Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients

Abstract

Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non^small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen. Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's m 2 tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. Results: The CDA Lys 27 Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade z3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys 27 Lys polymorphism. Conclusions: Our data suggested the role of CDA Lys 27 Lys polymorphism as a possible predictive marker of activity, toxicity,TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys 27 Lys CDA and offer a potential new tool for treatment optimization. Lung cancer is the leading cause of cancer-related deaths inWestern countries. Non -small cell lung cancer (NSCLC) accounts for >85% of primary lung cancers and approximately two thirds of NSCLC patients are diagnosed at an advanced stage (1).Pooled data from older randomized trials of cisplatin-based chemotherapy versus best supportive care showed that cisplatin-based chemotherapy was associated with a modest improvement in overall survival (OS; ref. 2). In more recent randomized trials, new cytotoxic drugs such as paclitaxel, docetaxel, vinorelbine, or gemcitabine in combination with a platinum compound have shown an absolute 15% to 20% improvement of survival in favor of chemotherapy versus best supportive care. In particular, the 1-year survival rate for best supportive care was 11% to 17% versus 30% to 35% for chemotherapy, which prolonged median survival by 3 to 4 months (3). However, none of the last-generation doublets was shown to be superior to the others and they all seemed to have reached the therapeutic plateau, with objective response rates of 30% to 40%, median survival time of 8 to 10 months, and 1-year survival rate of 30% to 40% (4). Indeed, a four-arm randomized phase III trial showed no substantial differences in response rate, time to progression (TTP), and OS among paclitaxel (24-hour infusion) -cisplatin, docetaxel-cisplatin, paclitaxel-carboplatin, and gemcitabine-cisplatin combination (4). Therefore, the cisplatin-gemcitabine combination is one of the standard regimens for the treatment of ...

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

“…All polymorphisms followed Hardy-Weinberg equilibrium, and genotype frequencies for the CDA A79C SNP were comparable with those reported in a previous study in Caucasians affected by NSCLC, 19 as calculated with the w 2 test (P ¼ 0.836).…”

“…19,27,29 No significant associations were detected for both RRM1 G2464A and A2455G polymorphisms and RRM1 gene expression. These results are in agreement with a previous study showing no significant association between mRNA levels of wild-type and polymorphic types in RRM1 G2464A alone (P ¼ 0.301), or a combination of several types of RRM1, including RRM1 A2455G, in 62 human cancer cell lines were used, including six lung cancer cell lines.…”

“…48 These data might explain the correlation of the A79A genotype with clinical benefit, time-to-progression and overall survival in advanced NSCLC patients treated with cisplatin plus gemcitabine. 19 However, functional genomics analysis showed a moderate decrease in CDA activity in the C79C variant with respect to the wildtype genotype, 49 and no effects of this polymorphism on gemcitabine pharmacokinetics were observed in a study carried out in 256 Japanese patients treated with gemcitabine. 50 These conflicting results suggest that genotype-phenotype correlation of CDA, as well as the role of this SNP in the pharmacokinetics/pharmacodynamics of gemcitabine is still unclear, and should be further evaluated with appropriate retrospective and prospective studies including analysis of genotype, gene expression and activity in tissues, pharmacokinetics and correlation with clinical outcome after gemcitabine therapy.…”

“…16 Recent studies evaluated also specific single-nucleotide polymorphisms (SNPs) within the CDA gene, 17 and found that the CDA A79C was a predictive marker of response, toxicity, time-to-progression and survival in advanced NSCLC patients treated with gemcitabine and cisplatin. 18,19 Resistance to gemcitabine was also associated with RR overexpression in several cancer cells. 20,21 In particular, an increase in the expression of the RRM1 has been associated with gemcitabine resistance in NSCLC cell lines, 22 while clinical studies demonstrated that NSCLC patients with low mRNA expression benefited from gemcitabine-cisplatin chemotherapy.…”

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…In a recent prospective non-randomized clinical pharmacogenomic study among non-small cell lung cancer patients treated with cisplatin plus gemcitabine, the CDA Lys 27 Lys polymorphism genotype significantly correlated with improved clinical benefit, worse hematological toxicity, including neutropenia and thrombocytopenia, as well as longer time to progression and overall survival (OS) than the other CDA genotypes. 3 In a more recent non-randomized, retrospective larger study of 149 patients with locally advanced pancreatic cancer patients receiving combinations of gemcitabine and platinum drugs, the CDA Lys 27 Lys polymorphism was associated with less hematological toxicity and no survival benefit compared with patients with either the CDA Lys 27 Gln or CDA Gln 27 Gln genotype. 4 However, other data does not find an association between this CDA polymorphism and treatment outcome with gemcitabine.…”