A study of thymidylate synthase expression as a biomarker for resectable colon cancer: Alliance (cancer and Leukemia group B) 9581 and 89803

Donna Niedzwiecki, Rian M. Hasson, Heinz Josef Lenz, Cynthia Ye, Mark Redston, Shuji Ogino, Charles S. Fuchs, Carolyn Compton, Robert J. Mayer, Richard M. Goldberg, Thomas A. Colacchio, Leonard B. Saltz, Robert S. Warren, Monica M. Bertagnolli

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Abstract

Purpose. Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. Patients and Methods. Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMRD) and BRAF c.1799T>A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. Results. Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR)50.67, 95% confidence interval (CI)50.53, 0.84; and OS HR50.68, 95% CI50.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR50.94; OS: interaction HR50.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p=.0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p=.0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. Conclusion. This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy.

Original languageEnglish (US)
Pages (from-to)107-114
Number of pages8
JournalOncologist
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Thymidylate Synthase
Colonic Neoplasms
Leukemia
Biomarkers
Neoplasms
Disease-Free Survival
Glycogen Synthase
Survival
Fluorouracil
Drug Therapy
Mutation
Colorectal Neoplasms

Keywords

  • Adjuvant therapy
  • Biomarkers
  • Colon cancer
  • Microsatellite instability
  • Mismatch repair deficiency
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A study of thymidylate synthase expression as a biomarker for resectable colon cancer : Alliance (cancer and Leukemia group B) 9581 and 89803. / Niedzwiecki, Donna; Hasson, Rian M.; Lenz, Heinz Josef; Ye, Cynthia; Redston, Mark; Ogino, Shuji; Fuchs, Charles S.; Compton, Carolyn; Mayer, Robert J.; Goldberg, Richard M.; Colacchio, Thomas A.; Saltz, Leonard B.; Warren, Robert S.; Bertagnolli, Monica M.

In: Oncologist, Vol. 22, No. 1, 01.01.2017, p. 107-114.

Research output: Contribution to journalArticle

Niedzwiecki, D, Hasson, RM, Lenz, HJ, Ye, C, Redston, M, Ogino, S, Fuchs, CS, Compton, C, Mayer, RJ, Goldberg, RM, Colacchio, TA, Saltz, LB, Warren, RS & Bertagnolli, MM 2017, 'A study of thymidylate synthase expression as a biomarker for resectable colon cancer: Alliance (cancer and Leukemia group B) 9581 and 89803', Oncologist, vol. 22, no. 1, pp. 107-114. https://doi.org/10.1634/theoncologist.2016-0215
Niedzwiecki, Donna ; Hasson, Rian M. ; Lenz, Heinz Josef ; Ye, Cynthia ; Redston, Mark ; Ogino, Shuji ; Fuchs, Charles S. ; Compton, Carolyn ; Mayer, Robert J. ; Goldberg, Richard M. ; Colacchio, Thomas A. ; Saltz, Leonard B. ; Warren, Robert S. ; Bertagnolli, Monica M. / A study of thymidylate synthase expression as a biomarker for resectable colon cancer : Alliance (cancer and Leukemia group B) 9581 and 89803. In: Oncologist. 2017 ; Vol. 22, No. 1. pp. 107-114.
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abstract = "Purpose. Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. Patients and Methods. Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMRD) and BRAF c.1799T>A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. Results. Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR)50.67, 95{\%} confidence interval (CI)50.53, 0.84; and OS HR50.68, 95{\%} CI50.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR50.94; OS: interaction HR50.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2{\%} vs. 12.8{\%}; p=.0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77{\%}, compared with 58{\%} for those whose tumors had low TS and were non-MMR-D (log-rank p=.0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. Conclusion. This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy.",
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T1 - A study of thymidylate synthase expression as a biomarker for resectable colon cancer

T2 - Alliance (cancer and Leukemia group B) 9581 and 89803

AU - Niedzwiecki, Donna

AU - Hasson, Rian M.

AU - Lenz, Heinz Josef

AU - Ye, Cynthia

AU - Redston, Mark

AU - Ogino, Shuji

AU - Fuchs, Charles S.

AU - Compton, Carolyn

AU - Mayer, Robert J.

AU - Goldberg, Richard M.

AU - Colacchio, Thomas A.

AU - Saltz, Leonard B.

AU - Warren, Robert S.

AU - Bertagnolli, Monica M.

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N2 - Purpose. Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. Patients and Methods. Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMRD) and BRAF c.1799T>A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. Results. Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR)50.67, 95% confidence interval (CI)50.53, 0.84; and OS HR50.68, 95% CI50.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR50.94; OS: interaction HR50.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p=.0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p=.0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. Conclusion. This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy.

AB - Purpose. Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. Patients and Methods. Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMRD) and BRAF c.1799T>A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. Results. Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR)50.67, 95% confidence interval (CI)50.53, 0.84; and OS HR50.68, 95% CI50.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR50.94; OS: interaction HR50.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p=.0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p=.0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. Conclusion. This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy.

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KW - Biomarkers

KW - Colon cancer

KW - Microsatellite instability

KW - Mismatch repair deficiency

KW - Thymidylate synthase

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