Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Our plain-English summary of Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma, by K. Goricar, V. Kovac, V. Dolzan (Radiology and Oncology, 2014).

The study

• Authors: K. Goricar, V. Kovac, V. Dolzan
• Journal: Radiology and Oncology
• Published: 2014;48(2):163-72
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM.

Methods: MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival.

Results: Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03-0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10-8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06-0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06-0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05-0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03-0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15-52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64-19.66).

Conclusions: MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.

In plain English

This study asked whether inherited gene variants were linked to how Slovenian patients with malignant pleural mesothelioma fared on the drug pemetrexed. The 41 patients were in a randomized phase II trial at the Institute of Oncology Ljubljana from 2008 to December 2012. Of them, 33 had occupational or environmental asbestos exposure. The authors tested 19 variants in folate pathway and drug transporter genes. Overall, 31.7% of patients responded. MTHFD1 variant carriers were less likely to respond (odds ratio 0.12, 95% CI 0.03 to 0.54). Among 29 patients given pemetrexed as first treatment, these carriers also had shorter progression-free survival after adjustment for C-reactive protein level (hazard ratio 3.10, 95% CI 1.10 to 8.74). Their overall survival did not differ significantly. Some SLCO1B1 and ABCC2 variants were associated with less liver toxicity. An ABCC2 rs717620 variant was linked to more gastrointestinal toxicity (57.1% of carriers versus 11.1% of non-carriers). The authors concluded these variants could serve as potential markers of treatment outcome. They noted a small sample with low statistical power and did not adjust for multiple comparisons.

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: Exploratory pharmacogenetic study of patients in a prospective randomized phase II clinical trial (AGILI); no adjustment for multiple comparisons
• Who was studied: 41 patients with malignant pleural mesothelioma in the AGILI trial at the Institute of Oncology Ljubljana, Slovenia, 2008 to December 2012. 29 received pemetrexed as first-line and 12 as second-line chemotherapy. 33 (80.5%) were occupationally or environmentally exposed to asbestos; no fiber types are given.
• Exposure: 19 genetic polymorphisms in five folate pathway genes and six transporter genes, studied in patients treated with pemetrexed (with cisplatin, or carboplatin in some patients). Asbestos exposure was described but was not the subject of the analysis.
• Main results:
  • The overall response rate among the 41 patients was 31.7%: 1 complete and 12 partial responders.
  • Carriers of at least one polymorphic MTHFD1 rs2236225 allele had a lower response rate than patients with two wild-type alleles (p = 0.005; OR = 0.12; 95% CI 0.03 to 0.54). This remained after adjustment for TNM stage (p = 0.016; OR = 0.14; 95% CI 0.03 to 0.70).
  • Among the 29 patients receiving pemetrexed as first-line treatment, MTHFD1 rs2236225 carriers had shorter progression-free survival after adjustment for C-reactive protein level (p = 0.032; HR = 3.10; 95% CI 1.10 to 8.74).
  • MTHFD1 rs2236225 was not significantly associated with overall survival in all 41 patients (HR 1.81; 95% CI 0.72 to 4.57; p = 0.207).
  • ABCC2 rs2273697 carriers had a better response rate (p = 0.031; OR = 4.75; 95% CI 1.15 to 19.65). This was no longer significant after adjustment for TNM stage.
  • Liver toxicity was less frequent in carriers of polymorphic SLCO1B1 rs11045879 (OR = 0.18; 95% CI 0.05 to 0.71), SLCO1B1 rs4149056 (OR = 0.23; 95% CI 0.06 to 0.85) and ABCC2 rs2273697 (OR = 0.23; 95% CI 0.06 to 0.85). It was also less common with the SLCO1B1 GCC haplotype (OR = 0.17; 95% CI 0.03 to 0.98).
  • Gastrointestinal toxicity occurred in 8 (57.1%) carriers of polymorphic ABCC2 rs717620 versus 3 (11.1%) non-carriers (OR = 10.67; 95% CI 2.15 to 52.85). It was also more common with the ABCC2 CAG haplotype (OR = 5.67; 95% CI 1.64 to 19.66).
• The authors' conclusion: The authors concluded that the MTHFD1 polymorphism affected treatment response and survival, and that ABCC2 and SLCO1B1 transporter gene polymorphisms influenced toxicity risk. They said these could serve as potential markers of pemetrexed treatment outcome in MPM.
• Limitations the authors state:
  • Small sample size, giving low statistical power

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Cisplatin, Clinical Trial, Overall Survival, Odds Ratio, confidence interval, Progression-Free Survival.

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