Thymidylate Synthase Genotype-Directed Chemotherapy for Patients with Gastric and Gastroesophageal Junction Cancers

Authors

Laura W. Goff, Vanderbilt-Ingram Cancer Center
Nilay Thakkar, University of Kentucky
Liping Du, Vanderbilt-Ingram Cancer Center
Emily Chan, Vanderbilt-Ingram Cancer Center
Benjamin R. Tan, Washington University
Dana B. Cardin, Vanderbilt-Ingram Cancer Center
Howard L. McLeod, Moffitt Cancer Center
Jordan D. Berlin, Vanderbilt-Ingram Cancer Center
Barbara Zehnbauer, Centers for Disease Control and Prevention
Chloe Fournier, Washington University
Joel Picus, Washington University
Andrea Wang-Gillam, Washington University
Wooin Lee, University of KentuckyFollow
A. Craig Lockhart, Washington University

Abstract

BACKGROUND: Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.

METHODS: In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with "good risk" TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%).

RESULTS: The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response.

CONCLUSIONS: In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00515216.

Document Type

Article

Publication Date

9-18-2014

Notes/Citation Information

Published in PLOS One, v. 9, no. 9, article e107424, p. 1-9.

© 2014 Goff et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pone.0107424

Funding Information

This study was supported in part by the grants from the National Cancer Institute, NIH (R21 CA123881, K23 CA098011), the National Center for Research resources, NIH (5 M01 RR-000095). Additional funding was provided by BJC Foundation Cancer Frontier Fund and Sanofi-Aventis. The authors confirm that the funding agencies, with the exception of the NIH, had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Goff, Laura W.; Thakkar, Nilay; Du, Liping; Chan, Emily; Tan, Benjamin R.; Cardin, Dana B.; McLeod, Howard L.; Berlin, Jordan D.; Zehnbauer, Barbara; Fournier, Chloe; Picus, Joel; Wang-Gillam, Andrea; Lee, Wooin; and Lockhart, A. Craig, "Thymidylate Synthase Genotype-Directed Chemotherapy for Patients with Gastric and Gastroesophageal Junction Cancers" (2014). Pharmaceutical Sciences Faculty Publications. 38.
https://uknowledge.uky.edu/ps_facpub/38