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.
OBJECTIVE
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.


METHODS
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.


METHODS
Fluorouracil plus leucovorin with or without oxaliplatin.


METHODS
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
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00004931.
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Nan
N
Song
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Katherine L
KL
Pogue-Geile
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Patrick G
PG
Gavin
NRG Oncology, Pittsburgh, Pennsylvania3University of Pittsburgh, Pittsburgh, Pennsylvania.
Greg
G
Yothers
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
S Rim
SR
Kim
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Nicole L
NL
Johnson
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Corey
C
Lipchik
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania4Department of Medicine, University of Florida Health, Gainesville.
Carmen J
CJ
Allegra
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania5Helen F. Graham Cancer Center and Research Institute at Christiana Care, Newark, Delaware.
Nicholas J
NJ
Petrelli
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania.
Michael J
MJ
O'Connell
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania6Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, Pennsylvania.
Norman
N
Wolmark
National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, Pittsburgh, Pennsylvania7Division of Medical Oncology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
Soonmyung
S
Paik
D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D020895:Enterocytes; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020558:GTP Phosphohydrolases / Q000235:genetics; D020869:Gene Expression Profiling; D020397:Goblet Cells; D006801:Humans; D007249:Inflammation; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
C117307:KRAS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002955:Leucovorin; D005472:Fluorouracil