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© 2002 American Society for Clinical Oncology
Thymidylate Synthase Levels: Prognostic, Predictive, or Both?National Cancer Institute, Bethesda, MD AS THE 21ST CENTURY unfolds, we find ourselves at the doorstep of a revolution in molecular diagnostics. High-throughput gene expression and protein technologies are enabling the discovery of cellular profiles that will aid in the prognosis of various malignant states and, most importantly, the prediction of which therapeutic intervention will most likely benefit a given patient.1 The discovery, refinement, and use of these molecular diagnostic tools will ultimately revolutionize the practice of oncology. As these promising technologies are being developed, the refinement of more traditional diagnostics is progressing, particularly for patients with colorectal cancer. Although colorectal cancer is the second leading cause of mortality due to cancer in the United States, more than 60% of patients present with localized disease. For such individuals, adjuvant treatment is considered the standard of care. Yet 65% of patients are cured with surgery alone and only one third of the 35% of individuals who would have relapsed after surgical intervention derive benefit from currently available adjuvant therapy. Thus, only a minority of patients with stage II and III colorectal cancer either require or derive benefit from the use of adjuvant therapy. Stage has been found to be the single most reliable prognosticator of outcome. However, individuals within a given stage, particularly stages II and III, clearly may have widely divergent outcomes. Thus, there is an urgent need to discover, verify, and apply in clinical practice molecular diagnostics capable of more precisely prognosticating clinical outcome and predicting which patients are most likely to derive benefit from therapeutic interventions. In this issue of the Journal of Clinical Oncology, Edler et al2 examined the prognostic and predictive value of thymidylate synthase (TS) protein expression in 862 patients with stage II and III colorectal cancer. Approximately half of these patients received adjuvant treatment with fluorouracil (5-FU) and leucovorin with or without levamisole. These authors found that high expression of TS as measured by the TS 106 monoclonal antibody was associated with a significantly worse disease-free and overall survival, both in a univariate and a multivariate analysis. TS levels provided independent prognostic information even after correction for stage, the most powerful known prognosticator. Similar results were reported in a series of 294 patients with rectal cancer treated on National Surgical Adjuvant Breast and Bowel Project study R-01.3 Since this initial publication in 1994, which demonstrated the prognostic significance of TS, 11 of 13 reported studies in almost 3,000 patients with colorectal cancer have confirmed the stage-independent prognostic value of TS expression in patients with colorectal cancer. Although it seems clear that high TS levels in the metastases of patients with advanced disease predict for nonresponsiveness to TS inhibitors such as 5-FU,4-6 it is far less certain that TS levels measured in primary colorectal cancer predict clinical benefit resulting from 5-FU–based adjuvant treatment. This may be explained in part by the finding from several reports suggesting that TS expression levels measured in primary colorectal cancer may not be an accurate reflection of TS levels in metastatic or micrometastatic deposits, which represent the mechanism of relapse in patients with local and locally advanced disease.7-9 Although the reason for this discordance is not known, it is likely that metastases represent a subclone with altered kinetics and genetics compared with the primary cancer. In the present investigation, patients whose cancer expressed high levels (grades 2 and 3) of TS did not seem to derive significant benefit from the use of adjuvant therapy, whereas those with the highest level of expression (grade 3) were found to benefit significantly from adjuvant chemotherapy. Although such an association has been inconsistently observed in previous reports,3,10,11 this finding was determined by retrospective subset analysis and must be viewed with caution. In addition, the marginally significant P value does not seem to have been corrected for the multiple analyses that undoubtedly were performed to uncover this finding. A completely unexpected finding was the association of low TS expression with a detrimental effect of adjuvant therapy. This observation, while statistically significant, cannot be explained within the context of our present extensive body of knowledge concerning 5-FU and the role of TS as the primary intracellular target and the critical determinant of sensitivity to 5-FU. Since low TS levels are most commonly associated with responsiveness to 5-FU in patients with advanced disease, a detrimental effect of adjuvant therapy in patients with low TS levels is counterintuitive and apparently unexplainable. No other reported studies have found such a deleterious effect. In sharp contrast with the present report, a recent investigation using TS polymorphisms as an assay for TS levels in 221 patients with stage II and III colorectal cancer demonstrated a significant benefit for the use of adjuvant chemotherapy in patients with the polymorphism associated with low intratumoral TS levels.12 In addition, a report from a