Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study

R. Dienstmann, M. J. Mason, Frank A Sinicrope, A. I. Phipps, S. Tejpar, A. Nesbakken, S. A. Danielsen, A. Sveen, D. D. Buchanan, M. Clendenning, C. Rosty, B. Bot, Steven Robert Alberts, J. Milburn Jessup, R. A. Lothe, M. Delorenzi, P. A. Newcomb, D. Sargent, J. Guinney

Research output: Contribution to journalArticle

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Abstract

Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively.

Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation.

Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782).

Original languageEnglish (US)
Pages (from-to)1023-1031
Number of pages9
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume28
Issue number5
DOIs
StatePublished - May 1 2017

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Colonic Neoplasms
Biomarkers
Survival
Microsatellite Instability
Neoplasm Staging
Adjuvant Chemotherapy
Mutation
Clinical Trials
Drug Therapy
Proportional Hazards Models
Area Under Curve
Observational Studies
Cohort Studies
Population

Keywords

  • BRAF mutation
  • colon cancer
  • KRAS mutation
  • microsatellite instability
  • prognosis

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Prediction of overall survival in stage II and III colon cancer beyond TNM system : a retrospective, pooled biomarker study. / Dienstmann, R.; Mason, M. J.; Sinicrope, Frank A; Phipps, A. I.; Tejpar, S.; Nesbakken, A.; Danielsen, S. A.; Sveen, A.; Buchanan, D. D.; Clendenning, M.; Rosty, C.; Bot, B.; Alberts, Steven Robert; Milburn Jessup, J.; Lothe, R. A.; Delorenzi, M.; Newcomb, P. A.; Sargent, D.; Guinney, J.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 28, No. 5, 01.05.2017, p. 1023-1031.

Research output: Contribution to journalArticle

Dienstmann, R, Mason, MJ, Sinicrope, FA, Phipps, AI, Tejpar, S, Nesbakken, A, Danielsen, SA, Sveen, A, Buchanan, DD, Clendenning, M, Rosty, C, Bot, B, Alberts, SR, Milburn Jessup, J, Lothe, RA, Delorenzi, M, Newcomb, PA, Sargent, D & Guinney, J 2017, 'Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 28, no. 5, pp. 1023-1031. https://doi.org/10.1093/annonc/mdx052
Dienstmann, R. ; Mason, M. J. ; Sinicrope, Frank A ; Phipps, A. I. ; Tejpar, S. ; Nesbakken, A. ; Danielsen, S. A. ; Sveen, A. ; Buchanan, D. D. ; Clendenning, M. ; Rosty, C. ; Bot, B. ; Alberts, Steven Robert ; Milburn Jessup, J. ; Lothe, R. A. ; Delorenzi, M. ; Newcomb, P. A. ; Sargent, D. ; Guinney, J. / Prediction of overall survival in stage II and III colon cancer beyond TNM system : a retrospective, pooled biomarker study. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2017 ; Vol. 28, No. 5. pp. 1023-1031.
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T1 - Prediction of overall survival in stage II and III colon cancer beyond TNM system

T2 - a retrospective, pooled biomarker study

AU - Dienstmann, R.

AU - Mason, M. J.

AU - Sinicrope, Frank A

AU - Phipps, A. I.

AU - Tejpar, S.

AU - Nesbakken, A.

AU - Danielsen, S. A.

AU - Sveen, A.

AU - Buchanan, D. D.

AU - Clendenning, M.

AU - Rosty, C.

AU - Bot, B.

AU - Alberts, Steven Robert

AU - Milburn Jessup, J.

AU - Lothe, R. A.

AU - Delorenzi, M.

AU - Newcomb, P. A.

AU - Sargent, D.

AU - Guinney, J.

PY - 2017/5/1

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N2 - Results: TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers, 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively.Conclusions: Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation.Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782).

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KW - colon cancer

KW - KRAS mutation

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KW - prognosis

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