DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy

Our plain-English summary of DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy, by N. Erčulj, V. Kovač, J. Hmeljak, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: N. Erčulj, V. Kovač, J. Hmeljak, A. Franko, M. Dodič-Fikfak, V. Dolžan
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(10):1609-17
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This study from Slovenia looked at whether common inherited variations in four DNA-repair genes (XRCC1, NBN, RAD51 and XRCC3) were linked to how patients with malignant mesothelioma fared on gemcitabine-platinum chemotherapy. The 109 patients (99 pleural, 10 peritoneal) were diagnosed between 1997 and 2010. All were treated at the Institute of Oncology, Ljubljana. Of the 109, 78 (71.6%) had occupational or environmental asbestos exposure. None of the gene variants was associated with tumor response. After adjustment for clinical factors, carrying an XRCC1 399Gln variant was associated with shorter overall survival (hazard ratio 1.70; 95% CI 1.06–2.73). Carriers who also had above-median C-reactive protein levels had a median overall survival of 10.0 months, compared with 17.0 months for other patients. XRCC1 399Gln carriers had lower odds of low white-cell, neutrophil and platelet counts during treatment. Variants in NBN and XRCC3 were linked to some other side effects. The authors concluded that DNA-repair gene variants, particularly XRCC1 Arg399Gln, may modify response to this chemotherapy. They said the findings should be confirmed in independent studies and noted their relatively small sample size.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic association study of treated patients. Separate case-control analyses were used for tumor response and toxicity, and Cox survival analysis for survival.
• Who was studied: 109 patients with histologically confirmed malignant mesothelioma (99 pleural, 10 peritoneal). They were diagnosed between 1997 and 2010 at the University Clinic of Pulmonary and Allergic Diseases in Golnik and at the University Clinical Centre Maribor, Slovenia, and all were treated at the Institute of Oncology, Ljubljana. The group was 83 men and 26 women, with a median age of 62. Asbestos exposure (occupational or environmental) was recorded for 78 patients (71.6%).
• Exposure: Ten inherited variants (SNPs) in the DNA-repair genes XRCC1, NBN, RAD51 and XRCC3. These were studied in patients receiving first-line gemcitabine combined with cisplatin or carboplatin. Asbestos exposure was recorded as a patient characteristic but was not the focus of the analysis.
• Main results:
  • No investigated variant was associated with complete or partial tumor response, among the 105 patients assessable for response.
  • In unadjusted analysis, no variant was associated with progression-free or overall survival. In the model adjusted for clinical predictors, XRCC1 Arg399Gln was associated with overall survival (HR = 1.70; 95% CI 1.06–2.73; p = 0.028).
  • Carriers of at least one XRCC1 399Gln allele who had above-median C-reactive protein levels (n = 35) had a median overall survival of 10.0 months, compared with 17.0 months for other patients (log-rank p < 0.001). In the adjusted model this group's HR was 2.47 (95% CI 1.56–3.92).
  • In the adjusted model, carriers of the XRCC1 399Gln allele had lower odds than non-carriers of three toxicities: leukopenia of grade 2 or higher (OR = 0.25; 95% CI 0.09–0.67), neutropenia of grade 2 or higher (OR = 0.24; 95% CI 0.09–0.68), and thrombocytopenia of grade 1 or higher (OR = 0.27; 95% CI 0.09–0.84).
  • NBN 3474A/C+C/C genotypes were associated with higher odds of alopecia of grade 2 or higher (OR = 2.81; 95% CI 1.13–7.00; p = 0.027).
  • XRCC3 -316A/G+G/G genotypes were associated with lower odds of thrombocytopenia of grade 1 or higher (OR = 0.18; 95% CI 0.05–0.68; p = 0.012).
  • XRCC3 241Thr/Met+Met/Met genotypes were associated with lower odds of nausea/vomiting of grade 2 or higher (OR = 0.34; 95% CI 0.14–0.85; p = 0.021).
• The authors' conclusion: The authors concluded that their results support the hypothesis that DNA-repair gene variants, particularly XRCC1 Arg399Gln, may modify response to gemcitabine-platinum chemotherapy in mesothelioma patients. They said the findings should be replicated in independent prospective studies.
• Limitations the authors state:
  • The relatively small sample size gave low statistical power in some cases, which might lead to false findings.
  • DNA came from different sources (tumor tissue or blood), which might have influenced results. The authors reported confirming concordance between the two sources.
  • The findings on the combination of the XRCC1 variant and C-reactive protein are preliminary because of wide confidence intervals, and need validation in larger cohorts.
  • The lack of association for RAD51 -98G>C may reflect insufficient statistical power, given the low frequency of the variant and the small study population.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Gemcitabine, Chemotherapy, Overall Survival, confidence interval, Odds Ratio, Neutropenia.

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