Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients

Our plain-English summary of Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients, by T. Powrózek, D.M. Kowalski, P. Krawczyk, et al (Clinical Lung Cancer, 2014).

The study

• Authors: T. Powrózek, D.M. Kowalski, P. Krawczyk, R. Ramlau, T. Kucharczyk, E. Kalinka-Warzocha, M. Knetki-Wróblewska, K. Winiarczyk, W. Dyszkiewicz, M. Krzakowski, J. Milanowski
• Journal: Clinical Lung Cancer
• Published: 2014;15(6):455-65
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients.

Patients And Methods: Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients.

Results: Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients.

Conclusion: Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.

Copyright © 2014 Elsevier Inc. All rights reserved.

In plain English

This retrospective study, carried out at four oncology centers in Poland, looked at 59 mesothelioma patients (31 men, 28 women, median age 62). Between 2008 and 2012 they were given first-line chemotherapy with pemetrexed, mostly combined with cisplatin. Using DNA from blood samples, the authors tested whether inherited variants in three genes (TS, MTHFR and ERCC1) were linked to how well treatment worked. The study did not examine asbestos exposure. Disease was controlled in 79.7% of patients. Median progression-free survival was 9 months and median overall survival 20 months. Previous surgery, anemia and weight loss were linked to earlier progression or shorter survival. Most gene variants showed no link to outcome, and none affected overall survival. One TS variant, called 1494del6, was linked to differences in disease control and progression-free survival. In a combined analysis its hazard ratio was 2.3258 (95% CI 1.1566 to 4.6766), but the article is inconsistent about which form of the variant carried the higher risk. The authors concluded that this marker should be studied further. They noted that their small, mixed and retrospective sample limited the study's power.

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 multicenter study of gene variants (polymorphisms) and chemotherapy outcomes
• Who was studied: 59 mesothelioma patients (31 men and 28 women, median age 62 years) treated with first-line pemetrexed-based chemotherapy between 2008 and 2012. Blood samples came from 4 oncology centers in Poland, and patients were observed up to February 2014.
• Exposure: Not an asbestos-exposure study; asbestos exposure was not assessed. The factors studied were first-line chemotherapy (53 patients cisplatin and pemetrexed, 3 carboplatin and pemetrexed, 3 pemetrexed alone) and inherited variants in the TS, MTHFR and ERCC1 genes, measured in DNA from blood.
• Main results:
  • Whole group: 9 patients (15.3%) had a partial response, 38 (64.4%) stable disease and 12 (20.3%) progressive disease. The overall disease control rate was 79.7%.
  • Median progression-free survival for the whole group was 9 months.
  • Median overall survival for the whole group was 20 months.
  • Early progression was significantly more frequent in patients with anemia (8 of 22, 36.4%, vs 4 of 37, 10.8%, without anemia) and in patients with previous surgery (6 of 9, 66.7%, vs 6 of 50, 12%, without), according to Table 2.
  • Median progression-free survival was significantly shorter in patients with weight loss (6 vs 14 months) and in patients with previous surgical resection (2 vs 10 months), according to Table 2.
  • The authors reported that shorter overall survival was significantly associated with anemia, weight loss, previous surgery and not receiving second-line chemotherapy.
  • The authors reported that having the 6-base-pair insertion in both copies of the TS gene (1494del6) was the only genetic factor linked to more frequent early progression. Table 3 lists early progression in 9 of 29 (31%) of these patients.
  • Median progression-free survival was shorter in patients with the insertion in both TS alleles (7 months) than in patients with the deletion in at least one allele (14 months), but the difference was not statistically significant (P .06 in Table 3).
  • In the multivariate analysis of progression-free survival, the TS 1494del6 genotype row (labeled D/D) had a hazard ratio of 2.3258 (95% CI 1.1566 to 4.6766), P .0185.
  • None of the studied TS, MTHFR or ERCC1 variants affected median overall survival.
• The authors' conclusion: The authors concluded that most of the TS, MTHFR and ERCC1 variants studied failed to predict outcome with pemetrexed-based chemotherapy. They found that variants of TS 1494del6 were associated with differences in disease control rate and progression-free survival, and said this marker should be evaluated further.
• Limitations the authors state:
  • The study may have had limited power to detect links between genotype and outcome because the patient group was small and varied and the analysis was retrospective.
  • The results need confirmation in large prospective trials with more than one chemotherapy arm.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Chemotherapy, Mesothelioma, Pleural Mesothelioma, Antifolate, Progression-Free Survival, Overall Survival, Disease Progression.

Related studies

• 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)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• 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)
• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy — S. Papa, S. Popat, et al. (2013)
• The efficacy of the frontline platinum-based combination chemotherapy in malignant peritoneal mesothelioma — S.T. Kim, J.Y. Park, et al. (2010)

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