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

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, G. P. Articles by Allegra, C. J. Search for Related Content PubMed PubMed Citation Articles by Kim, G. P. Articles by Allegra, C. J. Related Articles Related Editorial Social Bookmarking                            What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge
  C. Richard Boland
  JCO 2007 25: 754-756 [Full Text]

This article has been cited by other articles:

				S. D. Markowitz and M. M. Bertagnolli Molecular Basis of Colorectal Cancer N. Engl. J. Med., December 17, 2009; 361(25): 2449 - 2460. [Full Text] [PDF]

				A. Zaanan, P. Cuilliere-Dartigues, A. Guilloux, Y. Parc, C. Louvet, A. de Gramont, E. Tiret, S. Dumont, B. Gayet, P. Validire, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin Ann. Onc., October 15, 2009; (2009) mdp383v1. [Abstract] [Full Text] [PDF]

				M. Mei, D. Deng, T.-H. Liu, X.-T. Sang, X. Lu, H.-D. Xiang, J. Zhou, H. Wu, Y. Yang, J. Chen, et al. Clinical Implications of Microsatellite Instability and MLH1 Gene Inactivation in Sporadic Insulinomas J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3448 - 3457. [Abstract] [Full Text] [PDF]

				M. M. Bertagnolli, D. Niedzwiecki, C. C. Compton, H. P. Hahn, M. Hall, B. Damas, S. D. Jewell, R. J. Mayer, R. M. Goldberg, L. B. Saltz, et al. Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803 J. Clin. Oncol., April 10, 2009; 27(11): 1814 - 1821. [Abstract] [Full Text] [PDF]

				S. Ogino, K. Nosho, G. J. Kirkner, K. Shima, N. Irahara, S. Kure, A. T. Chan, J. A. Engelman, P. Kraft, L. C. Cantley, et al. PIK3CA Mutation Is Associated With Poor Prognosis Among Patients With Curatively Resected Colon Cancer J. Clin. Oncol., March 20, 2009; 27(9): 1477 - 1484. [Abstract] [Full Text] [PDF]

				S. Ogino, K. Nosho, G. J Kirkner, T. Kawasaki, J. A Meyerhardt, M. Loda, E. L Giovannucci, and C. S Fuchs CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer Gut, January 1, 2009; 58(1): 90 - 96. [Abstract] [Full Text] [PDF]

				C. J. Braun, X. Zhang, I. Savelyeva, S. Wolff, U. M. Moll, T. Schepeler, T. F. Orntoft, C. L. Andersen, and M. Dobbelstein p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest Cancer Res., December 15, 2008; 68(24): 10094 - 10104. [Abstract] [Full Text] [PDF]

				S. Ogino, K. Nosho, J. A. Meyerhardt, G. J. Kirkner, A. T. Chan, T. Kawasaki, E. L. Giovannucci, M. Loda, and C. S. Fuchs Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer J. Clin. Oncol., December 10, 2008; 26(35): 5713 - 5720. [Abstract] [Full Text] [PDF]

				C. M. Sturgeon, M. J. Duffy, U.-H. Stenman, H. Lilja, N. Brunner, D. W. Chan, R. Babaian, R. C. Bast Jr., B. Dowell, F. J. Esteva, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers Clin. Chem., December 1, 2008; 54(12): e11 - e79. [Abstract] [Full Text] [PDF]

				L. Terrin, E. Rampazzo, S. Pucciarelli, M. Agostini, R. Bertorelle, G. Esposito, P. DelBianco, D. Nitti, and A. De Rossi Relationship Between Tumor and Plasma Levels of hTERT mRNA in Patients with Colorectal Cancer: Implications for Monitoring of Neoplastic Disease Clin. Cancer Res., November 15, 2008; 14(22): 7444 - 7451. [Abstract] [Full Text] [PDF]

				D. Frumkin, A. Wasserstrom, S. Itzkovitz, T. Stern, A. Harmelin, R. Eilam, G. Rechavi, and E. Shapiro Cell Lineage Analysis of a Mouse Tumor Cancer Res., July 15, 2008; 68(14): 5924 - 5931. [Abstract] [Full Text] [PDF]

				K. Imai and H. Yamamoto Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics Carcinogenesis, April 1, 2008; 29(4): 673 - 680. [Abstract] [Full Text] [PDF]

				A. Wu and J. Ji Adjuvant Chemotherapy for Gastric Cancer or Not: A Dilemma? J Natl Cancer Inst, March 19, 2008; 100(6): 376 - 377. [Full Text] [PDF]

				S. Ogino and A. Goel Molecular Classification and Correlates in Colorectal Cancer J. Mol. Diagn., January 1, 2008; 10(1): 13 - 27. [Abstract] [Full Text] [PDF]

				C. Richard Boland In Reply J. Clin. Oncol., October 20, 2007; 25(30): 4857 - 4858. [Full Text] [PDF]

				Predictive Role of MSI-H in Colorectal Cancer Prognosis Journal Watch Oncology and Hematology, April 13, 2007; 2007(413): 4 - 4. [Full Text]

				C. R. Boland Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge J. Clin. Oncol., March 1, 2007; 25(7): 754 - 756. [Full Text] [PDF]