Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer
Christine M. Ribic, M.Sc., Daniel J. Sargent, Ph.D., Malcolm J. Moore, M.D., Stephen N. Thibodeau, Ph.D., Amy J. French, B.A., Richard M. Goldberg, M.D., Stanley R. Hamilton, M.D., Pierre Laurent-Puig, M.D., Ph.D., Robert Gryfe, M.D., Ph.D., Lois E. Shepherd, M.D., Dongsheng Tu, Ph.D., Mark Redston, M.D., and Steven Gallinger, M.D.
Background Colon cancers with high-frequency microsatelliteinstability have clinical and pathological features that distinguishthem from microsatellite-stable tumors. We investigated theusefulness of microsatellite-instability status as a predictorof the benefit of adjuvant chemotherapy with fluorouracil instage II and stage III colon cancer.
Methods Tumor specimens were collected from patients with coloncancer who were enrolled in randomized trials of fluorouracil-basedadjuvant chemotherapy. Microsatellite instability was assessedwith the use of mononucleotide and dinucleotide markers.
Results Of 570 tissue specimens, 95 (16.7 percent) exhibitedhigh-frequency microsatellite instability. Among 287 patientswho did not receive adjuvant therapy, those with tumors displayinghigh-frequency microsatellite instability had a better five-yearrate of overall survival than patients with tumors exhibitingmicrosatellite stability or low-frequency instability (hazardratio for death, 0.31 [95 percent confidence interval, 0.14to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy,high-frequency microsatellite instability was not correlatedwith increased overall survival (hazard ratio for death, 1.07[95 percent confidence interval, 0.62 to 1.86]; P=0.80). Thebenefit of treatment differed significantly according to themicrosatellite-instability status (P=0.01). Adjuvant chemotherapyimproved overall survival among patients with microsatellite-stabletumors or tumors exhibiting low-frequency microsatellite instability,according to a multivariate analysis adjusted for stage andgrade (hazard ratio for death, 0.72 [95 percent confidence interval,0.53 to 0.99]; P=0.04). By contrast, there was no benefit ofadjuvant chemotherapy in the group with high-frequency microsatelliteinstability.
Conclusions Fluorouracil-based adjuvant chemotherapy benefitedpatients with stage II or stage III colon cancer with microsatellite-stabletumors or tumors exhibiting low-frequency microsatellite instabilitybut not those with tumors exhibiting high-frequency microsatelliteinstability.
Colorectal cancer is the fourth most common type of cancer inWestern society and the second leading cause of cancer-relateddeath in North America.1 Although surgical resection alone ispotentially curative, local or distant recurrences develop inmany patients, and those with the highest risk of recurrenceare advised to receive fluorouracil-based systemic adjuvantchemotherapy, which has been shown to be beneficial in a numberof cooperative-group trials and analyses.2,3,4,5,6,7,8,9,10,11,12
Traditional pathological staging systems have been useful inpredicting the outcome of colorectal cancer, but it is now evidentthat these cancers are heterogeneous. The natural history ofcolorectal cancer correlates strongly with genetic alterationsthat occur during the progression from adenoma to carcinomato metastatic disease.13,14 The most common genetic alterations,occurring in approximately 85 percent of colorectal cancers,are allelic losses or loss of heterozygosity, chromosomal amplifications,and translocations.15,16,17,18,19 These alterations are characteristicof the chromosomal-instability pathway, also known as the microsatellite-stabilitypathway. The remaining 15 percent of colorectal cancers displayframe-shift mutations and base-pair substitutions that are commonlyfound in short, tandemly repeated nucleotide sequences knownas microsatellites.16,20,21,22,23,24,25,26,27 This form of geneticdestabilization is most commonly caused by the loss of the DNAmismatch-repair function and is referred to as the microsatellite-instabilitypathway. The phenotype of tumors with this defect is termedthe high-frequency–microsatellite-instability phenotype.16,20,22,28,29,30,31,32The chromosomal-instability phenotype and the high-frequency–microsatellite-instabilityphenotype do not represent alterations of single genes, butrather discrete molecular pathways involving multiple somaticgenetic targets.20
Recently, distinct clinical and pathological features of colorectaltumors arising from these two separate mutational pathways havebeen identified. High-frequency microsatellite instability isobserved more frequently in colorectal cancers that occur proximalto the splenic flexure. These tumors also exhibit poor differentiation,mucinous cell type, and peritumoral lymphocytic infiltration;they are usually diploid, unlike microsatellite-stable tumors,which are commonly aneuploid.26,27,33,34,35 Colorectal cancersexhibiting high-frequency microsatellite instability have alsobeen associated with a larger size of the primary tumor buta more favorable stage distribution.22,33 Patients with colorectalcancers that exhibit high-frequency microsatellite instabilityhave longer survival than stage-matched patients with cancersexhibiting microsatellite stability.16,22,23,26,36,37,38
