Predictive Value of Microsatellite Instability-High Remains Controversial
Authors: George P. Kim, Linda H. Colangelo, Soonmyung Paik, Michael J. O'Connell, Ilan R. Kirsch, Carmen Allegra, Norman Wolmark
Journal: Journal of Clinical Oncology (2007)

In his editorial, Dr Boland raises several issues that deserve additional comment.One is the issue of patient selection.Although it is true that retrospective analyses have inherent biases, because adjuvant chemotherapy has been the standard of care since the late 1980s, specimens from surgery-only patients are and will continue to be available to us only from archived tissue banks.Prospective analyses of microsatellite instability-high (MSI-H) patients treated with surgery alone, the essential control group, compared directly to MSI-H patients treated with chemotherapy, are no longer possible.Despite the potential for bias, the inclusion of the surgery-alone treated subset of patients is a strength of our study.Dr Boland also highlights additional patient selection flaws that are ironically present in the large study 1 cited as able to "correct prior errors."In particular, that study represents a collection of patient samples from different trials, different countries, different times of patient enrollment, and varying fluorouracil (FU) regimens.In contrast, the National Surgical Breast and Bowel Project specimens used in our analysis were from the tissue bank of an established cooperative group that used the same FU/leucovorin (FULV) regimen across the studies.A critical issue that remains is whether the present body of information supports a change in the use of adjuvant chemotherapy for colon cancer patients.More specifically, based on the available data, can mismatch repair status be used to predict benefit from the use of adjuvant chemotherapy?Our study failed to identify an interaction between MSI status and FULV therapy, suggesting that patients benefit equally from the use of adjuvant fluoropyrimidine-based chemotherapy regardless of mismatch repair status.Our data support the conclusion that patients with MSI-H should not be managed differently from those with microsatellite stability (MSS) with respect to the relative benefit from adjuvant fluoropyrimidinebased chemotherapy.An additional important issue is whether these analyses are applicable to the use of other agents including oxaliplatin and, potentially, bevacizumab or cetuximab.Preclinical data suggest that MSI-H cells are sensitive to oxaliplatin yet resistant to the majority of platinums. 2Intriguingly, an interim analysis from an adjuvant trial with an irinotecan-containing regimen, reported that the MSI-H patients surprisingly benefited more than did those with MSS. 3 An immediate answer is not available, but the researchers in two large national trials-National Surgical Breast and Bowel Project C-08 (oxaliplatin, fluorouracil, and folinic acid Ϯ bevacizumab) and North Central Cancer Treatment Group N0147 (oxaliplatin, fluorouracil, and folinic acid Ϯ cetuximab-plan to investigate whether MSI-H patients do better or worse than MSS patients.These results will remain entangled in whether it is the prognostic or predictive characteristic of MSI-H that results in improved survival, as no comparative surgery-alone arm is available.The unfortunate reality is that, despite a laudable effort by numerous investigators, the existing body of work does not currently support the use of MSI testing to predict benefit from the use of adjuvant chemotherapy.