Clinical Cancer Review just published an "OnlineFirst" article on February 2, 2012 (link to abstract) that reviews microsatellite instability (MSI) in colorectal cancer. There have been several recent reviews on this topic in various journals, including Archives of Pathology and Laboratory Medicine in October 2011. The review by Drs Geiersbach and Samowitz in Archives is excellent (and recommended too) but has a decidedly technical, lab-oriented focus. I recommend this one to pathologists looking for a more clinically-oriented review that especially addresses current and future studies looking at how the molecular heterogeneity of "MSI" tumors may have different chemosensitivity responses. It is very readable and certainly is the most current. If you're looking for an article that makes you look good in tumor board, this is it!
A couple of highlights:
- MSI as prognostic marker in CRC. Observational studies, retrospective data from randomized clinical trials and meta-analyses have consistently shown that tumors that show MSI or deficient mismatch repair (MMR) are independently associated with improved survival and reduced recurrence rates compared with individuals with MSS tumors.
- ECOG 5202 is a ongoing trial of stage II CRC patients stratifying them into low-risk versus high-risk based on MSI and allelic loss of 18q. Low-risk patients (MSI and intact 18q) are assigned to an observational arm post-op while high-risk patients (MSS and allelic loss of 18q) are assigned to standard post-op chemo for stage III patients (FOLFOX). Unfortunately, this study will not address the use of MSI as a predictive marker for response to 5-FU therapy.
- MSI as predictive marker in CRC. Mutliple studies, including RCTs, retrospective case series, in vitro cell line data, and a meta-analysis, have consistently shown that MSI is a negative predictive marker for response to 5-FU. It has been recently recommended that patients with stage II colon cancer showing MSI not receive 5-FU as adjuvant therapy given their favorable prognosis and lack of benefit from 5-FU. Incidentally, in discussing whether to routinely test for MSI in stage II and II patients with the oncologists, it was evident that there is a lot of "catch-up" and education that needs to be done here.
- Currently, there are only limited data in MSI tumors from patients treated with oxaliplatin combined with 5-FU and predictive information is lacking. This is an important confounding problem interpreting the literature since standard first-line treatment for CRC is 5-FU and oxaliplatin. It appears, however, from in vitro studies that oxaliplatin sensitivity is independent of the MMR system.
- Since KRAS testing is becoming more routine for CRC, especially in high stage III/stage IV cancers, it is important also to note that sporadic MSI CRCs (with epigenetic inactivation of hMLH1) show frequent (~50%) co-occurrence of BRAFV600E mutations (compared to an overall BRAF mutation frequency of about 10% among all CRCs). Note: The presence of a BRAF mutation indicates a sporadic MSI CRC and essentially excludes a diagnosis of Lynch syndrome.
- There's a lot of interesting stuff on possible additional targets for therapy you should check out.