T.n.t. chemo driver#

Multiple investigators have shown higher rates of response with higher radiotherapy doses, with maximum pCR rates of 25–30%. 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. Treatment typically consists of excisional surgery with neoadjuvant therapy if the cancer is locally advanced, consisting of either short course radiotherapy (25 Gy in 5 fractions over 1 week) with surgery the following week, or long course neo-adjuvant chemoradiotherapy (nCRT) (45–50 Gy in 25 fractions over 5 weeks, with synchronous iv 5-FU or oral capecitabine) with surgery 6–10 weeks later. Rectal cancer is a common malignancy, with approximately 11,000 cases per year in the UK. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance. The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score.

T.n.t. chemo driver#

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. Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. 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. Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. 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. 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.