Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed-carboplatin.

Abstract

PURPOSE:

To correlate candidate polymorphisms affecting pemetrexed and carboplatin activity with clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated in second-line with pemetrexed or pemetrexed plus carboplatin.

METHODS:

Functional polymorphisms in thymidylate synthase (TS), reduced folate carrier (RFC), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and xeroderma pigmentosum group D (XPD) genes were evaluated in 208 patients either treated within randomized phase II trials NVALT-7 and GOIRC-02.2006, comparing second-line pemetrexed with pemetrexed plus carboplatin, or with the same regimens outside of these trials. Univariate and multivariate analyses correlated genotyping data with response, clinical benefit, toxicity, progression-free (PFS) and overall survival (OS) using Pearson-χ2 test, log-rank test and Cox proportional hazards model.

RESULTS:

Patients harboring the MTHFR-T667T variant had significantly longer PFS (5.4 versus 3.4 months; p=0.012) and OS (16.4 versus 8.5 months; p=0.026) than patients with CC-CT genotypes. No correlation was observed for other polymorphisms, except for XPD-Gln751Gln, which was associated with shorter PFS (p=0.021) and OS (p=0.044) in the subgroup of patients treated with pemetrexed plus carboplatin. Multivariate analysis confirmed the independent prognostic significance of MTHFR-C677T both in risk of disease progression (CC-CT genotypes hazard ratio [HR] 1.94, 95%CI 1.15-3.28; p=0.012) and of death (HR 2.00, 95% CI 1.12-3.54; p=0.018).

CONCLUSIONS:

MTHFR-C667T polymorphisms appear to predict survival differences in pemetrexed-treated NSCLC. These results should be validated in larger and adequately designed prospective studies using pemetrexed.

• Authors: Marcello Tiseo, Elisa Giovannetti, Carmelo Tibaldi, Andrea Camerini, Francesco Di Costanzo, Fausto Barbieri, Jacobus A Burgers, Andrew Vincent, Godefridus J Peters, Egbert F Smit, Andrea Ardizzoni
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 78 Issue 1 Pg. 92-9 (Oct 2012) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 22889494 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Glutamates
• Reduced Folate Carrier Protein
• Pemetrexed
• Guanine
• Carboplatin
• Methylenetetrahydrofolate Reductase (NADPH2)
• Thymidylate Synthase
• gamma-Glutamyl Hydrolase
• Xeroderma Pigmentosum Group D Protein

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carboplatin (administration & dosage, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, mortality)
• Female
• Gene Frequency
• Genotype
• Glutamates (administration & dosage, therapeutic use)
• Guanine (administration & dosage, analogs & derivatives, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, genetics, mortality)
• Male
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics)
• Middle Aged
• Neoplasm Staging
• Pemetrexed
• Polymorphism, Single Nucleotide
• Reduced Folate Carrier Protein (genetics)
• Retrospective Studies
• Thymidylate Synthase (genetics)
• Treatment Outcome
• Xeroderma Pigmentosum Group D Protein (genetics)
• gamma-Glutamyl Hydrolase (genetics)