ESMO 2016: POLE Mutations Identified in Stage II/III Colorectal Cancer as a Biomarker for Favourable Prognosis

Mutations in the POLE proofreading domain identifiy a subset of colorectal cancers that have enhanced immunogenicity

DNA polymerase epsilon (POLE) proofreading domain mutations, a biomarker for enhanced immunogenicity and improved prognosis in endometrial cancer, also confer bettter prognosis in colorectal cancer, investigators reported at the ESMO 2016 Congress in Copenhagen, Denmark on October 10th.

Mark Andrew Glaire, of the Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK underscored the importance of using biomarkers, even those occurring at low frequencies, in defining distinct tumour subgroups.  He explained that while exceptionally mutated (ultramutated) tumours resulting from mutations that impair POLE proofreading function confer enhanced immunogenicity and excellent prognosis in the approximately 10% of endometrial cancers in which they are found; their effect in colorectal cancer had not yet been defined.

POLE Mutations Identified in Stage II/III Colorectal Cancer as a Biomarker for Favourable Prognosis

Results – Tumour recurrence and disease-free survival. © Mark Andrew Glaire

In order to determine the clinical relevance of POLE mutations in colorectal cancer, Dr. Glaire and colleagues performed Cox regression analysis on pooled data from more than 4500 patients participating in 3 clinical trials (VICTOR, QUASAR2 and PETACC-3) and multiple patient cohorts (LUMC, Oslo, Bern, AMC-AJCC-II, EPICOLON, and TCGA), and investigated the association between POLE mutations and prognosis in stage II/III disease. They detected POLE mutations in just 66 of 6,448 (1.0%) colorectal cancer samples.

The presence of POLE mutations is associated with a reduced risk of disease recurrence

Although uncommon, POLE mutations were significantly associated with several patient and tumour factors, including young age, male sex, right-sided location, early disease stage, and absence of mismatch repair deficiency (MMR-D; p ≤ 0.003 for all associations).

Importantly, multivariable analysis revealed a statistically significant association between POLE mutation and a greatly reduced risk of disease recurrence: hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.11, 0.76 (p = 0.006). This reduced risk was particularly strong in stage II disease, HR 0.22; 95%CI 0.02, 0.78 (p = 0.014). This reduction in relative risk was greater than that associated with MMR-D (HR 0.72; 95%CI 0.60, 0.87), an accepted biomarker of favourable prognosis in this setting. 

These results may be explained by increased immune activity in POLE-mutant tumours including increased CD8+ lymphocyte infiltration, expression of cytotoxic T cell markers, and effector cytokines, which was similar to that observed MMR-D cancers, well-recognised to be immunogenic.

Conclusions

POLE proofreading domain mutations define a subset of colorectal cancers that are more immunogenic and have a favourable prognosis. This novel biomarker shows promise to improve stratification of patients with colorectal cancer.

Reference

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POLE proofreading domain mutation defines a subset of immunogenic colorectal cancers with excellent prognosis

M.A. Glaire, E. Domingo, L. Vermeulen, T. van Wezel, G.-J. Liefers, R.A. Lothe, A. Nesbakkend, S.A. Danielsen, I. Zlobec, V. Koelzer, M. Berger, S. Castellví-Bel, M. de Bruyn, M. Novelli, S. Tejpar, M. Delorenzi, R. Kerr, D. Kerr, I. Tomlinson, D.N. Church 

This study was supported by: Cancer Research UK (C6199/A10417), the European Union Seventh Framework Programme (FP7/207- 2013) grant 258236 collaborative project SYSCOL, European Research Council project EVOCAN, the Oxford NIHR Comprehensive Biomedical Research Centre, core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z), the Dutch Digestive Foundation (MLDS) FP13-13 (to TvW), NWO-grants 40-00506-98-9021 and 175-010-2009-023 (to HN and MdB), the Southern and Eastern Norway Regional Health Authority (project number 2011024), the Norwegian Cancer Society (72190-PR-2006-0442), the Research Council of Norway, the Fondo de Investigación Sanitaria/FEDER (14/00173), Ministerio de Economía y Competitividad (SAF2014-54453-R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología) and Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, 2014SGR255, 2014SGR135) and COST Action BM1206. CIBERehd is funded by the Instituto de Salud Carlos III. The VICTOR trial was supported by the University of Oxford and enabled by an educational study grant from Merck. QUASAR2 was funded by Hoffman La Roche. The PETACC3 study was funded by Pfizer.