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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2020 Dec 23;39(6):642–651. doi: 10.1200/JCO.20.01600

Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials

Romain Cohen 1,2,✉, Julien Taieb 3, Jack Fiskum 2, Greg Yothers 4, Richard Goldberg 5, Takayuki Yoshino 6, Steven Alberts 7, Carmen Allegra 8, Aimery de Gramont 9, Jean-Francois Seitz 10, Michael O'Connell 7, Daniel Haller 11, Norman Wolmark 12, Charles Erlichman 7, Alberto Zaniboni 13, Sara Lonardi 14, Rachel Kerr 15, Axel Grothey 16, Frank A Sinicrope 7, Thierry André 1, Qian Shi 2
PMCID: PMC8189604  PMID: 33356421

Abstract

PURPOSE:

In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.

MATERIALS AND METHODS:

Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.

RESULTS:

MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.

CONCLUSION:

Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

INTRODUCTION

Microsatellite instability (MSI) is a molecular phenotype related to a deficient DNA mismatch repair system (MMR). MMR deficiency (dMMR) results from MMR gene germline mutations (ie, Lynch syndrome) or from an epigenetic silencing of the MMR system (ie, sporadic), the latter being frequently associated with the BRAFV600E mutation.1

CONTEXT

  • Key Objective

  • To determine the effect of fluoropyrimidine (FP) with or without oxaliplatin among patients with microsatellite instability (MSI) stage III colon cancer (CC) and the main prognosticators of patients with MSI stage III CC treated with FP plus oxaliplatin.

  • Knowledge Generated

  • Adding oxaliplatin to FP significantly improves disease-free survival and overall survival of patients with MSI stage III CC. T stage and N stage are the strongest prognosticators of patients with MSI treated with FP plus oxaliplatin.

  • Relevance

  • FP plus oxaliplatin should be the standard-of-care adjuvant treatment for patients with resected stage III MSI CC. With one third of patients with T4 and/or N2 MSI stage III CC experiencing disease recurrence or death within 2 years after curative tumor resection, innovative therapeutic strategies should be sought for this population.

The MSI and/or dMMR (MSI/dMMR) phenotype is observed in approximately 15%-18% of stage II colon cancers (CCs), 9%-10% of stage III CCs, and 4%-5% of metastatic colorectal cancers (mCRCs).2-6 MSI/dMMR has been demonstrated as a favorable prognostic marker in stage II CC. Data regarding its value as a prognostic marker are more controversial in stage III and patients with mCRC, suggesting a possible shift in the prognostic impact of MSI/dMMR across disease stages and an heterogeneity in the outcomes of patients with MSI/dMMR.4-17 However, in all these studies, patient numbers were limited and not all patients were treated with the current standard adjuvant treatment for patients with stage III CC combining fluoropyrimidine (FP) plus oxaliplatin.

Previous studies have reported that adjuvant FP may be ineffective or even detrimental in patients with MSI/dMMR CC with localized diseases, especially in those patients with CC with stage II disease.2,3,18 However, more recent data showed the superiority of FP plus oxaliplatin over FP alone in patients with stage III MSI/dMMR CC.4,19 Importantly, clinical trials evaluating immune checkpoint inhibitors for patients with MSI/dMMR mCRC have demonstrated impressive results, raising the interest for evaluating these agents for adjuvant treatment of patients with stage III MSI/dMMR CC.20-24 Therefore, there is a need to understand the effectiveness of adjuvant treatments and what are the main prognostic factors in patients with MSI/dMMR stage III CC.

In this individual patient data analysis, we aimed at evaluating the prognostic value of MSI status and the effect of oxaliplatin-based adjuvant treatments on overall survival (OS) and disease-free survival (DFS) among patients with MSI stage III CC. Prognosticators of patients with MSI/dMMR stage III CC treated with oxaliplatin-based adjuvant therapy were also studied.

MATERIALS AND METHODS

Patients

All patients with stage III CC with available microsatellite and/or MMR status from randomized trials included in the ACCENT database testing surgery with or without adjuvant FP or FP with or without oxaliplatin, or from oxaliplatin-based adjuvant treatment arms, were included. Exclusion criteria were stage I-II CC, unknown tumor stage, unknown MSI and MMR status, discrepant results from polymerase chain reaction and immunochemistry assays (MSI but proficient mismatch repair [pMMR] or microsatellite stable [MSS] but dMMR), and patients who were assigned to treatment arms other than those prescribing FP or FP plus oxaliplatin (ie, irinotecan or targeted therapies).