Few studies have examined the effect of adjuvant treatment incolorectal cancers with high-frequency microsatellite instability.23,24,36,39,40Furthermore, studies that have controlled for the effects ofadjuvant therapy have had small or nonrandomized study populationswith potential selection biases.24,36,39,40 We used specimensfrom patients with resected stage II or stage III colon cancerwho were previously enrolled in prospective, randomized trialsof fluorouracil-based chemotherapy. The pooled data base forthese trials includes phase 3 studies with groups that receivedno treatment, thus permitting an analysis of the true survivaladvantage for patients whose tumors exhibited high-frequencymicrosatellite instability and who had not received adjuvantchemotherapy. In addition, studying this population of patientsallowed us to analyze whether the phenotype of high-frequencymicrosatellite instability could be an independent predictorof a benefit from fluorouracil-based adjuvant chemotherapy.
Methods
Patients and Specimens
We studied specimens from 570 patients with colon cancer whohad previously been enrolled in five phase 3 trials of adjuvantchemotherapy (Table 1). The primary objective of each of thetrials was to determine whether fluorouracil-based adjuvantchemotherapy improved disease-free survival, overall survival,or both among patients who had undergone curative resectionof stage II or stage III colon cancer. Three studies randomlyassigned patients to fluorouracil plus leucovorin or no treatment,and two studies randomly assigned patients to fluorouracil pluslevamisole or no treatment. The median duration of follow-upfor all patients was 7.4 years. The current analysis was inaccordance with the original informed consent signed by allpatients.
Blocks of formalin-fixed, paraffin-embedded specimens were requestedfrom the relevant pathology departments. In total, 570 specimenswere included in the analysis of microsatellite instability.Collected specimens that were excluded from the analysis hadlow tumor cellularity (<60 percent) or could not be amplifiedby polymerase chain reaction (PCR).
Microsatellite-Instability Testing and Analysis
Extracted DNA was amplified by PCR with the use of 2 to 11 microsatelliteloci. Specifically, specimens from the North Central CancerTreatment Group (protocols 784852 and 874651) and GastrointestinalIntergroup trial 0035 of the National Cancer Institute werescreened with 4 to 11 dinucleotide markers, as described previously.23,41Nearly all specimens collected from the C.03 trial of the NationalCancer Institute of Canada were amplified with 5 to 10 microsatelliteloci derived from the panel of microsatellite loci defined bythe National Cancer Institute, as described previously.22,34,42,43Specimens obtained from the trial conducted by the FondationFrançaise de Cancérologie Digestive, as well asfive specimens from the C.03 trial of the National Cancer Instituteof Canada, were screened only with mononucleotide markers BAT25and BAT26, since non-neoplastic control tissue was not available.44
The presence of additional bands observed in the PCR productsfrom tumor DNA that were not observed in DNA from normal tissuefrom the same patient was scored as instability at that particularlocus. In accordance with consensus definitions of the NationalCancer Institute, tumor samples were classified as displayinghigh-frequency microsatellite instability (instability at 30percent or more of the loci screened), low-frequency microsatelliteinstability (instability at less than 30 percent of the lociscreened), or microsatellite stability (stability at all theloci tested).34,42 Since extensive data indicate that tumorswith low-frequency microsatellite instability are not biologicallydistinct from those exhibiting microsatellite stability, thesetwo molecular phenotypes were grouped together in all analyses.23,45
The microsatellite-instability status of tumors from patientswithout available corresponding normal tissue was analyzed withthe use of the BAT25 and BAT26 markers, without the need foramplified normal DNA, as described previously.40,46 Specifically,samples with instability at both markers were scored as exhibitinghigh-frequency microsatellite instability, whereas samples withno instability at these markers were scored as microsatellite-stable.No specimen exhibited instability at only one of the two mononucleotidemarkers.
