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Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with
M Joerger1, R H N van Schaik2, M L Becker3
1Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland.
Background:
This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC).
Methods:
The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival.
Results:
Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS.
Conclusions:
The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.
Insights
Genetic variations in organic cation transporter 1 (OCT1) influence metformin toxicity and efficacy in castration-resistant prostate cancer (CRPC). The OCT1 C-allele is linked to reduced toxicity but increased tumor progression risk.
Area of Science:
- Pharmacogenomics
- Oncology
- Clinical Pharmacology
Background:
- Investigating the role of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms in metformin's clinical activity and toxicity.
- Focus on patients with castration-resistant prostate cancer (CRPC).
Purpose of the Study:
- To determine the relationship between OCT1 and MATE1 mutations and progression-free survival (PFS) and PSA response at 12 weeks.
- To analyze the association between OCT1, MATE1 mutations, metformin-related toxicity, PSA response, and overall survival.
Main Methods:
- Analysis of 44 CRPC patients treated with metformin in the SAKK 08/09 trial.
- Assessment of OCT1 (rs622342) and MATE1 (rs2289669) gene polymorphisms.
- Evaluation of primary endpoints: 12-week PFS and PSA response; secondary endpoints: toxicity and overall survival.
Main Results:
- Homozygous carriers of the polymorphic OCT1 C-allele experienced no metformin-related toxicity compared to 41.9% in wild-type carriers (P=0.07).
- Disease progression (RECIST) was significantly higher in homozygous OCT1 C-allele carriers (80%) versus wild-type carriers (28.6%) (P=0.002).
- MATE1 polymorphisms showed a trend towards increased progression (44%) versus wild-type (12.5%) (P=0.07), but OCT1 and MATE1 did not correlate with PFS.
Conclusions:
- The polymorphic OCT1 C-allele is associated with decreased metformin toxicity but an increased risk of tumor progression in CRPC patients.
- OCT1 and MATE1 genetic variations may serve as predictive biomarkers for metformin efficacy in future clinical studies.
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