Microsatellite Instability and Survival in Stage II Colorectal Cancer: A Systematic Review and Meta-analysis

Abstract

Background/Aim: About 15-20% of colorectal cancers (CRCs) have deficiency in a mismatch repair (MMR) protein. MMR has a high level of microsatellite instability (MSI-H). We have conducted this review and meta-analysis to determine the prognostic role of MSI-H status in stage II CRC. Materials and Methods: We searched PubMed, EMBASE, The Cochrane Library, Web of Science, and SCOPUS for studies reporting data on overall survival (OS) and disease-free or relapse-free survival (DFS or RFS) for MSI-H compared to microsatellite stable (MSS) CRC. Results: A total of 39 studies were analysed, including 12,110 patients. MSI-H status was associated with a significantly reduced risk of death (HR=0.64, 95%CI=0.52-0.8, p<0.01) and relapse (HR=0.59, 95%CI=0.45-0.77, p<0.01) in stage II CRC. Conclusion: MSI-H represents an important prognostic determinant in stage II CRC and may be considered when estimating the risk of recurrence in stage II CRC. Stage II colorectal cancer (CRC) is usually associated with a good prognosis; five-year overall survival (OS) rates range from 75 to 87.5% (1). However, the administration of postoperative 5-fluorouracil (5-FU)-based chemotherapy in this group of patients remains controversial, since it has been shown that survival gain generally does not exceed 5% (2). Several prognostic factors have been evaluated in order to identify a high-risk stage II CRC subgroup, for which adjuvant chemotherapy would have a better indication. High-risk features include an inadequate sampling of lymph nodes (less than 12), extension of primary tumor (pT4), poor differentiation (grade 3), acute onset of the disease with obstruction or perforation, lymph-vascular and perineural invasion, and close, indeterminate or positive resection margins (3). Recently, microsatellite instability status (MSI) has been identified as a reliable prognostic indicator in stage II CRC, with an additional role in predicting the lack of benefit of 5-FU-based adjuvant chemotherapy (4-6). These data have been replicated in the large randomized phase III Quick and Simple and Reliable (QUASAR) trial, where 2,291 patients with stage II CRC were randomized to receive adjuvant chemotherapy with 5-FU and folinic acid or to undergo observation. An analysis performed on these patients found a prognostic role for MMR status, even if it was not shown to be predictive of any benefit from adjuvant chemotherapy (6). Although a number of molecular markers of outcome in CRC has been proposed (BRAF/KRAS), there has been no clear consensus about their role in early stage CRC. Despite that a series of studies have investigated the relationship between MSI status and survival in CRC patients, they often included mixed populations of early (stage II-III) and advanced CRCs (stages IV). The aim of our study was to evaluate the prognostic significance of MMR status in stage II CRC by analyzing all the available data coming from prospective and retrospective studies.

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

“…A meta-analysis composed of 5998 patients from 19 different studies has cast some doubts on the usage of MSI status as a determining factor for the postoperative management of stage II CRC patients, as they found no significant link between MSI status and overall or relapse-free survival [37]. However, a very recent large meta-analysis, including 38 studies with 12,110 patients, further establishes the prognostic significance of MSI status in stage II CRC [46] and indicates the need to implement MSI screening for all resected stage II CRC patients. The MSI status is less informative in stage III patients, as the risk differences are limited between MSI-high and MSS patients [35,38].…”

Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression

“…14 An MSI-high status correlates significantly with improved survival as well as lower risk of relapse in colorectal cancer patients, as stated in two meta-analyses including 71 studies in total. 15,16 MSI status also seems to predict clinical benefit of immune checkpoint inhibition in this entity. 17,18 The reason for this effect is the higher mutational burden caused by a deficient mismatch-repair system.…”

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

“…Associated with a better outcome [8,[10][11][12][13]30], especially in stage II CRC [14][15][16][17] Conflicting results: Shorter survival in patients treated with adjuvant 5-FU [10,23,24,67] Stage II CRC had improved RFS treated with 5-FU + irinotecan [14] APC Conflicting results: Poor prognostic marker in 5-FU treated stage III CRC [68] Associated with better outcomes in MSS tumors [69] No prognostic value [70][71][72] No predictive value Glossary: DFS; disease-free survival, OS; overall survival, RFS; recurrence-free survival, pMMR; proficient mismatch repair, 5-FU; 5-fluorouracil, CRC; colorectal cancer dMMR (n = 35) vs. pMMR (n = 261) 5-FU treated and no ACT 80% vs. 75% DFS respectively, p = 0.5 89% vs. 85% OS respectively, p = 0.6 no survival benefit, according to MMR status dMMR (n = 18) vs. pMMR (n = 191) 5-FU treated and no ACT 73% vs. 61% DFS respectively, p = 0.4 78% vs. 75% OS respectively, p = 0.8 no survival benefit according to MMR status The underlined terms refer to a subgroup, the italicized terms indicate which independent factors are being assessed in that subgroup for prognostic/predictive value, the regular text details the survival data, and the bolded text is the data interpretation and summary.…”