Background
The delivery of precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) tumours caused by mutations that impair DNA polymerase epsilon (POLE) proofreading. While these mutations confer enhanced immunogenicity and excellent prognosis in the ∼10% of endometrial cancers in which they occur, their consequences in colorectal cancer, where they are less common, are unclear.
Methods
We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from the VICTOR, QUASAR2 and PETACC-3 clinical trials, and multiple patient cohorts (LUMC, Oslo, Bern, AMC-AJCC-II, EPICOLON, TCGA). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from these series, comprising more than 4,500 cases.
Results
POLE mutations were detected in 66/6,448 (1·0%) colorectal cancers and were significantly associated with young age, male sex, right-sided location, early disease stage, and absence of mismatch repair deficiency (MMR-D) (P ≤ 0.003 for all associations). POLE-mutant tumours displayed increased CD8+ lymphocyte infiltration and expression of cytotoxic T cell markers and effector cytokines, similar to immunogenic MMR-D cancers. In multivariable analysis, POLE mutation was associated with a greatly reduced risk of cancer recurrence (HR = 0·34, 95%CI = 0·11–0·76, P = 0·006); particularly in stage II disease (HR = 0·22, 95%CI = 0·02–0·78, P = 0·014). This reduction appeared to exceed that associated with MMR-D (HR = 0.72 95%CI 0·60-0·87) – an established biomarker of favourable prognosis. Exploratory analysis suggested that the favourable outcome of POLE-mutant tumours was independent of chemotherapy.
Conclusions
POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This novel biomarker holds promise to improve patient stratification in colorectal cancer.
Clinical trial identification
Legal entity responsible for the study
Mark Glaire
Funding
This work 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.
Disclosure
M. de Bruyn: Funded by Dutch Cancer Society/Alpe d'HuZes grant RUG 2014-6719 S. Tejpar: Received research funding from Pfizer D. Kerr: Employee of, and owns stock in Oxford Cancer Biomarkers, has acted as a consultant for Amgen and Merck Serono, received speaker fees from Fresenius Kabi and research funding from Roche. All other authors have declared no conflicts of interest.