MSI/dMMR Status Determination

MSI/dMMR status was determined by immunohistochemistry or polymerase chain reaction (PCR) testing. Tumors showing loss of MMR protein expression by immunohistochemistry and/or exhibiting a high level of MSI by PCR testing were defined as MSI/dMMR. Tumors with no loss of MMR protein expression and/or MSS or a low level of MSI were defined as MSS and/or pMMR (MSS/pMMR).

Objectives

The objectives of this work were (1) to evaluate the added value of oxaliplatin in addition to adjuvant FP in relation with MSI/dMMR status, and (2) to evaluate the prognostic value of MSI status in patients with stage III CC treated with a standard oxaliplatin-based adjuvant therapy. The analysis of the added value of adjuvant FP to surgery alone in relation with MSI/dMMR status was a secondary objective.

Statistical Analysis

The outcomes included OS and DFS. T stage and N stage were combined in a TN variable (T1-3 and N1: low risk; T4 and/or N2: high risk) as defined in the pooled analysis of the IDEA project.25 The ratio of positive to examined lymph nodes was calculated (LNR) and analyzed with a cutoff defined at 0.3.26

Because of potential stage migration over time,27 only trials in which there was a direct comparison of surgery with or without adjuvant FP were analyzed for the evaluation of the MSI/dMMR predictive effect on the efficacy of adjuvant FP (secondary objective). Randomized trials evaluating a direct comparison of adjuvant FP with or without oxaliplatin were analyzed to assess the MSI/dMMR predictive value on oxaliplatin-based adjuvant treatment efficacy (primary objective). Treatment arms of trials evaluating FP plus oxaliplatin were analyzed for the evaluation of the prognostic value of MSI/dMMR status and for the determination of prognostic factors among patients with MSI/dMMR treated with FP plus oxaliplatin.

The direct adjusted Kaplan-Meier curve28 was used to estimate the distributions of primary and secondary end points by treatment and MSI or MMR status, adjusting for age, sex, performance score, T stage, and N stage. Multivariable Cox models stratified by studies with interaction tests were used to evaluate the predictive value of MSI or MMR status. Within patients treated with FP plus oxaliplatin, the association of baseline factors with OS was assessed using univariate Cox analyses, and then parameters with P values < .05 were entered into a multivariable Cox regression model after considering the amount of missing values and collinearity among variables with a correlation matrix. The proportional hazard (PH) assumption for the stratified Cox model was examined using the scaled Schoenfeld residuals or testing the interaction with time for covariates.29 Analyses were carried out using SAS software (version 9.4; SAS Institute Inc, Cary, NC).

RESULTS

Population Characteristics

Five thousand four hundred and fifty-seven patients with stage III CC who were enrolled in 12 randomized trials were included in this study (Appendix Fig A1 and Appendix Table A1, online only), including 609 patients with MSI/dMMR (11.8%) and 4,848 patients with MSS/pMMR (88.8%). Of those studies, there were six randomized trials testing surgery with or without FP (49 MSI/dMMR and 357 MSS/pMMR), two trials testing FP with or without oxaliplatin (185 MSI/dMMR and 1,440 MSS/pMMR), and four additional trials with at least one treatment arm consisting of oxaliplatin plus FP (375 MSI/dMMR and 3,051 MSS/pMMR).

Overall, patients with MSI/dMMR CC were more frequently female and T1-3 tumor stage, with a larger number of lymph nodes examined and moderate or poor tumor differentiation. They more frequently had tumors arising from the right colon and harboring BRAFV600E mutation (Appendix Table A2, online only). The overall median follow-up was 7.2 years (95% CI, 7.2 to 7.3).

Effect of Adjuvant Therapy With FP Alone on Survival

Individual patient data from six randomized trials testing surgery with or without FP as adjuvant treatment were pooled. One thousand seven hundred fifty of 3,270 patients enrolled in these studies had stage III CC, of which 23% had known MSI/dMMR status, leading to 406 patients (49 MSI/dMMR and 357 MSS/pMMR) available for analysis (Appendix Table A1). Adjuvant treatment with FP alone was associated with better outcomes in the MSS/pMMR group but not in the MSI/dMMR population (Appendix Tables A3 and A4, and Appendix Fig A2, online only).

