Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients.
The prognosis of lung cancer patients treated with chemotherapy is poor, motivating the search for predictive factors. Single nucleotide polymorphisms (SNPs) in membrane transporter genes could influence the pharmacokinetics of cytostatic drugs and therefore affect treatment outcome. We examined 6 SNPs with known or suspected phenotypic effect: ABCG2 G34A, C421A; ABCC3 C-211T, G3890A, C3942T and CNT1 G565A. For 349 Caucasian patients with primary lung cancer [161 small cell lung cancer (SCLC), 187 nonsmall cell lung cancer (NSCLC) and 1 mixed] receiving first-line chemotherapy 3 different endpoints were analyzed: response after the 2nd cycle (R), progression-free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analyzed using multivariable logistic regression, calculating odds ratios (ORs) when comparing genotype frequencies in responders and nonresponders after the 2nd cycle. Hazard ratios (HRs) for PFS and for OS were calculated using Cox regression methods. In all lung cancer patients, none of the investigated polymorphisms modified response statistically significant. The only significant result in the histological subpopulations was in SCLC patients carrying the ABCC3 -211T allele who showed significantly worsened PFS (HR: 1.79; 95% confidence interval (CI) 1.13-2.82). In an exploratory subgroup analysis significantly worse OS was seen for carriers of the ABCG2 421A-allele treated with platinum-based drugs (HR: 1.60; 95% CI 1.04-2.47; n = 256). In conclusion, this study prioritizes ABCC3 C-211T and ABCG2 C421A as candidate transporter SNPs to be further investigated as possible predictors of the clinical outcome of chemotherapy in lung cancer patients.
Müller
Phillip J
PJ
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Dally
Heike
H
Klappenecker
Cornelia N
CN
Edler
Lutz
L
Jäger
Birgit
B
Gerst
Martina
M
Spiegelhalder
Bertold
B
Tuengerthal
Siegfried
S
Fischer
Jürgen R
JR
Drings
Peter
P
Bartsch
Helmut
H
Risch
Angela
A
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016896:Treatment Outcome
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C065171:cif nucleoside transporter; C114462:multidrug resistance-associated protein 3