Trial Information

Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal (GEJ) Tumors: A Phase II Study

Gastric and gastroesophageal junction (GEJ) cancers are a leading cause of cancer mortality.
Despite the development of newer chemotherapies, the response rates and median survival in
patients with these tumors has remained essentially stagnant. Defining host and
molecular/biologic tumor characteristics to customize treatment may lead to improved
survival outcomes. Retrospective studies have identified genetic markers that predict
treatment outcome. However, there have been no prospective studies in gastric and GEJ cancer
evaluating the clinical utility of these genetic factors. We hypothesize that genomically
based treatment will improve the expected response rate in patients with gastric and GEJ
cancers. We propose a prospective, multi-institutional Phase II clinical trial testing a
germline polymorphism in the thymidylate synthase (TS) gene, the number of tandem repeats in
the TS enhancer region (TSER) as a treatment selection marker. The polymorphic variant
conferring three tandem repeats (TSER*3) has been associated with 5-FU resistance due to
high tumor TS expression in comparison to the TSER*2 variant (two tandem repeats). The
TSER*3 polymorphism is common (allelic frequency of 0.5-0.8). In the proposed study, we will
prospectively genotype patients with gastric and GEJ cancers. Patients who are expected to
be 5-FU sensitive (carrying a TSER*2 allele) will receive a 5-FU containing regimen (5-FU,
leucovorin, oxaliplatin). Patients who are expected to be 5-FU resistant (homozygous for
TSER*3) will not be included in the study. In completing this study, we will determine
whether treatment selection based on germline TSER polymorphism status improves the response
rate in patients with metastatic gastric and GEJ tumors. Additional correlative studies are
proposed to identify confounding factors that may alter the expected outcomes of this
treatment approach.