Effect of FP Plus Oxaliplatin on Survival: Pooled Analysis of the C-07 and MOSAIC Trials

Individual data from patients with known MSI/dMMR status enrolled in the C-07 and MOSAIC trials (FP-based adjuvant therapy with or without oxaliplatin) were analyzed. One hundred and eighty five patients were MSI/dMMR (11.4%) and 1,440 patients were MSS/pMMR (88.6%) (Appendix Table A5, online only). Kaplan-Meier curves for OS and DFS are displayed in Figure 1. The adjusted hazard ratios (HRs) for OS comparing FP plus oxaliplatin with FP alone were 0.52 (95% CI, 0.28 to 0.93) and 0.89 (95% CI, 0.74 to 1.06) in the MSI/dMMR and MSS/pMMR populations, respectively. The interaction effect between MSI/dMMR status and oxaliplatin effect did not reach statistical significance (interaction test P value = .11). Similar results were observed for DFS (HR, 0.47; 95% CI, 0.27 to 0.82 and HR, 0.82; 95% CI, 0.70 to 0.97 in MSI/dMMR and MSS/pMMR groups; interaction test P value = .14). The efficacy of oxaliplatin combined with 5-fluorouracil plus leucovorin by subgroups of the MSI/dMMR population is displayed in Appendix Figure A3 (online only). No violation to PH assumption regarding the treatment variable (P = .75) was detected.

FIG 1.

FIG 1.

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Effect of FP-based and oxaliplatin-based adjuvant treatment according to the MSI/dMMR status. Overall survival (A) and disease-free survival (B) of patients treated with FP or FP plus oxaliplatin therapy. dMMR, mismatch repair system deficiency; FP, fluoropyrimidine; HR, hazard ratio; KM, Kaplan-Meier; MSI, microsatellite instability; OX, oxaliplatin.

Prognostic Value of MSI Status in Patients Treated With Oxaliplatin Plus FP Combination

Four thousand two hundred fifty patients (461 MSI/dMMR and 3,789 MSS/pMMR) treated with the combination of FP and oxaliplatin in MOSAIC, C-07, C-08, PETACC-8, N0147, and AVANT trials were included in this analysis (Appendix Table A1). BRAFV600E mutational status was available for 93.4% of this population. Baseline characteristics are summarized in Appendix Table A6 (online only).

No interaction was observed between MSI/dMMR and T stage, primary tumor sidedness, or BRAFV600E mutational status (interaction P > .12). However, MSI/dMMR had different prognostic effects depending on the N stage category (interaction test for OS P = .029). Compared with MSS/pMMR, MSI/dMMR was associated with better OS in the N1 population (HR, 0.66; 95% CI, 0.46 to 0.95) but a similar OS in the N2 population (HR, 1.13; 95% CI, 0.86 to 1.48) (Figs 2 and 3A). This significant interaction was confirmed for DFS, with an excess of events in the first 2 years of follow-up in the MSI/dMMR N2 population compared with patients with MSS/pMMR N2, though the log-rank test remained not significant (Fig 3B). This interaction was also observed between MSI/dMMR and the TN stage grouped as high- and low-risk stage III patients (T4 and/or N2 v T1-3 and N1; interaction test for OS P value = .004) (Figs 3C and 3D). The significant departure of PH assumption was detected regarding the MSI variable for OS in N1 (P = .002) and high-risk subgroups (P = .005) after Bonferroni multiplicity adjustment. Further analyses were performed by modeling the varying HR over time. For patients with N1 disease, the improved survival associated with MSI/dMMR status was strengthened if a patient can survive beyond 3-4 years. For the high-risk subgroup, the detrimental survivorship in patients with MSI/dMMR status was likely during the early time after treatment (before 3-4 years).

FIG 2.

FIG 2.

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Forest plot for MSI effect on overall survival by baseline factors in the population treated with oxaliplatin and FP. FP, fluoropyrimidine; MSI, microsatellite instability; MSS, microsatellite stable.

FIG 3.

FIG 3.

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Outcomes of patients treated with oxaliplatin plus FP according to MSI status and N stage. Overall survival (A) and disease-free survival (B) of patients treated with FP plus oxaliplatin therapy by MSI/MSS status and N stage; overall survival (C) and disease-free survival (D) of patients treated with FP plus oxaliplatin therapy by MSI/MSS status and TN stage. FP, fluoropyrimidine; HR, hazard ratio; MMR, mismatch repair system; MSI, microsatellite instability; MSS, microsatellite stable.

Prognosticators of the MSI/dMMR Population Treated With Oxaliplatin Plus FP

Table 1 summarizes results from the univariate and multivariable analyses among the 461 patients with MSI/dMMR treated with oxaliplatin plus FP. In univariate analysis, sex, T stage, N stage, TN stage, and LNR were found prognostic for OS. BRAFV600E mutation was not associated with poorer outcomes in the MSI/dMMR population (HR, 1.18; 95% CI, 0.77 to 1.81) or the proximal location of the tumor. LNR and TN stage were excluded from the multivariable model because of collinearity with the N stage. The prognosticators for patients with MSI/dMMR stage III CC in the multivariable model were N stage (N2 v N1; HR, 3.10; 95% CI, 2.13 to 4.50), T stage (T4 v T1-3; HR, 2.39; 95% CI, 1.56 to 3.66), and sex (male v female; HR, 1.71; 95% CI, 1.14 to 2.58). Kaplan-Meier 3-year DFS estimates were, respectively, 65.0% (95% CI, 6% to 70.0%) versus 87.0% (95% CI, 84.3% to 89.9%) for N2 and N1 MSI/dMMR groups, 60.4% (95% CI, 52.9% to 68.9%) versus 82.1% (95% CI, 79.5% to 84.9%) for T4 and T1-3 MSI/dMMR groups, and 64.5% (95% CI, 60.1% to 69.2%) versus 90.1% (87.5%-92.8%) for high-risk and low-risk MSI/dMMR CC patients.

TABLE 1.

Prognosticators for Microsatellite Instability Patients Treated With Standard-of-Care Oxaliplatin Plus FP

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DISCUSSION

We report here an evaluation of prognostic and predictive values of MSI/dMMR among patients with stage III CC. We showed that: (1) There is no benefit or detrimental effect of adjuvant FP in patients with MSI/dMMR tumors; (2) The combination of FP plus oxaliplatin significantly improves OS for patients with MSI/dMMR stage III CC; (3) MSI/dMMR is a positive prognostic factor for patients with N1 CC and is not prognostic for patients with N2 CC; and (4) N stage and T stage are the main prognosticators for patients with MSI/dMMR stage III CC treated with FP plus oxaliplatin adjuvant therapy.

The structure of the ACCENT database enabled robust analyses of MSI/dMMR data from multiple phase III randomized trials at an individual patient level, especially for this relatively rare subpopulation in stage III CC. The ACCENT database has trials that enrolled patients over a time period spanning more than three decades (1977-2009 for this study), and because therapeutic strategies should be taken into account for biomarker studies we explored MSI/dMMR along with the type of adjuvant therapy (no adjuvant therapy, FP, or FP plus oxaliplatin). First, we evaluated the predictive value of MSI/dMMR for the efficacy of FP as adjuvant treatment. FP in MSI/dMMR CC has been a matter of controversy for decades, with some studies showing a lack of efficacy of this therapeutic class and other studies evoking a detrimental effect of FP among patients with stage II MSI/dMMR CC.2,18,30-32 A previous analysis of the ACCENT database led by Sargent et al33 on FP-based adjuvant treatment showed a consistent prognostic impact of MSI/dMMR but did not evaluate the effect of FP-based regimens for the MSI/dMMR stage III population. Here, we decided to limit our analysis to trials that randomly assigned patients with resected stage III CC between follow-up with no adjuvant chemotherapy and adjuvant FP. In taking this approach, we limited potential biases, such as unbalanced factors with potential prognostic impact, by doing an analysis stratified by study. Whereas FP-based adjuvant treatment significantly improves the outcome of MSS/pMMR patients, it was not found effective for the MSI/dMMR group. Importantly, even if no significant detrimental effect of FP-based adjuvant treatment in the MSI/dMMR population was observed in our study, the limited percentage of patients tested for MSI/dMMR in the adjuvant trials assessing surgery ± adjuvant FP preclude drawing definitive conclusions. As the current work is the largest ever published on adjuvant FP for patients with MSI stage III CC, it suggests that FP alone should not be recommended as adjuvant treatment for these patients.

To investigate the efficacy of oxaliplatin-based adjuvant chemotherapy for patients with MSI/dMMR stage III CC, we pooled data of the C-07 and MOSAIC trials, two randomized phase III trials that established oxaliplatin plus FP as standard-of-care adjuvant treatment for patients with stage III CC.34,35 Post hoc analyses of each study failed to demonstrate the added value of oxaliplatin efficacy for patients with MSI/dMMR CC, but (i) they were underpowered, and (ii) in these analyses, the cohorts with stage II and stage III diseases were combined.4,8,36 In addition, some patients from the C-07 trial were excluded from our analysis because of potential misdiagnosis for MSI/dMMR status, having discrepant results between PCR and immunohistochemistry tests.37 Here we show that patients with stage III MSI/dMMR CC significantly benefit from oxaliplatin-based adjuvant treatment (HR, 0.52; 95% CI, 0.28 to 0.93). Interestingly, even if the interaction test did not reach statistical significance, the added value of oxaliplatin seemed to have more impact on DFS and OS for the MSI/dMMR population than it did for the MSS/pMMR population (absolute change in 5-year OS rates: + 9.4% and + 2.0%, respectively). These results bring contrast to the negative results of the FoxTrot trial, which showed a very low rate of pathological responses (73.6% with no regression) and no survival benefit from neoadjuvant FOLFOX in the 106 MSI/dMMR patients treated in that trial.38

Among the MSI/dMMR population, older patients represent a clinically meaningful and challenging situation. MSI/dMMR tumors are more frequent in patients older than 70 years. Several clinical trials suggest that this population may have attenuated benefit from the addition of oxaliplatin to FP-based adjuvant treatment.39-41 Given the lack of efficacy of FP as a single agent for MSI stage III CC, it would have been of interest to evaluate the effect of oxaliplatin in patients with MSI tumors older than 70 years. Unfortunately, with only 37 patients with MSI CC older than 70 years randomly assigned between FP alone and FP plus oxaliplatin groups, we could not address this important question because of small patient numbers. Nonetheless, we did not detect any significant interaction between age and the addition of oxaliplatin to FP-based adjuvant treatment (Appendix Figure A3).

It is of interest to evaluate the MSI/dMMR prognostic value in patients treated with standard-of-care adjuvant treatment, namely a combination of FP and oxaliplatin (as we confirmed here). Toward this end, we pooled individual patient data from the oxaliplatin plus FP treatment arms of trials included in the ACCENT database (ie, MOSAIC, C-07, C-08, AVANT, N0147, and PETACC-84,8,42-45). In the overall population, MSI/dMMR was not associated with better outcomes (HR, 0.94; 95% CI, 0.76 to 1.17). As observed in a combined analysis of NCCTG N0147 and PETACC-8 trials,15,46 the prognostic impact of MSI/dMMR showed a significant interaction with the lymph node stage. Compared with MSS/pMMR, MSI/dMMR was indeed associated with better outcomes for N1 patients (P = .027) but poorer survival for N2 patients. This last result did not reach significance, though (P = .374). More precisely, for the N2 population, MSI/dMMR was associated with an excess risk of death or disease relapse in the first 2 years of follow-up, but afterward, the survival curves crossed. This interaction was also observed when pooling T and N stages in low- and high-risk groups as defined in the IDEA collaboration (T1-3 and N1 versus T4 and/or N2) and MSI/dMMR status. We did not detect any interaction between primary tumor sidedness and MSI/dMMR status (data not shown) as it has been previously reported for patients treated with FOLFOX with or without cetuximab in the NCCTG N0147 trial.15 Unfortunately, we did not have the necessary data elements to properly dichotomize MSI tumors between Lynch syndrome–related tumors and sporadic cases. Nonetheless, no statistically significant difference in patients' outcomes was observed for those with BRAFV600E-mutated as compared with BRAF wild-type MSI/dMMR, confirming results from the PETACC-8 and NCCTG N0147 trials.47,48 It is noteworthy that some classic prognostic factors such as lymphovascular invasion, carcinoembryonic antigen level,49 or obstruction were not available in the database. T stage and N stage were the strongest prognosticators of patients with MSI stage III treated with oxaliplatin plus FP adjuvant treatment, with a 3-year DFS rate of 65.0% (95% CI, 6 to 70.0) for N2 patients and 60.4% (95% CI, 52.9 to 68.9) for patients with T4 stage III CC.

