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.

File_S1.docx (33 kB)
File S1. Supporting Tables.

Checklist_S1.pdf (362 kB)
Checklist S1. TREND Checklist.

Protocol_S1.pdf (644 kB)
Protocol S1. Trial Protocol.

journal.pone.0107424.g001.png (32 kB)
Figure 1 (PNG). A schematic diagram of the current phase II study design.

journal.pone.0107424.g001.ppt (118 kB)
Figure 1 (PPT). A schematic diagram of the current phase II study design.

journal.pone.0107424.g001.TIF (130 kB)
Figure 1 (TIFF). A schematic diagram of the current phase II study design.

journal.pone.0107424.g002.png (286 kB)
Figure 2 (PNG). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) with 95% confidence intervals (CI) in the patients enrolled.

journal.pone.0107424.g002.ppt (63 kB)
Figure 2 (PPT). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) with 95% confidence intervals (CI) in the patients enrolled.

journal.pone.0107424.g002.TIF (1203 kB)
Figure 2 (TIFF). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) with 95% confidence intervals (CI) in the patients enrolled.

journal.pone.0107424.g003.png (523 kB)
Figure 3 (PNG). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) according to TSER genotypes.

journal.pone.0107424.g003.ppt (60 kB)
Figure 3 (PPT). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) according to TSER genotypes.

journal.pone.0107424.g003.TIF (1615 kB)
Figure 3 (TIFF). Kaplan-Meier curves showing overall survival (A) and progression free survival (B) according to TSER genotypes.

journal.pone.0107424.t001.png (46 kB)
Table 1 (PNG). Baseline clinical and demographic characteristics of enrolled patients (n = 26).

journal.pone.0107424.t001.ppt (32 kB)
Table 1 (PPT). Baseline clinical and demographic characteristics of enrolled patients (n = 26).

journal.pone.0107424.t001.TIF (350 kB)
Table 1 (TIFF). Baseline clinical and demographic characteristics of enrolled patients (n = 26).

journal.pone.0107424.t002.png (120 kB)
Table 2 (PNG). Toxicities observed in the treated patients (n = 25).

journal.pone.0107424.t002.ppt (37 kB)
Table 2 (PPT). Toxicities observed in the treated patients (n = 25).

journal.pone.0107424.t002.TIF (452 kB)
Table 2 (TIFF). Toxicities observed in the treated patients (n = 25).

journal.pone.0107424.t003.png (30 kB)
Table 3 (PNG). Tumor responses to the FOLFOX regimen in patients of differing TSER genotypes.

journal.pone.0107424.t003.ppt (29 kB)
Table 3 (PPT). Tumor responses to the FOLFOX regimen in patients of differing TSER genotypes.

journal.pone.0107424.t003.TIF (170 kB)
Table 3 (TIFF). Tumor responses to the FOLFOX regimen in patients of differing TSER genotypes.

journal.pone.0107424.t004.png (73 kB)
Table 4 (PNG). Univariate association between additional retrospectively analyzed genotypes and tumor response (PR: partial response and SD: stable disease).

journal.pone.0107424.t004.ppt (43 kB)
Table 4 (PPT). Univariate association between additional retrospectively analyzed genotypes and tumor response (PR: partial response and SD: stable disease).

journal.pone.0107424.t004.TIF (466 kB)
Table 4 (TIFF). Univariate association between additional retrospectively analyzed genotypes and tumor response (PR: partial response and SD: stable disease).

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