Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed-carboplatin.
OBJECTIVE
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.
Division of Oncology, University Hospital of Parma, Parma, Italy. mtiseo@ao.pr.it
Marcello
M
Tiseo
Elisa
E
Giovannetti
Carmelo
C
Tibaldi
Andrea
A
Camerini
Francesco
F
Di Costanzo
Fausto
F
Barbieri
Jacobus A
JA
Burgers
Andrew
A
Vincent
Godefridus J
GJ
Peters
Egbert F
EF
Smit
Andrea
A
Ardizzoni
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005971:Glutamates / Q000008:administration & dosage / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
D000970:Antineoplastic Agents; D005971:Glutamates; D058978:Reduced Folate Carrier Protein; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D011623:gamma-Glutamyl Hydrolase; D051759:Xeroderma Pigmentosum Group D Protein