Open AccessA Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803
Author(s) -
Niedzwiecki Donna,
Hasson Rian M.,
Lenz HeinzJosef,
Ye Cynthia,
Redston Mark,
Ogino Shuji,
Fuchs Charles S.,
Compton Carolyn C.,
Mayer Robert J.,
Goldberg Richard M.,
Colacchio Thomas A.,
Saltz Leonard B.,
Warren Robert S.,
Bertagnolli Monica M.
Publication year - 2017
Publication title -
the oncologist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.176
H-Index - 164
eISSN - 1549-490X
pISSN - 1083-7159
DOI - 10.1634/theoncologist.2016-0215
Subject(s) - medicine , thymidylate synthase , colorectal cancer , oncology , hazard ratio , cancer , biomarker , fluorouracil , stage (stratigraphy) , confidence interval , paleontology , biochemistry , chemistry , biology
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 (MMR‐D) 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) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). 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. Implications for Practice This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility.