Microsatellite instability in colorectal cancer: Prognostic, predictive or both? Authors' reply

The need for robust markers for a better prognostic definition of patients with colorectal cancer (CRC) has been increasingly pressing during the last decade. The introduction of adjuvant chemotherapy in the routine clinical management of patients with stage III CRC or in patients with high-risk stage II disease further enhanced the need for more precise prognostic indicators to efficiently direct the therapeutic choice. In the last years, several studies have investigated the prognostic significance of highfrequency microsatellite instability (MSI-H) in colon cancer, sometimes yielding conflicting results.1–5 Notwithstanding, the positive prognostic value of MSI-H in CRC has been convincingly demonstrated by recent large population-based studies in which standardized criteria for MSI-H assessment have been used.4,5 Besides confirming the favorable clinical outcome of MSI-H CRC, our results also demonstrated that the prognostic value of the MSI status alone is significantly enhanced by the combined evaluation of the number of intratumoral-activated cytotoxic lymphocytes.6 This supports the hypothesis that MSI-H tumors may continuously produce new immunogenic epitopes as a consequence of the inherent defective DNA mismatch repair and may explain why patients with MSI-H CRC who are able to mount effective antitumor immune responses have a particularly favorable clinical outcome. We fully agree with van Rijnsoever et al that MSI has relevant implications for the selection of CRC patients to receive adjuvant chemotherapy. Nevertheless, the putative role of MSI as a predictor of response to chemotherapy is still controversial.4,7,8 Our recent results do not seem to support such a generalized role, since the large majority (79.8%) of patients from our series did not receive any additional therapy besides radical surgery, suggesting that adjuvant treatment could be useless in cases showing both MSI-H and high numbers of activated cytotoxic lymphocytes.6 On the other hand, adjuvant chemotherapy could be beneficial to those MSI-H cases (24% in our series of proximal CRC) showing no evidence of local antitumor immune responses. In this respect, it should be considered that, besides direct cytotoxic activity, 5FU-based regimens may also have immunomodulatory effects that could contribute to enhance the responsiveness of this subset of tumors.9–10 As pointed out by van Rijnsoever et al, validation of the predictive value of MSI-H should require prospective clinical trials including adjuvant treatment and nontreatment arms. Nevertheless, due to the difficulties to include non-treatment arms in future trials, particularly in stage III CRC, as a first approach, we would favor the re-evaluation of large retrospective studies comprising both treated and non-treated arms, using standardized MSI assessment criteria, as well as defined tumor stage, patients’ characteristics, and adjuvant therapy. In this respect, we also strongly recommend considering the number of activated cytotoxic lymphocytes infiltrating CRC, which may allow a more precise assessment of the prognostic and, perhaps, the predictive value of MSI-H.