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, F. A., Phipps, A. I., Tejpar, S., Nesbakken, A., Danielsen, S. A., Sveen, A., Buchanan, D. D., Clendenning, M., Rosty, C., Bot, B., Alberts, S. R., Jessup, J. Milburn, Lothe, R. A., Delorenzi, M., Newcomb, P. A., Sargent, D. and 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, 28 5: 1023-1031. doi:10.1093/annonc/mdx052


Author Dienstmann, R.
Mason, M. J.
Sinicrope, F. A.
Phipps, A. I.
Tejpar, S.
Nesbakken, A.
Danielsen, S. A.
Sveen, A.
Buchanan, D. D.
Clendenning, M.
Rosty, C.
Bot, B.
Alberts, S. R.
Jessup, J. Milburn
Lothe, R. A.
Delorenzi, M.
Newcomb, P. A.
Sargent, D.
Guinney, J.
Title Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study
Journal name Annals of Oncology   Check publisher's open access policy
ISSN 0923-7534
1569-8041
Publication date 2017-05-01
Sub-type Article (original research)
DOI 10.1093/annonc/mdx052
Open Access Status DOI
Volume 28
Issue 5
Start page 1023
End page 1031
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Abstract 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.

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).

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.

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.
Formatted abstract
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).

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.
Keyword Colon cancer
BRAF mutation
KRAS mutation
Microsatellite instability
Prognosis
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID U24 CA074783
U24 CA074794
U24 CA097735
P30 CA015083
U01 CA097735
K05 CA152715
UM1 CA167551
U01 CA074783
U24 CA074800
K07 CA172298
U01 CA074800
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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