Objective: Identification of biomarkers that could predict gemcitabine efficacy and toxicity is a key issue in the development of individualized therapy. The aim of our study was to evaluate the influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma (MM). Methods: In total, 107 patients with MM, treated with gemcitabine-platinum chemotherapy, were genotyped for 11 polymorphisms in deoxycytidine kinase, ribonucleotide reductase M1 (RRM1), and cytidine deaminase genes using KASPar assays. Binary logistic regression was used to evaluate the influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity, while their influence on survival was estimated by Cox proportional hazards model. A haplotype analysis was carried out to assess the combined effect of RRM1 polymorphisms. Results: Deoxycytidine kinase and cytidine deaminase polymorphisms did not influence treatment outcome in patients with MM. In multivariable analysis, RRM1 2927A)Cpolymorphism significantly decreased overall survival probability šhazard ratio (HR)=2.02; 95% confidence interval (CI)=1.11-3.65; P=0.021đ. Twopromoter polymorphisms, RRM1 -524T)C and -37C)A, decreased the odds of nausea/vomiting grade)/=2 occurrence šodds ratio (OR)=0.25; 95% CI=0.10-0.60; P=0.002 and OR=0.26; 95% CI=0.11-0.63; P=0.003, respectivelyđ. RRM1 TTCCA haplotype was associated with worse tumor response (OR=16.67; 95% CI=2.38-100.00; P=0.004) and worse overall survival (HR=2.97; 95% CI=1.46-6.06; P=0.003) compared with the most frequent TTCAA haplotype, while TCACA haplotype influenced nausea/vomiting grade)/=2 occurrence (OR=0.27; 95% CI=0.12-0.60; P=0.001). Conclusion: RRM1 polymorphisms as well as haplotypes showed an association with gemcitabine treatment efficacy and toxicity; therefore, they should be validated as potential markers for the prediction ofclinical outcome in patients with MM.
COBISS.SI-ID: 29194201
Soluble mesothelin-related peptides (SMRP) are a potential tumor marker for malignant mesothelioma. The aim of this study was to determine the differencesin SMRP levels in patients with malignant mesothelioma before treatment and in various responses to treatment and to investigate whether SMRP level could be useful in evaluating tumor response to treatment. The study included patients with malignant mesothelioma treated at the Institute of Oncology Ljubljana between March 2007 and December 2009. Blood samples werecollected before treatment and/or in various responses to treatment. SMRP levels were determined using ELISA assay based upon a combination of two monoclonal antibodies. Mann-Whitney test was used to determine the differencesin SMRP levels in various responses to treatment. Median SMRP was 2.80 nmol/L (range 0.00-34.80) before treatment, 0.00 nmol/L (range 0.00-0.00)in complete response, 0.48 nmol/L (range 0.00-4.40) in partial response, 1.65 nmol/L (range 0.00-20.71) in stable disease and 7.15 nmol/L (range 0.44-31.56) in progressive disease. Pre-treatment SMRP levels were significantly higher than in stable disease, partial response and complete response (p=0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p( 0.001). Our findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment.
COBISS.SI-ID: 29611737
INTRODUCTION: Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy. METHODS: In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model. RESULTS: There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p ( 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A)C, XRCC3 -316A)G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity. CONCLUSIONS: Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.
COBISS.SI-ID: 512300345