The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma

Our plain-English summary of The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma, by N. Erčulj, V. Kovač, J. Hmeljak, et al (Pharmacogenetics and Genomics, 2012).

The study

• Authors: N. Erčulj, V. Kovač, J. Hmeljak, A. Franko, M. Dodič-Fikfak, V. Dolžan
• Journal: Pharmacogenetics and Genomics
• Published: 2012;22(1):58-68
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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>C polymorphism significantly decreased overall survival probability [hazard ratio (HR)=2.02; 95% confidence interval (CI)=1.11-3.65; P=0.021]. Two promoter polymorphisms, RRM1 -524T>C and -37C>A, decreased the odds of nausea/vomiting grade≥2 occurrence [odds 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, respectively]. 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 of clinical outcome in patients with MM.

In plain English

This retrospective Slovenian study asked whether gemcitabine-pathway gene variants were linked to outcomes of gemcitabine-platinum chemotherapy in malignant mesothelioma. The authors tested 11 variants in three genes (DCK, RRM1 and CDA) in 107 patients (98 pleural, 9 peritoneal) diagnosed 1997–2010. Of these, 76 (71.0%) had asbestos exposure. DCK variants showed no associations with outcome. CDA variants alone did not affect survival, but one, -31delC, interacted significantly with the number of first-line chemotherapy cycles for overall survival; another, Lys27Gln, was linked to more nausea or vomiting only before adjustment. In adjusted analysis, RRM1 2927A>C carriers had worse overall survival (hazard ratio 2.02; 95% CI 1.11–3.65). Two other RRM1 variants were linked to lower odds of nausea or vomiting of grade 2 or higher. The RRM1 haplotype (variant combination) TTCCA was associated with worse tumor response and survival than the most common one. The authors noted a small sample and retrospective design, and judged the tumor-response link unlikely to be a true association because of very wide confidence intervals. They concluded that RRM1 variants should be confirmed in other patients as possible outcome markers.

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: Retrospective study of genetic variants (polymorphisms) and treatment outcome. Tumor response and toxicity were analyzed with a case-control design and logistic regression; survival was analyzed with Cox proportional hazards models.
• Who was studied: 107 patients with histologically confirmed malignant mesothelioma (98 pleural, 9 peritoneal), diagnosed between 1997 and 2010 in Slovenia and treated at the Institute of Oncology Ljubljana with first-line gemcitabine plus a platinum agent. There were 81 men and 26 women, with a median age of 62 years.
• Exposure: The study examined 11 polymorphisms in the DCK, RRM1 and CDA genes in patients receiving gemcitabine-platinum chemotherapy (mostly gemcitabine in prolonged infusion with cisplatin). Asbestos exposure was recorded at clinical interview: 76 patients (71.0%) were exposed. Asbestos exposure was examined as a clinical variable for survival but was not among the variables the authors reported as influencing overall survival. No fiber types are given.
• Main results:
  • Among the 101 patients who could be assessed for tumor response, the overall response rate (complete plus partial response) was 50.5%.
  • The authors stated that DCK and CDA polymorphisms showed no associations with treatment outcome. CDA polymorphisms did not influence overall survival in univariable analysis.
  • A significant interaction between the CDA -31delC polymorphism and the number of first-line chemotherapy cycles was observed for overall survival (HR = 0.57; 95% CI = 0.36–0.89; P = 0.013). After adjustment for other prognostic factors, this interaction remained significant (HR = 0.63; 95% CI = 0.40–1.00; P = 0.049).
  • In univariable analysis, CDA Lys27Gln was associated with a higher frequency of nausea/vomiting of grade 2 or higher (OR = 2.23; 95% CI = 1.01–4.91; P = 0.047). The authors reported that this association did not remain significant in the multivariable model.
  • In the multivariable model, the RRM1 2927A>C polymorphism was associated with worse overall survival (HR = 2.02; 95% CI = 1.11–3.65; P = 0.021).
  • Among carriers of at least one RRM1 2927C allele who received fewer than six cycles of first-line chemotherapy, the hazard of dying was more than eight-fold higher (HR = 8.13; 95% CI = 2.20–30.07; P = 0.002). The authors note that only four patients with the relevant genotype were in the group receiving fewer than six cycles.
  • After adjustment for age at diagnosis, RRM1 -524T>C was associated with lower odds of nausea/vomiting of grade 2 or higher (OR = 0.25; 95% CI = 0.10–0.60).
  • After adjustment for age at diagnosis, RRM1 -37C>A was associated with lower odds of nausea/vomiting of grade 2 or higher (OR = 0.26; 95% CI = 0.11–0.63; P = 0.003).
  • Compared with the most frequent haplotype (TTCAA), the RRM1 TTCCA haplotype was associated with worse tumor response in the adjusted model (OR = 16.67; 95% CI = 2.38–100.00; P = 0.004).
  • Compared with TTCAA, the RRM1 TTCCA haplotype was associated with worse overall survival in the adjusted model (HR = 2.97; 95% CI = 1.46–6.06).
  • Nausea/vomiting of grade 2 or higher was less frequent among carriers of the TCACA haplotype than among patients with the TTCAA haplotype (24.2 vs. 49.0% of patients). The association remained after adjustment for age (OR = 0.27; 95% CI = 0.12–0.60; P = 0.001).
• The authors' conclusion: The authors concluded that RRM1 polymorphisms and haplotypes could act as prognostic and predictive factors in patients with mesothelioma treated with gemcitabine-platinum chemotherapy. They wrote that, if confirmed in independent patient samples, this genotype information might be used to individualize gemcitabine-based chemotherapy.
• Limitations the authors state:
  • The low frequency of DCK variant alleles may have left too little statistical power to detect associations.
  • The sample size was small and only a limited number of candidate genes was investigated.
  • The study was restricted to key enzymes of a complex gemcitabine pathway, leaving out other possible candidate genes.
  • The study might be biased by its retrospective nature.
  • The cohort was heterogeneous in histological type, stage, performance status, first-line chemotherapy dose and use of second-line chemotherapy.
  • Different DNA sources were used for genotyping: tumor tissue for 42 patients and blood for 65.
  • Because the confidence intervals were very wide, the authors judged that the haplotype association with tumor response was not likely to be a true association. In that sentence the article names TTCAA, the reference haplotype, although the response association it reported was for TTCCA, so this appears to be a labeling error.

Topics

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

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

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