The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient.

PURPOSE: Chemotherapy with platinum compounds and gemcitabine is frequently used in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients in which tyrosine kinase inhibitors (EGFR or ALK) cannot be administered. Unfortunately, less than half of the patients achieve the benefit from chemotherapy. Gemcitabine is an analog of deoxycytidine (pyrimidine antimetabolite) with antitumor activity. The excess of deoxycytidine synthesized by RRM1 enzyme activity may be a cause of competitive displacement of gemcitabine, which reduces the efficacy of this cytostatic. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of the RRM1 promoter (-37C>A, -524C>T) and the effectiveness of first-line chemotherapy based on platinum compounds and gemcitabine in NSCLC patients. PATIENTS AND METHODS: SNPs were determined by SNaPshot PCR(®) in DNA isolated from peripheral blood of 91 NSCLC patients. RESULTS: The median progression-free survival (PFS) was significantly longer in carriers of AA (-37C>A) as well as CC (-524C>T) genotype of RRM1 compared to patients with other genotypes (10.5 vs 3.5 months, p = 0.0437; HR = 2.17, 95 % CI 1.02-4.62 and 10.5 vs 3.5 months, p = 0.0343; HR = 2.12, 95 % CI 1.06-4.27). In addition, the CC genotype carriers (-37C>A) showed a significant increase in the risk of shortening overall survival (OS) in comparison to patients with AA or AC genotypes (9.5 vs 18 months, p = 0.0193; HR = 2.13, 95 % CI 1.13-4.03). CONCLUSIONS: Presence of rare AA (-37C>A) and CC (-524C>T) genotypes of the RRM1 may be favorable predictive factors for chemotherapy with platinum compounds and gemcitabine in NSCLC patients.

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients.

INTRODUCTION: Platinum-based chemotherapy and 3rd generation drugs is still the main treatment option for advanced non-small cell lung cancer (NSCLC) patients without activating EGFR mutations or ALK rearrangements. However, the side effects associated with cytostatics are well known. Changes in the genes (e.g. single nucleotide polymorphisms, SNPs) encoding proteins regulating DNA repair or cell division could potentially influence on both the susceptibility of cancer cells to chemotherapy, and the occurrence of toxicities. MATERIALS AND METHODS: In presented study, the relationship between the fourteen SNPs in nine DNA repair and cell division regulating genes: ERCC1, XPD, XPA, XPC, XRCC1, XPG, RRM1, BRCA1, STMN1 and the toxicity of first-line chemotherapy in NSCLC patients were investigated. SNPs were determined by SNaPshot PCR® in DNA isolated from peripheral blood of 55 NSCLC patients treated with platinum compound and vinorelbine. The toxicity of therapy was evaluated according to the Common Toxicity Criteria (CTC) Version 4.03. RESULTS: The odds ratio (OR) of severe haematological toxicity was significantly lower in carriers of the T allele of XRCC1 gene (1196A > G, OR = 0.22, 95 % CI: 0.06-0.82, p = 0.018) and higher in the carriers of the T allele (2704C > A) of XPC gene (OR: 7.50, 95 % CI: 0.89-63.17, p = 0.036) compared to the remaining patients. Risk of severe hepatotoxicity was significantly lower in carriers of the C allele of STMN1 (-2166T > C, OR = 0.09, 95 % CI: 0.01-1.12, p = 0.025) than in patients with T allele of this gene. In carriers of G allele (2251A > C, OR: 0.24, 95 % CI: 0.07-0.81, p = 0.017) and T (934G > A, OR: 0.26, 95 % CI: 0.07-0.90, p = 0.029) of XPD gene, risk of severe nephrotoxicity was significantly lower than in other patients. CONCLUSIONS: Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.