Response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT pathway dysregulation and high tumour mutational burden

ABSTRACT PurposePathological complete response (pathCR) in rectal cancer, seen in examination of the pathological specimen post-surgery is the phenomenon whereby a tumour completely regresses under treatment with chemoradiotherapy. This is beneficial as up to 75% of patients do not experience regrowth of the primary tumour, allowing organ preservation and is poorly understood. We aimed to characterise the processes involved in pathCR. Materials & MethodsTwo groups of patients were identified with either complete response (pathCR group) or no response (poor response group) and biopsy and/or resection specimen blocks were retrieved. These underwent high read depth amplicon sequencing, exome sequencing, methylation arrays and immunohistochemistry for DNA repair pathway proteins. Sequencing data underwent analysis and the two cohorts were compared. ResultsSeven patients who underwent pathological complete response and twenty four who underwent poor response (to act as opposite “extreme phenotypes”) underwent molecular characterisation. Patients in the complete response group had significantly higher tumour mutational burden, neoantigen load and enrichments for mutations in the PI3K/AKT/mTOR signalling pathway as well as significantly lower numbers of structural variants. There were no differences in copy number variants or tumour heterogeneity. Methylation analysis demonstrated enrichment for changes in the PI3K/AKT/mTOR signalling pathway. ConclusionsThe phenomenon of pathCR in rectal cancer appears to be related to immunovisibility caused by a high tumour mutational burden phenotype. Resistance mechanisms seem to involve the PI3K/AKT/mTOR signalling pathway and tumour heterogeneity does not seem to play a role in resistance.