MSI/dMMR has become a major theranostic biomarker, harboring a high discrimination capacity for the efficacy of immune checkpoint inhibitors among patients with colorectal cancer. Given their impressive activity in the metastatic setting,20-22,50 this justifies evaluating these antibodies in the adjuvant setting. Two phase III randomized trials have been launched specifically for patients with resected MSI/dMMR stage III CC: the ATOMIC trial that evaluates FOLFOX with or without atezolizumab (ClinicalTrials.gov identifier: NCT02912559) and the POLEM trial (ClinicalTrials.gov identifier: NCT03827044; 24 weeks of FP or 12 weeks of FP plus oxaliplatin, with or without avelumab for MSI/dMMR or polymerase epsilon-mutated patients). Here, in the T4 and/or N2 MSI/dMMR groups, we were able to identify populations of patients with MSI/dMMR stage III CC with a high risk of disease recurrence. Indeed, the estimated 3-year DFS rates of patients with MSI/dMMR T4 stage III and N2 patients were, respectively, 60.4% (95% CI, 52.9 to 68.9) and 64.9% (95% CI, 60.2 to 70.0), the latter experiencing poorer survival than the MSS/pMMR N2 population. With one third of T4 and/or N2 high-risk stage III MSI/dMMR CC patients experiencing disease recurrence or death within 2 years after curative tumor resection, therapeutic innovations should be sought for this patient population.

To conclude, our individual patient data meta-analysis shows that the combination of oxaliplatin plus FP should be the standard-of-care adjuvant treatment for patients with MSI/dMMR stage III CC, and that N stage should be at least a stratification parameter in future trials dedicated to the MSI/dMMR population.

ACKNOWLEDGMENT

This work is dedicated to the memory of Daniel J. Sargent. Dan was one of the world's foremost experts in biostatistics and oncology who brought together disparate investigators and established data sharing across academia and industry internationally. His groundbreaking initiatives of integrating large collections of databases enabled research to answer questions otherwise beyond statistical possibility, to design important new clinical studies, to make regulatory observations, and to set new standards. He pushed these innovations farther to prospectively plan internationally combined analyses that answered questions previously believed to be impossible. The world of oncology statistics and analysis will not be the same without him, but his legacy continues.

APPENDIX

FIG A1.

FIG A1.

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CONSORT flowchart.

FIG A2.

FIG A2.

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Effect of FP-based adjuvant treatment according to the MSI/dMMR status. dMMR, mismatch repair system deficiency; FP, fluoropyridimine; MSI, microsatellite instability.

FIG A3.

FIG A3.

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Forest plot for the effect of oxaliplatin on overall survival among MSI patients (C-07 and MOSAIC trials). MSI, microsatellite instability.

TABLE A1.

Trials and Treatment Arms Included in the Analysis

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TABLE A2.

Comparison of Baseline Characteristics Between Patients with MSI/dMMR or MSS/pMMR Stage III Colon Cancer

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TABLE A3.

Baseline Characteristics of Patients Treated With Surgery With or Without FP

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TABLE A4.

HRs for Overall Survival in Univariate and Multivariable Analysis by MSI Status and Treatment Type (Surgery +/− FP)

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TABLE A5.

Baseline Characteristics of Patients Treated With FP With or Without Oxaliplatin

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TABLE A6.

Baseline Characteristics of Patients Treated with Oxaliplatin Plus FP

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SUPPORT

Supported by the National Cancer Institute at the National Institutes of Health (grant number U10CA180882), the ARCAD foundation, and research grants from the Nuovo-Soldati Foundation, ARC Foundation for Cancer Research, and Servier Institute.

CLINICAL TRIAL INFORMATION

NCCTG-78-48-52, FFCD, INT-0035, NCIC, NCCTG-87-46-51, GIVIO, NCT00275210 (MOSAIC), NCT00004931 (C07), NCT00096278 (C08), NCT00112918 (AVANT), NCT00079274 (N0147), NCT00265811 (PETACC8).

