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Journal of Clinical Oncology, Vol 23, No 35 (December 10), 2005: pp. 9031-9032 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.0394
TP53 Mutation and Microsatellite Instability Status for the Prediction of Survival in Adjuvant-Treated Colon Cancer PatientsDepartment of Surgical Oncology, University of Tokyo Hospital, Tokyo, Japan To the Editor: We read with interest "Determination of TP53 Mutation Is More Relevant Than Microsatellite Instability Status for the Prediction of Disease-Free Survival in Adjuvant-Treated Stage III Colon Cancer Patients" in a recent issue of the Journal of Clinical Oncology by Westra et al.1 The authors reported that TP53 status is a significant prognostic factor for patients with colorectal cancer after chemotherapy, whereas high-frequency microsatellite instability (MSI-H) is not. Westra et al introduced our results in their report; we have similar research that was published in the issue of the New England Journal of Medicine, but reached different conclusions.2 Westra et al showed that there was improved survival in MSI-H patients after fluorouracil-based chemotherapy as compared with microsatellite stable (MSS) patients (P = .034). This is in agreement with the results of past reports, including our study.2-6 However, Westra et al reported that in a multivariate model, the MSI status was not significantly associated with disease-free survival (DFS), whereas the TP53 status reached borderline significance. From these results, they concluded that presence or absence of a TP53 mutation, and not MSI, seems a better predictor for DFS in adjuvant-treated colon cancer patients. However, to draw this conclusion, there are two major issues to be discussed in their study. The first point is the number of patients. In a univariate analysis, they examined 273 patients, including 44 MSI-H and 229 MSS patients, and successfully showed significantly improved survival in MSI-H patients (P = .034). However, in a multivariate analysis, patients were examined only when both the MSI and the TP53 status could be determined. Therefore, they had to reduce a number of assessable patients from 273 to 194 in a multivariate analysis. This subgroup included 25 MSI-H and 169 MSS patients. However, the problem is that the reduction rate in the number of patients was higher in MSI-H than in MSS patients (43.2% [19 of 44 MSI-H patients] v 26.2% [60 of 229 MSS patients]). Threfore, they could examine only 25 MSI-H patients in a multivariate model, and, unfortunately, this number seems to be too small to evaluate the difference in DFS between MSI-H and MSS patients. In our previous study, we could examine 73 MSI-H patients and demonstrate a significant difference in DFS after chemotherapy between MSI-H and MSS patients.2 Considering these points, Westra's study may potentially bias the significance of MSI-H as a predictor of DFS in adjuvant-treated colon cancer patients.
The second point is about the definition of the MSI status. Westra et al addressed an important issue concerning how the MSI status has been determined in previous studies. As they stated in their report, different methods of MSI screening had been used in previous studies, and this might have hampered a direct comparison between studies. However, their study used two different sets of markers to determine the MSI status.1,7,8 They used either the Promega kit (Promega, Madison, WI) or the Roche kit (Roche, Manheim, Germany), which contain nine and five markers, respectively. The Roche kit contains the National Cancer Institute–recommended panel of five markers: BAT25, BAT26, D5S346, D2S123, and D17S250. Using this set of markers, they determined the MSI status exactly as the National Cancer Institute recommended.8 On the other hand, the Promega kit contains nine markers. When more than five markers are used, the National Cancer Institute recommended use of the percentage of markers demonstrating instability rather than the absolute number of markers. Using the percentage of markers, MSI-H tumors would be defined as having MSI in Although Westra et al's article discusses important issues, we need additional details, especially if we want to draw conclusions concerning the significance of MSI-H as a predictor of DFS in adjuvant-treated colon cancer patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Westra JL, Schaapveld M, Hollema H, et al: Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage iii colon cancer patients. J Clin Oncol 23:5635-5643, 2005 2. 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 3. Elsaleh H, Powell B, McCaul K, et al: P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res 7:1343-1349, 2001 4. Halling KC, French AJ, McDonnell SK, et al: Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91:1295-1303, 1999 5. Hemminki A, Mecklin JP, Jarvinen H, et al: Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 119:921-928, 2000[CrossRef][Medline] 6. 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] 7. Wu Y, Berends MJ, Mensink RG, et al: Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 65:1291-1298, 1999[CrossRef][Medline] 8. Boland CR, Thibodeau SN, Hamilton SR, et al: A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248-5257, 1998
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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30% to 40% of the markers tested. However, instead of using these criteria, Westra et al determined the MSI status by the absolute number of markers by using a kit of nine markers. This seems to have caused a significant inconsistency in determining the MSI status. For example, according to Westra et al's definition, tumors are classified as MSS when two (33%) of six markers show instability, and as MSI-H when three (33%) of nine markers show instability. However, in both cases, 33% of markers show instability. This suggests a possibility that some MSI-H cases might have been classified as MSS by the Promega kit in their study. In fact, there was a difference in the MSI-H ratio between two sets of markers. With the Roche kit, MSI-H was present in 22% of tumors, which is about the same ratio as in our previous study (21%). However, only 13% of tumors were classified as MSI-H by the Promega kit. Furthermore, the MSI status of the majority of cases was determined by using the Promega kit—192 patients with the Promega kit and only 23 patients with the Roche kit. Considering these points, it seems that MSS cases in Westra et al's study contains a certain number of MSI-H cases, and that this could have affected their results. 
