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.
To determine whether platinum-DNA adducts and/or mRNA expression of the excision nuclease excision repair cross-complementation 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/microg 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, 0.385-0.958; 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.
Darcy
Kathleen M
KM
Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, USA.
Tian
Chunqiao
C
Reed
Eddie
E
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D018736:DNA Adducts / Q000097:blood*; D004273:DNA, Neoplasm / Q000097:blood; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
D018736:DNA Adducts; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D017239:Paclitaxel; D002945:Cisplatin