Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis

https://doi.org/10.1016/j.ejca.2009.04.018Get rights and content

Abstract

Background

Microsatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial.

Materials and methods

Studies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI).

Results

A MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not.

For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62–1.49); HR OS (6 studies): 0.70 (95% CI: 0.44–1.09; p = 0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67–0.87)).

Conclusion

We found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.

Introduction

Colorectal cancer (CRC) is the third most common cancer and the fourth most frequent cause of cancer death worldwide.1 In addition to curative surgery, adjuvant chemotherapy is the mainstay of treatment. In adjuvant setting, for high risk stage II and stage III diseases, 5-fluorouracil (5FU) is always part of treatment and now generally used in combination with oxaliplatin (Folfox protocol).2

Among genetic abnormalities involved in carcinogenesis, microsatellite instability (MSI) is a major pathway of cancer development.3 MSI corresponds to a dysfunction of the mismatch repair (MMR) system resulting in a reduction in the length of highly repeated DNA sequences termed microsatellites. The MMR system corrects mismatches of DNA nucleotides occurring during replication. A germinal mutation inactivating one of the MMR genes may lead to a hereditary form termed Hereditary Non-Polyposis Colon Cancer (HNPCC).

A previous meta-analysis (MA) found that MSI status was a prognostic factor in CRC.9 It also concluded to a lack of benefit of adjuvant chemotherapy among MSI-H patients but included only two articles where adjuvant treatment was compared with no treatment.8, 11 In addition, the relative benefit of chemotherapy (meaning predictive value) among patients with high microsatellite instability (MSI-H) and microsatellite stable (MSS) was not detailed. This is a major issue since MSI-H status is not only found in the rare HNPCC forms (Lynch syndrome) but also found in 15% of sporadic forms of CRC.12

The main goal of our MA was to assess the predictive value of MSI-H status among patients receiving or not adjuvant chemotherapy for CRC. Although the prognostic value of MSI status has been firmly established, its predictive value is still a matter of debate. The distinction between prognostic and predictive factors has been clearly made.13

Many studies assessing the predictive role of MSI status on the efficacy of adjuvant chemotherapy in CRC have been published between 2000 and 2008. These works investigated the relationship between MSI status and relapse-free survival (RFS) or overall survival (OS) among patients with localised disease. Some studies were Randomised Controlled Trials (RCTs) initially designed to evaluate the benefit of adjuvant treatment.7, 8 Until now, no prospective study randomised chemotherapy according to MSI status and compared its efficacy among MSI-H and MSS patients. Also, the relationship between the MSI status and the efficacy of chemotherapy differed among studies. These facts justify the need for a meta-analysis of all publications assessing the predictive value of MSI status on the efficacy of treatments.

Section snippets

Publication selection

We performed our MA according to a predefined written protocol. To be eligible, studies had to deal with colon or rectum cancer (whatever be the stage at inclusion of patients in the individual studies) and had to assess the relationships between MSI status, chemotherapy and RFS or OS for localised disease. Studies (full articles) were identified by an electronic search using online PubMed, with a set of keywords used simultaneously ‘colorectal cancer, chemotherapy, microsatellite instability’.

Results

Our electronic data search using online PubMed retrieved a total of 159 references including 50 reviews. An EMBASE query did not provide us with any additional reference. After exclusion of the references that were out of the scope of our MA (by reading the abstracts), and of one reference providing only MSH2 gene expression but not MSI status,17 there remained 17 studies dealing with MSI.4, 5, 6, 7, 8, 10, 11, 18, 19, 20, 21, 22, 23, 24, 25, 26 Three studies5, 8, 27 were published in duplicate.

Discussion

Our MA is the first to deal with the predictive value of MSI status to assess the benefit of adjuvant chemotherapy. The issue of the comparative benefits of chemotherapy according to MSI status is crucial since no biological marker has so far been proved effective in predicting the efficacy of adjuvant chemotherapy in CRC.33 We showed that there was no survival difference among MSI-H patients whether or not they received chemotherapy, whereas MSS patients had a better response to chemotherapy,

Conflict of interest statement

None declared.

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