Clinical Data Base
A common clinical data base had previously been establishedand verified by investigators from centers in the InternationalMulticentre Pooled Analysis of Colon Cancer Trials. This database was maintained by the Clinical Trials Group of the NationalCancer Institute of Canada and was recently merged with theclinical data bases of Gastrointestinal Intergroup trial 0035of the National Cancer Institute and protocols 784852 and 874651of the North Central Cancer Treatment Group for combined analysis.All data bases were prepared and managed by persons with noknowledge of the molecular data.
Statistical Analysis
For the outcome analysis, patients were classified accordingto the presence of high-frequency microsatellite instability,low-frequency microsatellite instability, or microsatellitestability in the tumor specimens. The primary outcomes wereoverall survival and disease-free survival. Overall survivalwas defined as the time from study entry to death. Disease-freesurvival was defined as the time from study entry to the firstconfirmed relapse or death, whichever occurred first. Data onoverall and disease-free survival were censored at eight yearsfrom the date of randomization. Survival curves were generatedaccording to the method of Kaplan and Meier, and univariatesurvival distributions were compared with the use of the log-ranktest.47 Hazard ratios and 95 percent confidence intervals forunivariate and multivariate models were computed with the useof Cox proportional-hazards regression.48 P values for testsof interaction were computed with the use of the likelihood-ratiostatistic in comparisons between a model including main effectsbut no interaction and the same model with the inclusion ofthe term for interaction.
Differences in base-line prognostic factors according to themicrosatellite-instability status of the patients' tumors weretested for statistical significance with the use of a chi-squaretest for categorical variables or an unpaired Student's t-testfor continuous variables. The use of randomized clinical trialscomparing fluorouracil-based adjuvant treatment with no adjuvanttreatment permitted us to test directly for an effect of chemotherapy.In addition, a test for interaction between microsatellite-instabilitystatus and treatment effect was performed with the use of Coxproportional-hazards regression. The probability that chemotherapyis associated with a 5 percent or greater increase in the rateof five-year survival among patients with colon cancers exhibitinghigh-frequency microsatellite instability was analyzed withthe use of both a simulation based on a Weibull survival modeland a standard bootstrap technique.
All time-to-event analyses were stratified according to thetype of treatment protocol (levamisole or leucovorin in additionto fluorouracil-based adjuvant chemotherapy). Specifically,the C.03 trial of the National Cancer Institute of Canada, thetrial of the Fondation Française de CancérologieDigestive, and protocol 874651 of the North Central Cancer TreatmentGroup were treated as one stratum, and protocol 784852 of theNorth Central Cancer Treatment Group and Gastrointestinal Intergrouptrial 0035 of the National Cancer Institute were treated asa separate stratum for univariate analyses. Additional analyseswere further stratified according to the stage of disease, asindicated. All reported P values are two-sided, and P valuesof less than 0.05 were considered to indicate statistical significance.
