Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials

Eur J Cancer. 2021 Feb:144:101-112. doi: 10.1016/j.ejca.2020.11.016. Epub 2020 Dec 17.

Abstract

Background: Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group.

Materials & methods: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2.

Results: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours.

Conclusion: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.

Keywords: Adjuvant therapy; Colon cancer; Deficient mismatch repair; Microsatellite instability; Prognosis; Recurrence; Risk groups; Stage III.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cetuximab / administration & dosage
  • Chemotherapy, Adjuvant / mortality*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Female
  • Fluorouracil / administration & dosage
  • Follow-Up Studies
  • Humans
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Prospective Studies
  • Retrospective Studies
  • Survival Rate
  • Young Adult
  • ras Proteins / genetics

Substances

  • ras Proteins
  • Cetuximab
  • Leucovorin
  • Fluorouracil