Abstract
BackgroundPathological 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.MethodsTwo 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.ResultsTwenty 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.DiscussionThe 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.
Highlights
Rectal cancer is a common malignancy [1], with approximately 11,000 cases per year in the UK [2]
The current standard of care within the United Kingdom for locally advanced rectal cancer is long course chemoradiotherapy, the recent development of the concept of “total” neoadjuvant therapy (TNT), whereby consolidation chemotherapy is given after chemoradiotherapy, increased pCR rates from 15 to 25% in the consolidation group, acting as an additional therapeutic option in these patients which may lead to its introduction as standard of care [9]
Owing to the uncertainty surrounding the precise mechanisms of sensitivity of rectal cancer to chemoradiotherapy, we aimed to study the phenomenon of Pathological complete response (pathCR) in rectal cancer
Summary
Rectal cancer is a common malignancy [1], with approximately 11,000 cases per year in the UK [2]. Stockton et al Radiat Oncol (2021) 16:129 iv 5-FU or oral capecitabine) with surgery 6–10 weeks later The former regimen usually demonstrates little, if any tumour regression, but if it does occur, is associated with more favourable prognosis, and the latter regimen can lead to significant tumour shrinkage and downstaging, with pathological complete response (pathCR, defined as complete regression of tumour in the resection specimen) observed in approximately 10–15% of patients [6]. The current standard of care within the United Kingdom for locally advanced rectal cancer is long course chemoradiotherapy, the recent development of the concept of “total” neoadjuvant therapy (TNT), whereby consolidation chemotherapy is given after chemoradiotherapy, increased pCR rates from 15 to 25% in the consolidation group, acting as an additional therapeutic option in these patients which may lead to its introduction as standard of care [9]. 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
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