Results
Characteristics of the Patients and Microsatellite-Instability Status
Of 570 tumor samples tested for microsatellite instability,95 (16.7 percent) demonstrated high-frequency microsatelliteinstability, 60 (10.5 percent) demonstrated low-frequency microsatelliteinstability, and 415 (72.8 percent) were microsatellite-stable.High-frequency microsatellite instability was associated withlocalization of the tumor to a site proximal to the splenicflexure (P<0.001) and a high histologic tumor grade (P<0.001)(Table 2). In other respects, the patients with tumors exhibitinghigh-frequency microsatellite instability were similar to thepatients with tumors exhibiting microsatellite stability orlow-frequency microsatellite instability (Table 2).
Table 2. Characteristics of the 570 Patients with Colon Cancer.
Relation between Microsatellite-Instability Status and Survival
In total, 185 of the 570 patients (32.5 percent) died duringa median follow-up period of 7.4 years. In a pooled analysisthat did not control for the use or nonuse of adjuvant chemotherapy,the rate of five-year disease-free survival among patients withtumors exhibiting high-frequency microsatellite instability(75.3 percent) was significantly greater than that among patientswith tumors exhibiting low-frequency microsatellite instabilityor microsatellite stability (64.1 percent; P=0.04) (Table 3).In univariate analyses, there was no significant differencein five-year overall survival between these groups of patients(P=0.07) (Table 3). In multivariate models adjusted for thestage of disease and tumor grade, high-frequency microsatelliteinstability was significantly associated with overall survival(hazard ratio for death, 0.61 [95 percent confidence interval,0.38 to 0.96]; P=0.03) (Table 4).
Table 3. Univariate Analysis of Survival among Patients with Stage II or Stage III Colon Cancer According to Microsatellite-Instability Status or Adjuvant-Chemotherapy Status.
Table 4. Hazard Ratios for Death with Adjustment for Stage of Disease and Tumor Grade.
Among patients who had not received adjuvant chemotherapy, patientswith tumors exhibiting high-frequency microsatellite instabilityhad longer overall survival (Figure 1A) and higher rates offive-year disease-free survival (Table 3) than patients withtumors exhibiting low-frequency microsatellite instability ormicrosatellite stability. Multivariate analysis controlled forthe stage of disease and tumor grade also demonstrated thathigh-frequency microsatellite instability in patients not receivingfluorouracil-based adjuvant chemotherapy was significantly andindependently associated with survival (hazard ratio for death,0.32 [95 percent confidence interval, 0.14 to 0.75]; P=0.008)(Table 4). However, the analysis of patients who did receiveadjuvant therapy failed to show significant differences in overallor disease-free survival according to microsatellite-instabilitystatus (Table 3 and Figure 1B).
Figure 1. Kaplan–Meier Estimates of Overall Survival among Patients with Stage II or Stage III Colon Cancer According to the Microsatellite-Instability Status of the Tumor.
In the absence of adjuvant chemotherapy, the patients with tumors displaying high-frequency microsatellite instability had significantly longer overall survival than patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004) (Panel A). When the analysis was limited to the group receiving adjuvant chemotherapy, patients with tumors exhibiting high-frequency microsatellite instability did not have a significant increase in overall survival as compared with patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80) (Panel B). The analysis included data for eight years from the date of randomization.
Relation between Microsatellite-Instability Status and Benefit of Adjuvant Chemotherapy
Analyses were performed to determine whether the effect of treatment,microsatellite-instability status, or both differed accordingto the stage of disease. Neither interaction was found to besignificant (P=0.48 and P=0.21, respectively), and therefore,patients were pooled regardless of stage for the analyses examiningtreatment effect and microsatellite-instability status. Whenthe entire group of 570 patients was analyzed, we found no significantdifference between those who were treated with fluorouracil-basedadjuvant chemotherapy and those who were not in the rates offive-year overall survival (P=0.12) or five-year disease-freesurvival (P=0.06) (Table 3). However, a significant interactionwas observed between microsatellite-instability status and thebenefit of treatment (P=0.01). This interaction remained significantafter stratification according to the stage of disease (P=0.02).Among patients with tumors exhibiting low-frequency microsatelliteinstability or microsatellite stability, adjuvant chemotherapywas associated with significant increases in the duration ofoverall survival (Figure 2A) and the rates of five-year disease-freesurvival (Table 3). This survival benefit was also seen in amultivariate analysis controlled for stage and grade (Table 4).There was no evidence of a three-way interaction among treatmenteffect, microsatellite-instability status, and stage of disease(P=0.39).
