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Originally published as JCO Early Release 10.1200/JCO.2006.05.8172 on January 16 2007 © 2007 American Society of Clinical Oncology. 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
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.
In the United States, colorectal cancer ranks second in overall deaths as a result of cancer, with 148,610 new cases diagnosed and 55,170 fatalities estimated for 2006.1 Patients with high-risk stage II disease and lymph node–positive stage III disease receive a survival benefit with the administration of adjuvant fluoropyrimidine-based chemotherapy after surgical resection. The combination of fluorouracil (FU) and leucovorin using either the Mayo Clinic (Rochester, MN) or Roswell Park (Buffalo, NY) regimens represented the standard of care before the introduction of oxaliplatin.2,3 It is acknowledged that not all patients with recurrent disease receive a survival benefit from adjuvant chemotherapy. With the evaluation of molecular markers that can potentially predict clinical outcomes with FU treatment, it is hoped that the patients who benefit from adjuvant chemotherapy can be more precisely identified. The microsatellite instability (MSI) pathway, which involves failure of the nucleotide mismatch recognition and repair system (DNA MMR), is one form of genomic instability.4,5 MSI is associated with improved overall survival (OS) and is present in a subset of sporadic colon cancer patients as well as hereditary nonpolyposis colorectal cancer patients.6-14 MSI results from loss of critical components, typically the MLH1 and MSH2 proteins.15,16 These proteins act in concert to repair interstrand nucleotide mismatches and the loops of DNA that result from a mismatched number of complementary nucleotides. This recognition of distortions in the DNA helix also serves to recognize DNA adducts formed by chemotherapeutic agents. The consequence of this loss of DNA damage sensor function leads to the lack of appropriate signals for apoptosis induction17,18 and resistance to specific chemotherapy drugs.19-21 Importantly, resistance to FU in MMR-defective cells has been reported.22,23 Despite improved survival in nonhereditory cancer patients exhibiting MSI, this relative resistance to clinically relevant agents may potentially influence treatment responses based on MSI status. These preclinical observations of possible FU drug resistance present the dilemma of whether administration of FU-based adjuvant treatment is beneficial or potentially detrimental to MSI patients. Two groups of investigators evaluated the predictive role of MSI in the context of FU treatment and reported contrasting results.24-26 A direct comparison between MSI patients treated with surgery alone versus patients treated with postoperative fluoropyrimidine-based chemotherapy is required to clarify the potential value of MSI as a true predictive marker, although such an analysis remains elusive. In an effort to investigate the role of MSI as a prognostic factor and to further define the potential predictive role of MSI with respect to chemotherapy, an analysis of MSI from archival tissues from four National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant chemotherapy trials was conducted.27-30 The first two trials, NSABP C-01 and C-02, consisted of patients treated with surgery alone and represent one of the last opportunities to chronicle the natural behavior of microsatellite-unstable cancers. The second set of archival patient tissues were derived from the NSABP C-03 and C-04 trials, in which patients were treated with adjuvant FU and leucovorin. This National Cancer Institute (NCI; Bethesda, MD) –NSABP collaborative study was conducted to compare the clinical outcome of MSI patients treated with surgery alone versus those treated with surgery followed by chemotherapy.
Patient Selection The patients enrolled onto this trial were drawn from four randomized NSABP colon cancer treatment trials (Table 1).
The formalin fixed, paraffin embedded tissue blocks of patient specimens were randomly selected and processed at the NSABP tissue repository. Several individual 7-micron sections were prepared from each specimen and mounted on glass slides. A unique number that was linked to the clinical database identified each slide; however, the investigators assessing MSI were blinded to the clinical data. The statistical analysis was performed independently by the statistical group (H.S.W., L.H.C.). A waiver of consent was granted for this study by the Allegheny General Hospital (Pittsburgh, PA) institutional review board under 45CFR 46.116(d). The Allegheny General Hospital institutional review board has oversight of the NSABP tissue bank.
MSI Methods For the entire cohort, 98 (18.1%) of 542 patients exhibited MSI-H. Among the markers from the Bethesda-guidelines panel, the Bat25 and Bat26 markers alone identified the MSI-H patients 82.6% and 78.3% of the time, respectively, in the C-01/C-02 cohort. In the C-03/C-04 group, the Bat25 and Bat26 markers identified the MSI-H patients 93.4% and 96.7% of the time, respectively. In this latter, treated group, one or both of these markers identified MSI-H patients in 95.3% of cases when considered in combination.
Immunohistochemistry Methods
Statistical Analysis
Marker scores were categorized for analysis purposes in the following manner: positive (mutant) versus negative (wild-type) for p53; MSI-H versus microsatellite stable (MSS)/MSI-L for MSI; 41% to 100% versus 0% to 40% for Ki-67; and definite staining of bright and/or high intensity (3) versus weaker or light-to-moderate intensity (0 to 3) for TS intensity. The relationship between marker pairs was assessed with The relationship between each marker and outcome was assessed for all patients (trials C-01 through C-04) and for each treatment group (trials C-01/C-02 versus C-03/C-04). Cox proportional hazards models (stratified by stage) were used to compare OS and RFS between marker categories and to obtain risk ratios. In analyses of combined treatment groups, models were stratified by treatment and stage. All P values presented are two-sided. Global tests for interactions of MSI with other covariates for predicting outcome were conducted using a likelihood ratio test.
