Genetic variation in cellular transporters could influence the pharmacokinetics of cytostatic drugs and therefore affect treatment outcome.

ABCC3 and ABCG2, both members of the ATB binding cassette transporter family, contribute to the efflux of xenobiotics. They are known to confer resistance to some drugs that are used in the treatment of lung cancer such as etoposide, doxorubicine or cisplatin.

The concentrative nucleoside transporter 1 (CNT1) plays a role in the uptake of pyrimidine nucleosides as well as nucleoside analogs, such as gemcitabine.

We examined 6 genetic polymorphisms with a known or suspected phenotypic effect: ABCG2 G34A, ABCG2 C421A, ABCC3 C-211T, ABCC3 G3890A, ABCC3 C3942T and CNT1 G565A.

For 349 Caucasian patients with primary lung cancer (161 small cell lung cancer (SCLC), 187 non small cell lung cancer (NSCLC) and 1 mixed) we assessed the response after the 2nd cycle of therapy based on RECIST criteria as well as progression free survival and overall survival.

The patients were treated with a variety of protocols, most frequently with etoposide for SCLC and gemcitabine for NSCLC, combined with carbo- or cisplatin respectively.

DNA isolated from peripheral blood was genotyped using fluorescence-based melting curve analysis (LightCycler).

The prognostic value of the SNPs was analyzed using multiple logistic regression, calculating odds ratios (OR) comparing genotype frequencies in responders (complete or partial remission) and non-responders (stable or progressive disease) after the 2nd cycle (adjusted for stage). In addition hazard ratio estimates (HR) based on the Cox proportional hazard model for progression free survival (adjusted for stage) as well as HR for overall survival (adjusted for stage and gender) were calculated.

In the group of all lung cancer patients, none of the polymorphisms above modified response statistically significantly.

The risk of progression was significantly increased for SCLC patients carrying the ABCC3 -211T allele (HR 1.79; CI 1.13-2.82). This effect could not be seen for the response after the 2nd cycle and for overall survival.

In the subgroup of the lung cancer patients receiving platinum-based therapy, carriers of the ABCG2 421A-allele showed a worse overall survival (HR 1.60; CI 1.04-2.47) compared to the homozygous wild type.

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.

Funded in part by the “Deutsche Krebshilfe” and the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science (MOS).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA