Complete response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT mutations and high tumour mutational burden

S:CORT Consortium

Research output: Contribution to journalArticlepeer-review

68 Downloads (Pure)

Abstract

BACKGROUND: Pathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness.

METHODS: Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins.

RESULTS: Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway.

DISCUSSION: The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance.

Original languageEnglish
Article number129
Number of pages12
JournalRadiation oncology (London, England)
Volume16
Issue number1
DOIs
Publication statusPublished - 13 Jul 2021

Bibliographical note

Funding Information:
This study was supported by grants from the Academy of Medical Sciences and the Wellcome Trust (Ref 102732/Z/13/Z). ADB is currently supported by a Cancer Research UK Advanced Clinician Scientist award (Ref C31641/A23923).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

Fingerprint

Dive into the research topics of 'Complete response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT mutations and high tumour mutational burden'. Together they form a unique fingerprint.

Cite this