Patient Characteristics This study includes eligible Dukes' B and C patients with follow-up who were randomly assigned or registered to surgery alone (untreated group) on trials C-01 and C-02 and patients randomly assigned to the fluorouracil plus leucovorin group (FU+LV; treated group) on trials C-03 and C-04. Paraffin blocks suitable for these analyses were available for 20% of untreated patients (C-01: 131 of 526 patients; C-02: 42 of 344 patients) and 31% (C-03: 159 of 518; C-04: 210 of 691) of treated patients. The characteristics of the patients included in this study were similar to those of patients who were not included. Importantly, age of the patients in the two cohorts was comparable, as were sex, disease stage, and tumor site (data not shown). To verify further the similarity between the patients selected for this study and the patients who were not selected, log-rank tests were performed to compare the 5-year RFS (0.71 v 0.68) and OS (0.72 v 0.68) of the 542 patients included in the study versus the 1,537 patients in the entire C-01 to C-04 cohort who were not included in this analysis. The P values were .52 and .49, respectively. This indicates the patients included in this analysis are representative of the patients participating in the four randomly assigned protocols.
MSI Analysis In an analysis using the entire cohort of patients (treated and untreated), there was a suggestion of an increased RFS for the MSI-H versus the MSS/MSI-L patients (P = .10; Fig 1). The estimated relative risk (RR) of relapse for MSI-H patients versus MSS/MSI-L patients was 0.68 (95% CI, 0.42 to 1.09). There was little evidence of an association with OS (P = .67), as the estimated RR of death for MSI-H patients versus MSS/MSI-L patients was 0.91 (95% CI 0.59 to 1.4; Fig 2).
When an interactive term was added to treatment and MSI status in a Cox proportional hazards model (Table 2), there was no evidence of interaction between MSI status and treatment for either RFS (P = .68) or OS (P = .62). The hazard ratios (HR) for RFS for MSI-H patients versus MSS/MSI-L patients were 0.77 (95% CI, 0.40 to 1.48; Fig 3) in the untreated C-01/C-02 group and was 0.60 (95% CI, 0.30 to 1.19; Fig 4) in the treated C-03/C-04 patients. The HRs for overall survival for MSI-H patients versus MSS/MSI-L patients were 0.82 (95% CI, 0.44 to 1.51; Fig 5) in the C-01/C-02 patient group and 1.02 (95% CI, 0.56 to 1.85; Fig 6) in the C-03/C-04 patient group.
Relationship of MSI With Patient Characteristics A logistic regression testing for an association of MSI with the patient characteristics Dukes' stage, tumor site, age, or sex had a global P value of less than .001. There was indication of a strong association between tumor site and MSI. Thirty-seven percent of the MSI-negative patients had a tumor in the right colon versus 61% of the MSI-positive patients (P < .001). No other statistically significant associations were observed (Table 3).
Using the Cox proportional hazards model, global tests of interaction of MSI with patient characteristics (age, sex, disease stage, and tumor site) to predict outcome were not statistically significant (P = .43 for recurrence and P = .92 for OS).
TGFßRII Mutation in MSI-H Patients
Relationship Between MSI and Other Markers Similar global analyses looking for interaction of MSI with the other markers (TS, Ki-67 and p53) failed to achieve statistical significance (P = .24 for recurrence, and P = .82 for survival). The only suggestion of a potential interaction was between MSI and p53 with recurrence-free interval as the outcome. With no adjustment for multiple comparisons, the associated P value was P = .03. Adjustment for the six marker interactions considered (three markers and two outcomes), would change this P value to P = .17. In patients who were MSS/MSI-L, the HR for mutant p53 or positive staining tumors was 1.99 relative to mutant p53-negative tumors. On the other hand, among patients who were MSI-H, the estimated HR for p53-positive staining tissues was 0.41 relative to that of patients who were p53-negative. However, there were only 31 patients who were p53-positive and MSI-positive, of whom five patients experienced recurrence. The test of interaction between MSI and p53 with OS as an end point did not approach statistical significance (P = .24).
