TY - JOUR
T1 - Correlation between polymorphisms of the reduced folate carrier gene (SLC19A1) and survival after pemetrexed-based therapy in non-small cell lung cancer
T2 - A north central cancer treatment group-based exploratory study
AU - Adjei, Araba A.
AU - Salavaggione, Oreste E.
AU - Mandrekar, Sumithra J.
AU - Dy, Grace K.
AU - Ziegler, Katie L.Allen
AU - Endo, Chiaki
AU - Molina, Julian R.
AU - Schild, Steven E.
AU - Adjei, Alex A.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2010/9
Y1 - 2010/9
N2 - Purpose: 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. Experimental design: 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. Conclusion: 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.
AB - Purpose: 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. Experimental design: 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. Conclusion: 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.
KW - Non-small cell lung cancer
KW - Pemetrexed
KW - Polymorphisms
KW - Reduced folate carrier gene
KW - SLC19A1
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UR - http://www.scopus.com/inward/citedby.url?scp=77956268512&partnerID=8YFLogxK
U2 - 10.1097/JTO.0b013e3181ec18c4
DO - 10.1097/JTO.0b013e3181ec18c4
M3 - Article
C2 - 20651609
AN - SCOPUS:77956268512
VL - 5
SP - 1346
EP - 1353
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
IS - 9
ER -