Pharamacogenomically Selected Treatment for Gastric and Gastroesophageal Junction

In our proposed multi-centered study, we will test the potential benefit of prospectively selecting treatment using a pharmacogenomic approach. 5-Fluorouracil (5-FU) is the backbone chemotherapy for most treatment regimens for gastric and GEJ cancers. One of the primary mechanisms of action of 5-FU is the inhibition of thymidylate synthase (TS), an enzyme required for DNA synthesis and repair. Elevated levels of TS expression in tumors have been linked with decreases in tumor responses to 5-FU treatment and patient survival. In gastric and GEJ cancer, a retrospective analysis demonstrated that patients who have high tumor TS expression had a lower response rate to 5-FU compared to patients with low tumor TS expression «30% vs. >60%) [32, 49]. Germline polymorphisms in the number of tandem repeats in the TSER (thymidylate synthase enhancer region) have been shown to influence tumor TS mRNA transcription and translation efficiencies. Specifically, individuals who are homozygous for TSER*3 (three tandem repeats) had significantly higher TS expression levels in tumor tissue than those with one or two TSER*2 alleles (two tandem repeats).