Integrated Analysis of Molecular and Clinical Prognostic Factors in Stage II/III Colon Cancer
Roth, Arnaud D × Delorenzi, Mauro Tejpar, Sabine Yan, Pu Klingbiel, Dirk Fiocca, Roberto d'Ario, Giovanni Cisar, Laura Labianca, Roberto Cunningham, David Nordlinger, Bernard Bosman, Fred Van Cutsem, Eric #
Oxford University Press
Journal of the National Cancer Institute vol:104 issue:21 pages:1635-1646
BackgroundThe prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.MethodsTumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.Results MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.ConclusionsConcomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.