Figure 2. Kaplan–Meier Estimates of Overall Survival among Patients with Stage II or Stage III Colon Cancer According to Treatment Status.
Patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability who received adjuvant chemotherapy had a significant increase in overall survival as compared with patients who received no adjuvant chemotherapy (hazard ratio for death, 0.69 [95 percent confidence interval, 0.50 to 0.94]; P=0.02) (Panel A). Among patients with tumors exhibiting high-frequency microsatellite instability, there was no significant difference in the duration of overall survival between patients who received adjuvant chemotherapy and those who did not (hazard ratio for death, 2.17 [95 percent confidence interval, 0.84 to 5.55]; P=0.10) (Panel B). The analysis included data for eight years from the date of randomization.
Conversely, among patients with tumors exhibiting high-frequencymicrosatellite instability, fluorouracil-based chemotherapydid not improve the outcome as compared with no chemotherapy(Table 3 and Figure 2B). The probability that fluorouracil-basedchemotherapy was associated with an increase of at least 5 percentin the rate of five-year survival among patients with tumorsexhibiting high-frequency microsatellite instability was lessthan 1 percent.
These trends were consistently maintained in analyses of subgroupsdefined according to the stage of disease. Treatment was associatedwith an improved outcome among patients with stage II or stageIII cancers with low-frequency microsatellite instability ormicrosatellite stability (hazard ratio for death among treatedpatients as compared with untreated patients, 0.67 [95 percentconfidence interval, 0.39 to 1.15] among patients with stageII cancer and 0.69 [95 percent confidence interval, 0.47 to1.01] among patients with stage III cancer). In contrast, amongpatients with tumors exhibiting high-frequency microsatelliteinstability, treatment was associated with a worse outcome forboth stage II and stage III cancer (hazard ratio for death,3.28 [95 percent confidence interval, 0.86 to 12.48] among patientswith stage II cancer and 1.42 [95 percent confidence interval,0.36 to 5.56] among patients with stage III cancer).
Discussion
Recent studies of colorectal cancer have identified two molecularpathways leading to the malignant phenotype — the pathwayof high-frequency microsatellite instability and that of microsatellitestability — which respond differently to DNA damage. Itis unlikely that tumors with these distinct pathways would respondsimilarly to chemotherapeutic agents that damage DNA. Sinceit may be unethical to withhold chemotherapy in a clinical trialfor potentially curable advanced-stage colon cancer, we usedsamples from previous multicenter, prospective, randomized,controlled trials to determine whether microsatellite-instabilitystatus could serve as a predictor of a survival benefit withfluorouracil-based adjuvant chemotherapy.
Our results in patients with stage II or stage III colon cancerconfirm previous reports of a survival benefit for patientswith tumors exhibiting high-frequency microsatellite instability.22,23,26,33,35,36,37,38In a univariate analysis that did not control for the possibleeffect of chemotherapy, high-frequency microsatellite instabilitywas associated with improved five-year disease-free survivalamong patients with stage II or stage III colon cancer. We alsofound that patients with tumors exhibiting microsatellite stabilityor low-frequency microsatellite instability tended to benefitfrom fluorouracil-based adjuvant chemotherapy, whereas suchchemotherapy did not benefit patients with high-frequency microsatelliteinstability and may in fact have led to worse outcomes amongsuch patients. These results remained consistent in models thatadjusted for the stage of disease and in models stratified accordingto stage, and they held true for both patients with stage IIcancer and patients with stage III cancer.
