A Gynecologic Oncology Group Study of Platinum-DNA Adducts and Excision Repair Cross-Complementation Group 1 Expression in Optimal, Stage III Epithelial Ovarian Cancer Treated with Platinum-Taxane Chemotherapy

Abstract

To determine whether platinum-DNA adducts and/or mRNA expression of the excision nuclease excision repair crosscomplementation group 1 (ERCC1) from peripheral blood leukocytes (PBL) were associated with clinical outcome in women with epithelial ovarian cancer (EOC), participants that had previously untreated, optimally resected, stage III EOC were randomized to paclitaxel plus cisplatin or carboplatin. DNA and RNA were extracted from PBLs collected 20 to 28 h post-drug infusion. DNA adducts were measured by atomic absorption spectroscopy. ERCC1 expression was evaluated by reverse transcription-PCR. There were 170 cases fully evaluable for DNA adducts and ERCC1 mRNA expression. Adduct levels ranged from 0.43 to 131 fmol platinum/Mg DNA in 140 samples; and adducts were not detectable in 30 samples. ERCC1 mRNA was detectable in 132 samples and undetectable in 38. ERCC1 mRNA expression in PBLs was not associated with any clinical end point measured. The presence of detectable versus undetectable adducts was associated with longer median progression-free survival (20.4 versus 15.6 months; P = 0.084) and overall survival (60.3 versus 36.3 months; P = 0.029), respectively. Unadjusted Cox regression modeling indicated a trend toward a reduced risk of disease progression [hazard ratio (HR), 0.686; 95% confidence interval (95% CI), 0.447-1.054; P = 0.086] and a statistically significant reduction in the risk of death (HR, 0.607; 95% CI,; P = 0.032) for women with detectable versus undetectable adducts. After adjusting for clinicopathologic variables, detectable adducts were not an independent predictor of progression-free survival or overall survival. The presence of platinum-DNA adducts, but not ERCC1 mRNA expression, in PBLs was associated with better survival, but was not an independent predictor of clinical outcome in optimal advanced EOC. [Cancer Res 2007;67(9):4474-81]

Correlation of ERCC1 expression in peripheral blood lymphocytes with outcomes of patients with gastric cancer treated with oxaliplatin-based adjuvant chemotherapy

“…In epithelial ovarian cancer, Darcy et al (2007) analyzed whether mRNA expression of ERCC1 in PBLs was associated with clinical outcomes in patients treated with platinum-taxane chemotherapy, although negative results were reported. Herein, we assessed correlations between expression of ERCC1 in PBLs and outcomes in 48 gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy.…”

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

“…Low ERCC1 protein expression was related to improved outcomes for adjuvant platinum-based chemotherapies in non-smallcell lung cancer (NSCLC) patients (10). Other studies have shown a correlation between increased gene and/or protein ERCC1 expression and unresponsiveness and/or decreased survival after platinum-based chemotherapy in different tumor types (11)(12)(13)(14). However, a high ERCC1 level might also be a positive prognostic variable because it may increase the removal of carcinogenic DNA lesions.…”

DNA Repair Enzymes and Platinum Drug Resistance in Tumors

“…More recently in a study involving over 700 completely resected tumors from patients with non-small-cell lung cancer, a signifi cant survival benefi t from cisplatin-based adjuvant chemotherapy compared to observation was associated with the absence of ERCC1 protein as assessed by immunohistochemistry (8). However, a prospective study in 170 patients with previously untreated ovarian cancer evaluating ERCC1 mRNA in peripheral blood leukocytes as a tumor surrogate, found no correlation with any clinical endpoint measured after receiving platinum-based chemotherapy (9). Finally, a genetic polymorphism in ERCC1 (codon 118 C to T) resulting in decreased ERCC1 protein levels has been associated with platinum sensitivity and higher response rates in colon and ovarian cancer (10).…”