Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer: a North Central Cancer Treatment Group-based exploratory study.
OBJECTIVE
To correlate polymorphisms in genes involved in the transport, activation, and inactivation of pemetrexed with the outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed.


METHODS
Data from a phase II NSCLC trial evaluating the optimal schedule of gemcitabine and pemetrexed were used. All patients with available DNA were genotyped for polymorphisms in FPGS, GGH, and SLC19A1 genes. Patients with various genotypes were compared for efficacy and adverse events resulting from pemetrexed.


RESULTS
Fifty-four patients had genotype results for all polymorphisms studied. Patients with the homozygous variant genotypes for SLC19A1 IVS4(2117) C>T, IVS5(9148) C>A, and wild-type genotype for exon6(2522) C>T had a significantly better overall survival compared with their counterparts (median overall survival in months: 8.9 [CC] versus 14.0 [CT] versus 16.7 [TT]; 9.4 [CC] versus 10.3 [CA] versus 22.7 [AA]; and 22.7 [CC] versus 10.3 [CT] versus 9.4 [TT] respectively; all log rank p = 0.03). Patients with the heterozygous TC genotype for GGH IVS5(1042) T>C had greater rates of confirmed response + stable disease compared with the TT genotype (85% versus 60%; odds ratio = 4.0; p = 0.06). A greater risk for grade 3/4 SGPT (ALT) elevation was observed in patients heterozygous (GA) for the FPGS IVS1 (28) G>A polymorphism compared with the GG genotype (43% versus 13%; odds ratio = 5.0, p = 0.07). All results were largely consistent within patients with nonsquamous (n = 40) histology.


CONCLUSIONS
Polymorphisms in SLC1A91 seem to predict for survival differences in pemetrexed-treated NSCLC. Additionally, polymorphisms in GGH and FPGS have marginal associations with response and adverse event. These results should be validated in larger prospective studies using pemetrexed.
Adjei
Araba A
AA
Departments of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. alex.adjei@roswellpark.org
Salavaggione
Oreste E
OE
Mandrekar
Sumithra J
SJ
Dy
Grace K
GK
Ziegler
Katie L Allen
KL
Endo
Chiaki
C
Molina
Julian R
JR
Schild
Steven E
SE
Adjei
Alex A
AA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D004273:DNA, Neoplasm / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005838:Genotype; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D015996:Survival Rate; D000093542:Gemcitabine
D004273:DNA, Neoplasm; D005971:Glutamates; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000093542:Gemcitabine