In this NCI-NSABP collaborative analysis, the prognostic and predictive roles of MSI were examined in colorectal cancer patients enrolled onto the NSABP C-01 through C-04 trials. There was suggestion of an improved RFS rate in patients with MSI-H in the entire C-01 to C-04 cohort, in the untreated C-01/C-02 subset and in the FU-treated C-03/C-04 subset, although none of these differences were statistically significant. There essentially was no suggestion of improvement for survival. In this analysis, which was distinct from other reported studies, the methods for detection of MSI-H were uniform, because only the NCI-sponsored "reference panel" of five loci was used.32 All five NCI markers had to be amplified to designate a sample as MSI-H; this was a stringent criterion maintained throughout the study. The overall percentage of patients with MSI-H in this study was 18.1%, which is within the established range of 15% to 21%. This NCI-NSABP study also examined the interactions between MSI-H and various molecular markers and found concordance with previously reported laboratory findings. In particular, our study confirms the inverse relationship between mutant p53 and MSI-H, as was described in the early characterization of microsatellite unstable tumors.5 In terms of the observed potential interaction of MSI-H status and mutated p53 with RFS presented in our study, it is unclear whether this represents a statistical artifact or a true interaction. With the number of subsets studied, a spurious observation could result and would either be supported or refuted in future analyses. A positive correlation between MSI-H and Ki67 might have been predicted from early pathologic descriptions of MSI tumors being poorly differentiated with high S phase fractions.33,34 In this analysis, a positive association between MSI-H and Ki67 was suggested (P = .03). The analyses involving the TGFßRII were done primarily to confirm results reported by Hamilton et al.35 No overall benefit associated with the TGFßRII (across all MSI-H patients) was observed; however, all the CIs were wide and overlapped. The interaction between MSI and TS, especially in relation to predicting outcome to fluoropyrimidine-based chemotherapy, is more intriguing. In general, several researchers established that elevated TS levels predict worse clinical outcomes.31,36-38 Interestingly, TS levels are two times higher in the MMR-defective HCT116 cell line versus the MMR-proficient HT29 cell line.39 These HCT116 cells are inherently resistant to fluoropyrimidines, by 17 times, compared with their genetically matched MLH1-intact counterparts.22,40 In xenograft models with either MMR-deficient or -proficient cells, a 21% relative cell enrichment of MMR-deficient cells was observed after FU treatment.23 Somewhat paradoxically, halogenated thymidine incorporation into DNA from MMR-defective HCT116 cells occured to a greater extent compared with MMR-intact cells.41 Despite these FU resistance observations, our NSABP study is the first to report that no interaction between MSI-H and TS was detectable. While retrospective, the strengths of this analysis are: (1) the selection of patients from prospective randomized multicentered NSABP trials with standard FU/leucovorin regimens; (2) the statistical verification that selected patients were representative of the entire cohort; (3) the use of the Bethesda guidelines MSI-H reference panel; (4) the concordance with other reports in terms of the percentage of MSI-H patients, the sensitivity of the Bat25 and Bat26 markers, and the inverse correlation with mutant p53; and (5) the observations of improved RFS in MSI-H patients and the poor outcomes in MSS patients with mutated-p53. As with other studies using archival specimens from large cooperative groups, this analysis was restricted by a relative lack of statistical power, since tumor specimens appropriate for analysis were available from only a minority of patients. Because patients selected for this study did not undergo concurrent random assignment to surgery alone or FU/LV, a direct comparison of treatment within MSI status was neither performed nor presented in the Results section. In contrast with other studies, we failed to identify an interaction between FU/LV therapy and MSI status (Table 2). However, the confidence intervals around the hazard ratio for the interaction term were wide (Table 2), so we cannot completely rule out such an effect. Specifically, these data do not suggest that adjuvant therapy provides substantially more benefit to patients with MSI-H cancers than those patients with MSS cancers. These results suggest that the improved prognosis for MSI-H patients, as previously reported, may be more dependent on the specific biology of these cancers as opposed to their response to adjuvant FU-based chemotherapy. Further evaluations are warranted to define the role of MSI as a potential predictive marker, as this question requires and deserves further study. Prospective randomized studies testing the impact of newer agents such as oxaliplatin and biologic agents in the adjuvant setting will continue to explore the potential predictive value of MSI-H.
The authors indicated no potential conflicts of interest.
Conception and design: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Ilan R. Kirsch, Carmen J. Allegra Financial support: George P. Kim Administrative support: George P. Kim, Ilan R. Kirsch, Norman Wolmark Provision of study materials or patients: George P. Kim, Soonmyung Paik Collection and assembly of data: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Carmen J. Allegra Data analysis and interpretation: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Ilan R. Kirsch, Carmen J. Allegra Manuscript writing: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Ilan R. Kirsch, Norman Wolmark, Carmen J. Allegra Final approval of manuscript: George P. Kim, Linda H. Colangelo, H. Samuel Wieand, Soonmyung Paik, Ilan R. Kirsch, Norman Wolmark, Carmen J. Allegra
We thank Barbara C. Good, PhD, director of scientific publications of the National Surgical Adjuvant Breast and Bowel Project, and Michael J. O’Connell, MD, of the National Surgical Adjuvant Breast and Bowel Project, for his thoughtful review.
published online ahead of print at www.jco.org on January 16, 2007. 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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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. Logistic regression was used to test for the association of MSI with sets of variables such as other markers or patient characteristics. 
21.4%) of 173 tumor samples exhibited MSI-H. In the chemotherapy-treated cohort, 61 (16.5%) of 369 had MSI-H–positive tumors. 
Deceased. 
