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In Reply:

Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Comprehensive Cancer Center, North Netherlands, Groningen, the Netherlands
Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Watanabe et al correctly pointed out a higher reduction rate in patients with high-frequency microsatellite instability (MSI-H) compared with microsatellite stable (MSS) patients in the multivariate analysis evaluating the combined effects of MSI and TP53 status. Although, drop-out occurred randomly in both TP53 tumor types (P = .836) there was a higher drop-out of MSI-H patients (P = .023). This will have resulted in loss of power to determine the exact impact of MSI-H status in the prediction of disease-free survival (DFS) in adjuvant-treated colon cancer patients as observed by Watanabe et al, and as we had noticed also.¹ However, as we stated in our article, our main message was the fact that in a multivariate model the additional value of determining MSI status next to TP53 is limited. Although we agree that with a sufficiently large number of patients it is probable that MSI-H status will have additional value for predicting DFS next to the presence of a TP53 mutation, proving such an effect will require a very high number of patients. As we showed, TP53 status will explain part of the differences in prognosis among MSI-H and MSS patients. On the basis of this observation, and given the relatively low frequency of patients with MSI-H tumors and the relatively high frequency of TP53 mutations among these patients, we concluded that TP53 status is a more appropriate predictor of DFS for use in normal clinical practice. Given the often-low number of patients in normal clinical practice, too few MSI-H patients can be expected to make determining MSI-H status worthwhile next to determining TP53 status.

The method of assessing MSI-H described in our article is largely in accordance with the National Cancer Institute consensus.^2,3 Using the Roche kit (Roche, Manheim, Germany), we classified any sample displaying instability in two or more of the five consensus loci as MSI-H and included a sample when all five markers could be interpreted, when four markers could be interpreted and all proved negative or two interpretable markers proved positive. Using the Promega kit (Promega, Madison, WI), we included a sample when five or more of nine markers were interpretable or three interpretable markers proved positive, which is in agreement with the definition of the National Cancer Institute and meets the needs of 30% to 40% instability of the scored loci. Besides, in all MSI-H cases, regarding the Promega kit, three or more markers were unstable, and in almost all cases, more than six markers were interpretable. Therefore we disagree with Watanabe et al because they suggested different interpretation of instability in 33% of the markers. Although not significant (P = . 097), the reasons of different MSI status of the Roche kit (22%) and Promega kit (13%) is inexplicable but mostly due to different fixation methods of formalin of the paraffin-embedded specimens in this multicenter study. We, however, agree with Watanabe and, as we suggested in our article, believe that it would be better to use one method because applying different MSI screening might hamper direct comparison of studies. What stands is that, because of the high frequency of TP53 mutations in colon cancer patients, this marker will remain more informative than MSI status irrespective of the MSI screening (approximately 50% v 20%, respectively).

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[Abstract/Free Full Text]

2. Kim H, Jen J, Vogelstein B, et al: Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 145:148-156, 1994[Abstract]

3. 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[Abstract/Free Full Text]

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