National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project collaborative investigation of more than 700 patients with stage II and III colon cancer found that patients with low TS derived the same benefit from adjuvant therapy as those whose cancers had high TS expression.13 An additional disconcerting feature of the study from Edler et al is the global lack of benefit noted with the use of adjuvant therapy in their study population, a finding that is inconsistent with the vast majority of literature. These conflicting data, coupled with the caveat concerning the apparent discordance between TS levels in primary colorectal cancer and metastatic deposits, suggest that the treatment interactions identified in the present report must be viewed with a great deal of caution. They clearly require prospective replication before one can conclude that adjuvant treatment decisions may be influenced by the measurement of TS levels in the primary cancer of patients with local and locally advanced colorectal cancer. Investigations with other markers, such as DCC and microsatellite instability, suggest that these markers may also have prognostic significance,14,15 but no marker has yet been definitively demonstrated to be predictive of therapeutic benefit for patients with colorectal cancer treated in the adjuvant setting. Recent investigations have found that TS polymorphisms in peripheral-blood cells may be used as a surrogate for intratumoral TS levels and may be predictive of chemotherapeutic benefit in patients treated in the adjuvant setting.12,16 The potential availability of this simple blood test may greatly enhance the value and utility of TS measurements. Future investigations should help to define the role of TS polymorphisms as a potential clinical tool. The weight of the published literature supports the value of TS as a prognosticator of natural history that provides information independent of stage and as a predictor of responsiveness to 5-FU if TS is measured in a metastatic lesion. The use of TS as a guide to therapeutic selection in patients with advanced disease requires definitive evaluation by a prospective randomized trial comparing the standard of care versus selecting 5-FU versus non–5-FU–containing regimens based on the level of TS measured in a metastasis. Its role as a predictor of benefit or detriment from adjuvant therapy in patients with stage II and III colorectal cancer, however, is far less clear and remains to be defined. While single-marker investigations have been the mainstay of molecular diagnostics, the development and introduction of multiplex technologies promise to revolutionize the practice of oncology by more clearly defining individuals who are most likely to benefit from specific therapeutic interventions. REFERENCES 1. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403: 503-511, 2000[CrossRef][Medline]
2.
Edler D, Glimelius B, Hallström M, et al: Thymidylate synthase expression in colorectal cancer: A prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 20: 1721-1728, 2001
3.
Johnston PG, Fisher ER, Rockette HE, et al: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12: 2640-2647, 1994 4. Lenz HJ, Hayashi K, Salonga D, et al: p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: An analysis of response and survival. Clin Cancer Res 4: 1243-1250, 1998[Abstract] 5. Leichman CG, Lenz HJ, Leichman L, et al: Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15: 3223-3229, 1997[Abstract] 6. Paradiso A, Simone G, Petroni S, et al: Thymidylate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 82: 560-567, 2000[CrossRef][Medline] 7. Findlay MPN, Cunningham D, Morgan G, et al: Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy. Br J Cancer 75: 903-909, 1997[Medline]
8.
Aschele C, Debernardis D, Tunesi G, et al: Thymidylate synthase protein expression in primary colorectal cancer compared with the corresponding distant metastases and relationship with the clinical response to 5-fluorouracil. Clin Cancer Res 6: 4797-4802, 2000 9. Ichikawa W, Yamada H, Uetake H, et al: Difference of thymidylate synthase gene expression in primary colorectal cancer and various metastatic sites. Proc Am Soc Clin Oncol 20: 151a, 2001 (abstr 601) 10. Takenoue T, Nagawa H, Matsuda K, et al: Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method. Ann Surg Oncol 7: 193-198, 2000[Abstract] 11. Yamachika T, Nakanishi H, Inada K, et al: A new prognostic factor for colorectal carcinoma, thymidylate synthase, and its therapeutic significance. Cancer 82: 70-77, 1998[CrossRef][Medline] 12. Elsaleh H, Grieu F, Joseph D, et al: Thymidylate synthase genotype and survival benefit from chemotherapy in patients with colorectal cancer. Proc Am Soc Clin Oncol 20: 124a, 2001 (abstr 493) 13. Allegra CJ, Paik S, Parr A, et al: Prognostic value of thymidylate synthase (TS), Ki-67 and p53 in patients (pts) with Dukes’ B & C colon cancer. Proc Am Soc Clin Oncol 20: 124a, 2001 (abstr 491) 14. Elsaleh H, Joseph D, Grieu F, et al: Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355: 1745-1750, 2000[CrossRef][Medline]
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Watanabe T, Wu TT, Catalano PJ, et al: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344: 1196-1206, 2001 16. Pullarkat ST, Ghaderi V, Ingles SA, et al: Human thymidylate synthase gene polymorphism determines response to 5-FU chemotherapy. Proc Am Soc Clin Oncol 19: 243a, 2000 (abstr 942)
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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