Microsatellite Instability and Colorectal Cancer Prognosis

Abstract

Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions,1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results:Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year^specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non^polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients.The survival benefit for patients with hereditary non^polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

“…Our finding of improved survival associated with MSI in colorectal carcinomas of any histologic subtype is consistent with previous reports [11][12][13]. This supports the recent WHO recommendation to grade mucinous carcinoma according to their MSI status [3].…”

“…Up to 15% of all colorectal carcinomas demonstrate MSI, more frequently secondary to acquired methylation of MLH1 (sporadic cases) than caused by a germline mutation in an MMR gene (Lynch syndrome). MSI has been reported to be a strong positive prognostic factor by multiple independent studies [11][12][13]. Some histologic subtypes of colorectal carcinomas are more commonly observed in MSI tumors, including medullary carcinomas, mucinous adenocarcinomas and signet ring cell carcinomas [14].…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Numerous studies have made direct comparisons between MSI CRC with and without 5-FU chemotherapy (Ribic et al, 2003;Tajima et al, 2004) (Benatti et al, 2005;Jover et al, 2006). Many early studies outlined an increased sensitivity of MSI patients to 5-FU treatment (Elsaleh et al, 2000;Hemminki et al, 2000;Jover et al, 2006;Jover et al, 2009).…”

“…Ribic et al combining data from RCTs of patients receiving surgery only versus those who also received adjuvant 5-FU-based treatment showed that patients with MSI were potentially harmed by chemotherapy (Ribic et al, 2003). The finding that 5-FU-based chemotherapy did not seem to improve survival among MSI patients was supported by a large retrospective analysis of over a thousand patients (Benatti et al, 2005) and by a metaanalysis (Des Guetz et al, 2009) …”

“…3. Chemotherapy response -Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible reduced response to 5-FU based chemotherapy in dMMR tumours (Benatti et al, 2005;Hutchins et al, 2011;Ribic et al, 2003;Sargent et al, 2010) According to the National Comprehensive Cancer Network (NCCN), MMR testing should be considered for all patients with stage-II disease, as stage-II MSI tumours have a good prognosis and may not benefit from chemotherapy (NCCN, 2015). 4.…”