE: To compare the clinical outcome of ovarian cancer patients whose tumors contain BRCA1 genes silenced by promoter hypermethylation to patients with germline BRCA1 mutations and to patients with wild-type BRCA genes. METHODS: Ovarian cancers from a hospital-based tumor bank were characterized as having a BRCA1 mutation; or a methylated BRCA1, BRCA1 pseudogene or MLH1 promotor; or a wild-type BRCA gene. Survival of patients with methylated BRCA1 promoters (N = 11) was compared to that of patients with wild-type BRCA genes (N = 30) and BRCA1 mutations (N = 22). A methylator phenotype was defined to include tumors with hypermethylation of BRCA1, hMLH1 and/or dBRCA1 pseudogene promoters (N = 23). RESULTS: All cohorts had comparable clinical factors except for age at diagnosis. Median age of methylated BRCA1 and wild-type BRCA patients was older than BRCA1 mutation carriers (60 and 63 versus 48 years; P = 0.04). The median disease-free interval was significantly shorter for patients with a methylated BRCA1 promoter (9.8 months) than for BRCA1 mutation carriers (39.5 months; P = 0.04). Median overall survival was also significantly shorter for patients with a methylated BRCA1 promoter (35.6 months) than BRCA1 mutation carriers (78.6 months; P = 0.02). The combined methylator phenotype cohort had significantly shorter survival (36.1 months) compared to wild-type BRCA patients (63.3 months; P = 0.02). CONCLUSION: These data suggest that methylation of the BRCA1 promoter is associated with poor patient outcome. BRCA1 may be part of a global panel of methylated genes associated with aggressive disease.