The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma

Our plain-English summary of The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma, by N. Erčulj, V. Kovač, J. Hmeljak, et al (Annals of Oncology, 2012).

The study

• Authors: N. Erčulj, V. Kovač, J. Hmeljak, V. Dolžan
• Journal: Annals of Oncology
• Published: 2012;23(4):961-7
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM.

Patients And Methods: In total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms.

Results: GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis.

Conclusions: Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.

In plain English

This Slovenian study asked whether common inherited variations in DNA-repair genes (XPD, ERCC1) and drug-detoxifying genes (GSTP1, GSTM1, GSTT1) were linked to outcomes in malignant mesothelioma. The authors genotyped 133 patients diagnosed 1997–2010: 97 given platinum-based chemotherapy, 36 not. No single variant was linked to tumor response or overall survival, though one variant combination (the CAAC haplotype) was linked to both survival measures in platinum-treated patients. In platinum-treated patients, the common (wild-type) XPD 751Lys/Lys and ERCC1 8092C/C forms were associated with better progression-free survival. After adjustment for clinical factors, only ERCC1 8092C>A stayed significant (HR = 1.69, 95% CI 1.04–2.74, P = 0.034). Patients with wild-type XPD 312Asp/Asp or ERCC1 8092C/C forms had side effects more often. After adjustment, only the link with low platelet counts (thrombocytopenia) remained. Deletion of both copies of the GSTT1 gene was linked to worse progression-free survival only in patients not given platinum. The authors concluded that XPD and ERCC1 genotyping might serve as a marker of platinum efficacy and toxicity. They noted the study was retrospective and relatively small, and called for a larger prospective study.

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 pharmacogenetic (gene-variant association) study of patients' treatment records and DNA
• Who was studied: 133 patients with histologically confirmed malignant mesothelioma, diagnosed at the University Clinic of Pulmonary and Allergic Diseases in Golnik and the University Clinical Centre Maribor, Slovenia, between 1997 and 2010. 97 were treated with platinum-based chemotherapy and 36 were not. The 36 untreated patients were significantly older and more often had non-epithelioid tumors.
• Exposure: The exposures studied were platinum-based first-line chemotherapy (mostly combinations with gemcitabine or pemetrexed) and eight gene variants: XPD Asp312Asn, XPD Lys751Gln, ERCC1 19007T>C, ERCC1 8092C>A, GSTP1 Ile105Val, GSTP1 Ala114Val, and GSTM1 and GSTT1 gene deletion. Asbestos exposure was only one of the clinical variables examined for influence on progression-free survival; no fiber types or doses are reported.
• Main results:
  • Among 89 patients assessable for tumor response, the overall response rate was 53.9% (5 complete, 43 partial responses).
  • None of the individual gene variants was significantly correlated with achieving a complete or partial tumor response.
  • In platinum-treated patients (n = 97), the wild-type XPD 751Lys/Lys and ERCC1 8092C/C genotypes were associated with reduced hazard of disease progression. The article prints HR = 2.01 (95% CI 1.18–3.41, P = 0.010) and HR = 1.81 (95% CI 1.15–2.86, P = 0.011) respectively. These genotypes had no effect in patients not treated with platinum.
  • After adjustment for non-epithelioid histology, TNM stage and LDH level, only ERCC1 8092C>A remained significantly associated with progression-free survival (HR = 1.69, 95% CI 1.04–2.74, P = 0.034).
  • In patients not treated with platinum (n = 36), homozygous GSTT1 gene deletion (both copies missing) was associated with worse progression-free survival (HR = 2.55, 95% CI 1.04–6.24, P = 0.041).
  • No individual gene variant influenced overall survival in either treatment group.
  • Among platinum-treated patients with toxicity data (n = 94), thrombocytopenia occurred in 25.7% of patients with wild-type XPD 312Asp/Asp versus 5.0% of carriers of at least one 312Asn allele (P = 0.008).
  • Thrombocytopenia occurred in 20.4% of platinum-treated patients with wild-type ERCC1 8092C/C versus 4.3% of those with at least one 8092A allele (P = 0.032).
  • Grade 2 alopecia (hair loss) was more common with wild-type XPD 312Asp/Asp than in 312Asn carriers (67.6% versus 36.7%, P = 0.005). It was also more common with wild-type ERCC1 8092C/C than in 8092A carriers (60.4% versus 34.8%, P = 0.014).
  • Nausea/vomiting of grade 2 or higher occurred in 46.9% of patients with wild-type ERCC1 8092C/C versus 21.7% of those with 8092C/A or 8092A/A (P = 0.011).
  • Patients with homozygous GSTM1 gene deletion had less leukopenia of grade 2 or higher than carriers of at least one functional allele (30.9% versus 51.3%, P = 0.048).
  • After adjustment for clinical factors, only thrombocytopenia remained significantly associated with the gene variants: XPD Asp312Asn (OR = 0.19, 95% CI 0.04–0.87, P = 0.032) and ERCC1 8092C>A (OR = 0.18, 95% CI 0.03–0.96, P = 0.044).
  • In haplotype analysis of platinum-treated patients, the polymorphic CAAC haplotype was significantly associated with progression-free survival (P = 0.005; Table 3 HR 1.95, 95% CI 1.23–3.12) and with overall survival (P = 0.041 in the text).
  • Carriers of the CGCT haplotype were more likely to develop thrombocytopenia than those with the wild-type AGCT haplotype (OR = 11.32, 95% CI 2.07–62.07, P = 0.005).
• The authors' conclusion: The authors concluded that wild-type XPD and ERCC1 genotypes were associated with improved survival and more treatment-related toxic effects. They concluded that XPD and ERCC1 genotyping might serve as a genetic marker of platinum-based chemotherapy efficacy and toxicity in patients with malignant mesothelioma.
• Limitations the authors state:
  • The study was retrospective.
  • The cohort was heterogeneous in clinical and treatment characteristics.
  • Different DNA sources (tumor tissue and blood) were used for genotyping, which might lead to misinterpretation. The authors found no difference in genotype frequencies between the two sources.
  • The patient cohort was relatively small.
  • The findings need validation in a larger prospective study.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Progression-Free Survival.

Related studies

• The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma — N. Erčulj, V. Kovač, et al. (2012)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)
• Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery — L. Frischknecht, M. Meerang, et al. (2015)
• Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study — I. Dianzani, L. Gibello, et al. (2006)

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