We read with interest the study by Jover and colleagues (Gut 2006;55:848–55) on the predictive value of the DNA mismatch repair (MMR) or microsatellite instability (MSI) phenotype for response of colorectal cancer patients to 5‐fluorouracil (5‐FU) chemotherapy. We are concerned however about the conclusion reached by the authors and the accompanying commentary (Gut 2006;55:759–61) that MSI status should be considered in decisions on the use of 5‐FU. While the clinical utility of MSI status for screening of hereditary non‐polyposis colorectal cancer (HNPCC) is unquestioned, we are of the opinion that currently available data cannot justify exclusion of patients with MSI tumours from receiving 5‐FU treatment.
The authors state that “5‐FU based chemotherapy may not be useful in stage II and III MMR deficient colorectal cancer and a revision in the management of this subgroup should be considered”. However, examination of the results shown in fig 3B and table 4 of their paper indicates a benefit from 5‐FU treatment for patients with MMR deficient (MSI‐H or MSI+) tumours, with survival rates of 89.5% and 82.4% for treated and non‐treated patients, respectively. A similar observation was recently made by Benatti and colleagues1 who reported a five year survival rate of 100% for stage II MSI+ patients treated with 5‐FU compared with approximately 90% for those treated by surgery alone. In both studies, the authors appear to have reached the opposite conclusion to what is suggested by their own data. In the absence of appropriately powered studies, it seems quite astonishing to conclude that MSI+ patients should not be treated with adjuvant 5‐FU chemotherapy, particularly for stage III cases.
The view that MSI+ tumours do not respond to 5‐FU chemotherapy has also been promulgated by other workers.2,3,4,5 In direct contrast with this view, other authors, including ourselves, have published evidence that patients with MSI+ tumours either gain a survival advantage from 5‐FU chemotherapy6,7,8 or have extremely good survival when treated with 5‐FU.9,10,11 There are several possible reasons for these discordances, including the methods used to evaluate MSI status and the small sample size and short follow up time of most studies. The Jover et al study examined only 19 MSI+ patients with a median follow up time of just two years.
Another potentially important issue that has been widely overlooked is the fact that MSI+ tumours show different molecular profiles according to patient age and genetic background. For example, both BRAF mutation and tumour suppressor gene methylation are rare in MSI+ tumours from young patients and HNPCC patients, but frequent in sporadic MSI+ tumours from older patients.12,13 This observation may not be relevant if the MSI+ phenotype itself is directly involved in the response to 5‐FU. However, it becomes a critical issue if BRAF mutations, DNA methylation, or other related phenotypic features are more important for 5‐FU response than MSI. Evidence that DNA methylation is a predictive marker for good survival benefit in 5‐FU treated colorectal cancer patients has already been published.14,15
It is therefore reasonable to hypothesise that non‐methylated MSI+ tumours from younger or HNPCC patients do not respond to 5‐FU whereas the heavily methylated MSI+ tumours typically seen in older sporadic patients do respond. In support of this, the only study on the predictive value of MSI+ carried out exclusively on HNPCC patients found no survival benefit from the use of 5‐FU.16 None of the other published studies on the predictive significance of MSI has taken into account the molecular heterogeneity of this phenotype in relation to patient age and genetic background (HNPCC or sporadic), particularly with respect to DNA methylation. Until this issue is addressed, we believe it is premature and potentially irresponsible to herald the arrival of MSI+ as a predictive marker to guide the use of 5‐FU in colorectal cancer.
Footnotes
Conflict of interest: None declared.
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