In vitro studies have shown that colon-cancer cell lines displayinghigh-frequency microsatellite instability are less responsivethan microsatellite-stable cell lines to fluorouracil.49,50,51,52,53,54However, our findings contrast with those of a large, selectedcase series of patients with stage III colon cancer, which demonstrateda significant association between an increased duration of survivaland high-frequency microsatellite instability among patientsreceiving adjuvant chemotherapy.40 But this nonrandomized caseseries has the potential for bias. For example, patients notreceiving chemotherapy were, on average, 13 years older thanthose who received adjuvant fluorouracil therapy. Increasingage has been demonstrated to be significantly and independentlyassociated with a poor outcome among patients with colorectalcancer, after adjustment for the microsatellite-instabilitystatus of the tumor.24 A significantly older mean age also makesit likely that the presence of coexisting disease was an importantreason why some patients in this nonrandomized study were notoffered adjuvant treatment.40
Although the results of our analysis and previous data fromin vitro studies suggest that fluorouracil-based adjuvant chemotherapyis not beneficial in patients with colon cancer exhibiting high-frequencymicrosatellite instability, other drugs, such as the topoisomerase-Iinhibitor camptothecin, have been shown to kill mismatch-repair–deficientcancer cells exhibiting high-frequency microsatellite instability.55It would therefore seem important to conduct molecular analysesof specimens from recent clinical trials of non–fluorouracil-basedchemotherapies and to ensure that future trials include analysesof molecular pathways.56
In our retrospective analysis, the finding that fluorouracil-basedadjuvant chemotherapy does not significantly increase, and maypotentially decrease, overall and disease-free survival amongpatients with tumors exhibiting high-frequency microsatelliteinstability raises several provocative issues regarding postoperativemanagement of stage II and stage III colon cancer. However,we would urge caution and not advocate altering clinical decisionmaking on the basis of our findings. If confirmed by other analysesof previous, well-designed clinical trials or by future prospective,randomized, controlled studies, however, our findings wouldindicate that microsatellite-instability testing should be conductedroutinely and the results used to direct rational adjuvant chemotherapyin colon cancer.
Supported in part by grants from the National Cancer Instituteof Canada (012200) and the National Cancer Institute, NationalInstitutes of Health (CA25224, CA60100, CA21115, CA62924, CA23318),and fellowship funding from the American Society of Colon andRectal Surgeons.
Source Information
From the Centre for Cancer Genetics, Samuel Lunenfeld Research Institute (C.M.R., R.G., S.G.), the Department of Medicine and Surgery, Princess Margaret Hospital (M.J.M., S.G.), and the Department of Surgery, Mount Sinai Hospital (R.G., S.G.), University of Toronto, Toronto; the Division of Biostatistics (D.J.S.), the Division of Medical Oncology (R.M.G.), and the Department of Laboratory Medicine and Pathology (S.N.T., A.J.F.), Mayo Foundation, Rochester, Minn.; the Clinical Trials Group, National Cancer Institute of Canada, Queen's University, Kingston, Ont. (M.J.M., L.E.S., D.T., S.G.); the Eastern Cooperative Oncology Group, Brookline, Mass. (S.R.H.); the M.D. Anderson Cancer Center, Houston (S.R.H.); the Fédération Francophone de Cancérologie Digestive, Paris (P.L.-P.); and Brigham and Women's Hospital, Boston (M.R.).
Address reprint requests to Dr. Gallinger at Mount Sinai Hospital, 600 University Ave., Suite 1225, Toronto, ON M5G 1X5, Canada, or at sgallinger{at}mtsinai.on.ca.
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Microsatellite Instability in Colon Cancer
Allegra C. J., Kim G., Kirsch I. R., Iacopetta B., Elsaleh H., Zeps N., Jimenez J. J., Blanes A., Diaz-Cano S. J., Gryfe R., Ribic C. M., Sargent D. J.
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349:1774-1776, Oct 30, 2003.
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