Originally published as JCO Early Release 10.1200/JCO.2006.05.8172 on January 16 2007

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Prognostic and Predictive Roles of High-Degree Microsatellite Instability in Colon Cancer: A National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study

George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Ilan R. Kirsch, Norman Wolmark, Carmen J. Allegra

From the National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers; Mayo Clinic, Jacksonville, FL; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Allegheny General Hospital, Pittsburgh, PA; and the Network for Medical Communication and Research, North Potomac, MD

Address reprint requests to George P. Kim, MD, Mayo Clinic Jacksonville, Davis Bldg 8-E, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: kim.george{at}mayo.edu

Purpose The role of high-degree microsatellite instability (MSI-H) as a marker to predict benefit from adjuvant chemotherapy remains unclear.

Patients and Methods To help define its impact, we conducted an analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) patients who were randomly assigned to a surgery-alone group (untreated cohort) and patients assigned to an adjuvant fluorouracil (FU) -treated group (treated cohort). MSI-H and other potential markers were assessed (TGF-BRII, p53, thymidylate synthase, and Ki67).

Results In all, 98 (18.1%) of 542 patients exhibited MSI-H, and there was a strong inverse relationship between MSI-H and mutant p53 status (P < .001). The prognostic analyses showed increased recurrence-free survival (RFS) for MSI-H patients versus MSS/MSI-L patients (P = .10), but showed no difference in overall survival (OS; P = .67). There was a potential interaction between MSI-H and mutant p53 in terms of improved RFS (P = .03). In the predictive marker analysis, we observed no interaction between MSI status and treatment for either RFS (P = .68) or OS (P = .62). Hazard ratios (HR) for RFS for MSI-H versus MSS/MSI-L patients were 0.77 (95% CI, 0.40 to 1.48) in the untreated-patients group and 0.60 (95% CI, 0.30 to 1.19) in the treated-patients group. HRs for OS were 0.82 (95% CI, 0.44 to 1.51) and 1.02 (95% CI, 0.56 to 1.85) for the respective groups. There was a trend toward improved RFS in patients with MSI-H and mutant p53.

Conclusion These results do not support the use of MSI-H as a predictive marker of chemotherapy benefit.

published online ahead of print at www.jco.org on January 16, 2007.

Deceased.

Supported by Public Health Service Grants No. U10CA-12027, P-U10CA-37377, U10CA-69651, and U10CA-69974 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.

Presented in abstract form at the 2nd Annual Gastrointestinal Cancers Symposium, Miami, FL, January 27-29, 2005 (abstr 1666).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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