Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial

Abstract

Importance: Oxaliplatin added to fluorouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but modest absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit.

Objective: To test our hypothesis that molecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy.

Design, setting, and participants: Participants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n = 881) cohorts based on the order of tissue block submission. A reestimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was examined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods.

Interventions: Fluorouracil plus leucovorin with or without oxaliplatin.

Main outcomes and measures: Percent recurrence-free survival.

Results: Among 1729 patients, 744 (43%) were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discovery cohort (hazard ratio, 0.22 [95% CI, 0.09-0.56]; P = .001 [N = 65]), no statistically significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22-1.24]; P = .14 [N = 70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III.

Conclusions and relevance: Patients with stemlike tumors may be appropriate for clinical trials testing experimental therapies because stemlike tumors were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts.

Trial registration: clinicaltrials.gov Identifier: NCT00004931.

Figure 1

Consolidated Standards of Reporting Trials Diagram, National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07

Figure 2

Procedure for Redeveloping Colorectal Cancer Assigner (CRCA) Classifier Using 72 Genes Included in the nCounter Data Profiled With the Customized nCounter Code Set (Colo-295)

Figure 3

Kaplan-Meier Plots for Recurrence-Free Survival of Stage III Patients

Figure 4

Exploratory Analyses: Forest Plot of Treatment Benefit for Subtypes Identified by Different Classifiers for C-07 Participants With Stage III Disease The box size is proportional to the precision. CCS indicates Colorectal Cancer Subtype; CRCA, Colorectal Cancer Assigner; CMS, Consensus Molecular Subtype; HR, hazard ratio; and TA, transit amplifying.

Figure 5

Kaplan-Meier Plots for Recurrence-Free Survival of Entire Cohort (Stage II or Stage III Patients) According to Colorectal Cancer Assigner (CRCA), Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) Subtypes NA indicates not assignable to a subtype.