MMR Status in Prognosis & Treatment of CRC

A. NCCN Clinical Practice Guidelines in Oncology. Colon cancer. Version 3.2012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

The comprehensive guideline from NCCN addresses treatment recommendations for patients with colon cancer. With respect to the use of tumor MMR testing to inform prognosis and treatment strategies, NCCN “recommends that MMR testing be considered for patients with stage II disease and planned adjuvant therapy with a flouropyrimidine alone. Grade 3 or 4 (poorly differentiated) is not considered a high-risk feature for stage II patients whose tumors are MSI-H.” In specific algorithms of the guideline, NCCN recommends that MMR testing should be considered for all colon cancer patients diagnosed less than age 50.

B. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247-257. [Abstract] [Full text]

In this retrospective study of 570 tissue specimens from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy, such treatment improved overall survival of stage II and stage III patients with microsatellite stable tumors or tumors exhibiting low-frequency MSI. This finding was based on a multivariate analysis that controlled for stage and grade. There was no benefit of adjuvant chemotherapy in the group with high-frequency MSI.

C. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of flurouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219-3226. [Abstract] [Full Text]

Researchers collected data from 457 patients who were previously assigned to fluorouracil-based therapy versus no post-surgical treatment and pooled data from a prior analysis to examine the relationship between MMR status and disease-free survival. The results showed that in patients whose tumors were MMR defective, adjuvant fluorouracil therapy was detrimental in patients with stage II but not stage III disease. The authors concluded that MMR assessment should be considered for patients who are candidates for fluorouracil therapy alone (stage II patients).

D. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890-6. [Abstract]

This meta-analysis of 7 studies representing 3,690 patients found that for MSI-H patients, relapse-free survival was not associated with whether they received 5-fluorouracil-based chemotherapy or not, indicating that they seem to be less sensitive to chemotherapy. However, there is a benefit in survival for patients with MSS patients who undergo this type of chemotherapy. The authors concluded that MSI-H status is predictor of favorable prognosis and non response to fluorouracil.

E. Sinicrope FA, Foster NR, Thibodeau SN, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863-75. [Abstract]

In this study of 2,141 stage II and stage III colon cancer patients treated in randomized trials of 5-fluorouracil-based adjuvant therapy, the authors found that compared to patients with proficient mismatch repair status, those with defective mismatch repair had reduced rates of tumor recurrence, delayed time to recurrence, and improved survival. However, in stage III patients with defective mismatch repair, distant recurrences were reduced by fluorouracil treatment.