AUTHOR CONTRIBUTIONS

Conception and design: Romain Cohen, Julien Taieb, Richard Goldberg, Daniel Haller, Norman Wolmark, Rachel Kerr, Axel Grothey, Frank A. Sinicrope, Thierry André, Qian Shi

Financial support: Frank A. Sinicrope

Administrative support: Richard Goldberg, Norman Wolmark, Charles Erlichman, Qian Shi

Collection and assembly of data: Romain Cohen, Julien Taieb, Jack Fiskum, Greg Yothers, Jean-Francois Seitz, Takayuki Yoshino, Steven Alberts, Daniel Haller, Charles Erlichman, Aimery de Gramont, Sara Lonardi, Rachel Kerr, Frank A. Sinicrope, Qian Shi

Data analysis and interpretation: Romain Cohen, Julien Taieb, Jack Fiskum, Richard Goldberg, Takayuki Yoshino, Steven Alberts, Carmen Allegra, Jean-Francois Seitz, Michael O'Connell, Alberto Zaniboni, Sara Lonardi, Rachel Kerr, Axel Grothey, Frank A. Sinicrope, Thierry André, Qian Shi

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Romain Cohen

Honoraria: Servier, MSD Oncology

Research Funding: Servier Institute

Julien Taieb

Consulting or Advisory Role: Roche, Merck KGaA, Amgen, Celgene, Lilly, Servier, Sirtex Medical, MSD, Pierre Fabre

Speakers' Bureau: Servier, Amgen, Roche/Genentech, Sanofi, Merck, Lilly, MSD, Pierre Fabre

Greg Yothers

Employment: Mountainview Pediatrics

Consulting or Advisory Role: Pharmacyclics, Orbus Therapeutics

Richard Goldberg

Honoraria: Amgen

Consulting or Advisory Role: Merck, Taiho Pharmaceutical, Novartis

Expert Testimony: Taiho Pharmaceutical, Genentech/Roche

Travel, Accommodations, Expenses: Merck KGaA, Merck, Amgen

Takayuki Yoshino

Research Funding: Chugai Pharma, Sumitomo Dainippon, MSD.K.K., Daiichi Sankyo, Parexel International Inc, Ono Pharmaceutical, Taiho Pharmaceutical, Amgen K.K., Sanofi

Jean-Francois Seitz

Honoraria: Lilly, Merck Serono, Sanofi

Consulting or Advisory Role: Servier, Pierre Fabre

Travel, Accommodations, Expenses: IPSEN

Daniel Haller

Speakers' Bureau: Taiho Pharmaceutical, Amgen, Exelixis, Lilly

Alberto Zaniboni

Consulting or Advisory Role: Amgen, Servier, Bayer, Merck Serono

Speakers' Bureau: Servier

Sara Lonardi

Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, Roche

Speakers' Bureau: Lilly, Bristol-Myers Squibb, Servier, Merck Serono

Research Funding: Amgen, Merck Serono

Axel Grothey

Honoraria: Elsevier, Aptitude Health, IMEDEX

Consulting or Advisory Role: Genentech/Roche, Bayer, Bristol-Myers Squibb, Lilly, Boston Biomedical, Amgen, Array BioPharma, Daiichi Sankyo, OBI Pharmaceuticals

Research Funding: Genentech/Roche, Bayer, Pfizer, Eisai, Lilly, Boston Biomedical, Daiichi Sankyo, Array BioPharma

Travel, Accommodations, Expenses: Genentech/Roche, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen, Array BioPharma

Frank A. Sinicrope

Stock and Other Ownership Interests: illumina

Honoraria: Imedex, American Society of Clinical Oncology

Consulting or Advisory Role: Roche, Bristol-Myers Squibb, Ventana Medical Systems, HalioDx

Research Funding: Ventana Medical Systems

Patents, Royalties, Other Intellectual Property: Patent royalty related to immune markers in colon cancer. Patent jointly held between myself and Roche/Ventana Medical Systems

Travel, Accommodations, Expenses: Ventana Medical Systems

Thierry André

Honoraria: Roche/Genentech, Bristol-Myers Squibb, Servier, Bayer, Sanofi, Amgen, Pierre Fabre, Vantana, GlaxoSmithKline

Consulting or Advisory Role: Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Servier, Bayer, AstraZeneca/MedImmune, Tesaro, Clovis Oncology, GIC Advice, Pierre Fabre, GamaMabs Pharma SA

Travel, Accommodations, Expenses: Roche/Genentech, Amgen, Bristol-Myers Squibb, MSD Oncology, Vantana

Qian Shi

Stock and Other Ownership Interests: Amgen, Johnson & Johnson, Merck

Consulting or Advisory Role: Yiviva Inc, Boehringer Ingelheim

Research Funding: Celgene, Roche/Genentech

No other potential conflicts of interest were reported.

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