Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study

Our plain-English summary of Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study, by Y. Takeda, G. Naka, Y. Katsuya, et al (BMC Cancer, 2023).

The study

• Authors: Y. Takeda, G. Naka, Y. Katsuya, K. Kobayashi, M. Suzuki, M. Hashimoto, S. Hirano, Y. Uemura
• Journal: BMC Cancer
• Published: 2023;23(1):800
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy.

Methods: This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC.

Results: The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A].

Conclusion: The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed.

Trial Registration: This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

© 2023. BioMed Central Ltd., part of Springer Nature.

In plain English

This single-center prospective observational study in Japan followed patients given pemetrexed-containing chemotherapy after vitamin B12 and folic acid premedication. Asbestos was not studied. From October 2012 to December 2019, 71 patients who agreed to genetic testing were analyzed for first-cycle side effects: 67 with non-squamous non-small cell lung cancer and four with malignant pleural mesothelioma. The authors examined 17 gene variants in 11 genes. Of these 71 patients, 38% had grade 3 or higher blood-related side effects. Survival was analyzed in 63 lung cancer patients, excluding the mesothelioma patients and four given chemotherapy after surgery. Their median progression-free survival was 6.8 months (95% confidence interval 4.1 to 9.5), and median overall survival was 33.3 months (24.1 to 42.5). After adjustment, side effects were associated with B12, folic acid and homocysteine levels, dose reduction, and MTHFR and SLC19A1 variants. Progression-free survival was associated with folic acid and B12 levels and with BHMT and DHFR variants. Overall survival was associated with folic acid level and an MTRR variant. The authors concluded this information helps predict pemetrexed's side effects and effectiveness. They noted a small sample and possible remaining bias, and called the results exploratory.

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: Prospective observational cohort study at a single center, with pharmacogenetic (gene variant) testing; logistic and Cox regression with propensity-score adjustment
• Who was studied: Patients planning pemetrexed-containing chemotherapy at the National Center for Global Health and Medicine in Tokyo, Japan, enrolled October 2012 to December 2019. 118 consented. The 71 who agreed to SNP testing were analyzed for toxicity: 67 with non-squamous non-small cell lung cancer and 4 with malignant pleural mesothelioma (median age 72; 49 male, 22 female). Efficacy was analyzed in 63 non-squamous NSCLC patients. The mesothelioma patients and four patients receiving postoperative adjuvant chemotherapy were excluded from that analysis.
• Exposure: Pemetrexed-containing chemotherapy, most often combined with platinum and in some patients with bevacizumab or pembrolizumab, given after vitamin B12 and folic acid premedication. The study also measured 17 single-nucleotide polymorphisms in 11 folate/methionine-cycle and related genes, and blood levels of homocysteine, B12, folic acid and nutritional markers. Asbestos exposure was not studied.
• Main results:
  • Among the 71 patients, 38% had grade 3 or higher blood-related (hematological) side effects in the first cycle. For non-hematological side effects of that grade, the text gives 37%, while Table 3 lists 26 of 71 (36.6%).
  • Propensity-score-adjusted lower-risk factors for grade 3–4 hematological side effects (71 patients): WBC count of 6120/µL or more (OR 0.06, 95% CI 0.01–0.35); standard dosage (OR 0.09, 95% CI 0.01–0.91); C/C genotype of MTHFR 677 C>T (OR 0.13, 95% CI 0.02–0.92); B12 of 486 pg/mL or more before premedication (OR 0.13, 95% CI 0.03–0.73); folic acid of 15.8 ng/mL or more before chemotherapy (OR 0.15, 95% CI 0.03–0.89).
  • Propensity-score-adjusted lower-risk factors for grade 2–4 non-hematological side effects (71 patients): C/T genotype of MTHFR 677 C>T (OR 0.07, 95% CI 0.009–0.54); transthyretin of 21.5 mg/dL or more (OR 0.06, 95% CI 0.006–0.50); homocysteine below 11.8 nmol/mL before premedication (OR 0.03, 95% CI 0.003–0.30); A/G genotype of SLC19A1 IVS2 (4935) G>A (OR 0.06, 95% CI 0.005–0.58).
  • In the 63 non-squamous NSCLC patients, the objective response rate was 28.2%. Median progression-free survival was 6.8 months (95% CI 4.1 to 9.5), and median overall survival was 33.3 months (24.1 to 42.5).
  • Propensity-score-adjusted favorable factors for progression-free survival (63 NSCLC patients): platinum combination (HR 0.27, 95% CI 0.11–0.65); A/G or A/A genotype of BHMT 742 G>A (HR 0.24, 95% CI 0.11–0.53); folic acid of 9.3 ng/mL or more before premedication (HR 0.14, 95% CI 0.06–0.32); bevacizumab combination (HR 0.37, 95% CI 0.14–0.97); B12 below 1136 pg/mL before chemotherapy (HR 0.35, 95% CI 0.17–0.73); A/C or A/A genotype of DHFR 680 C>A (HR 0.19, 95% CI 0.07–0.55).
  • Propensity-score-adjusted favorable factors for overall survival (63 NSCLC patients): better ECOG performance status (HR 0.22, 95% CI 0.11–0.39); BMI of 20.66 kg/m2 or more (HR 0.16, 95% CI 0.07–0.37); folic acid of 5.55 ng/mL or more before premedication (HR 0.18, 95% CI 0.07–0.46); higher retinol-binding protein (HR 0.56, 95% CI 0.38–0.82); smoking index below 22.5 (HR 0.16, 95% CI 0.06–0.38); A/G genotype of MTRR 66 A>G (HR 0.35, 95% CI 0.17–0.70).
• The authors' conclusion: The authors concluded that information on metabolites and gene variants of the folate, methionine and thymidylate cycles helps predict the toxicity and efficacy of pemetrexed. They also concluded that six SNPs were associated with efficacy and toxicity profiles.
• Limitations the authors state:
  • Single-center study with a relatively small sample size
  • Any pemetrexed-containing regimen and any line of chemotherapy were accepted, and both lung cancer and mesothelioma were included
  • Ethnically homogeneous Japanese cohort, so ethnic differences could not be examined
  • Statistical adjustment could not necessarily eliminate bias from background factors
  • The study was exploratory and its results need to be verified in a confirmatory study

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Antifolate, Non-Small Cell Lung Cancer, Pleural Mesothelioma, Chemotherapy, Progression-Free Survival, Overall Survival, Bevacizumab.

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