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

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.

Keywords: Betaine-homocysteine methyltransferase; Methionine cycle; Pemetrexed; Single-nucleotide polymorphism; Toxicities and efficacies.

Fig. 1

Flow chart of the accrual of patients and the performed analyses. Patients were accrued, and analyses were performed according to the flow chart

Fig. 2

Propensity score-adjusted risk factors for adverse events in the first cycle using multivariate logistic regression analysis. Variables with a P-value < 0.10 on univariate analysis were entered into multivariate logistic analysis using a simultaneous method. a Grades 3–4 hematologic toxicities (N = 71). b Grades 2–4 non-hematologic toxicities (N = 71) WBC white blood cell

Fig. 3

Progression-free survival (PFS) curve in patients with NSCLC who underwent SNP analyses. a PFS curve of total patients with NSCLC using the Kaplan–Meier method (N = 63). b PFS curves of patients with the GG genotype group (Short dash) and the AA + AG genotype group (Solid) of BHMT (742 G > A) using propensity score (PS)-adjusted multivariate Cox regression analyses. c PFS curves of patients with the CC genotype group (Short dash) and the AA + AC genotype group (Solid) of DHFR (680 C > A) using PS-adjusted multivariate Cox regression analyses

Fig. 4

Overall survival (OS) curve of patients with NSCLC who underwent SNP analyses. a OS curve of total patients with NSCLC using the Kaplan–Meier method (N = 63). b OS curves of patients with the AA + GG genotype group (Short dash) and the AG genotype group (Solid) of MTRR (66 A > G) using propensity score (PS)-adjusted multivariate Cox regression analyses

Fig. 5

Propensity score-adjusted efficacies using multivariate Cox regression analyses. Variables with a P-value < 0.10 on univariate analysis were entered into multivariate Cox analysis by a simultaneous method. a Progression-free survival (N = 63). b Overall survival (N = 63) RBP retinol-binding protein

Fig. 6

Mechanism of action and associated SNPs of pemetrexed. The text in red indicates SNPs that are related to efficacy. The text in blue indicates SNPs that are related to toxicity. The text in green indicates SNPs that are related to both efficacy and toxicity. The yellow text represents premedication supplements. AMP, adenosine monophosphate; B6, vitamin B6; B12, vitamin B12; BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine beta-synthase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; fGAR, form N²-formyl-N¹-(5-phospho-D-ribosyl)glycinamide; FPGS, folylpoly-γ-glutamate synthase; GAR, N¹-(5-phospho-D-ribosyl)glycinamide; GARFT, GAR transformylase; GGH, γ-glutamyl hydrolase; GMP, guanosine monophosphate; HIBCH, 3-hydroxyisobutyryl-CoA hydrolase; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; SLC19A1, folate carrier; THF, tetrahydrofolate; TYMS, thymidylate synthase