Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations

Abstract

Background:The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain.Methods:In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen.Results:Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73–88%) (four patients with clinical complete response declined surgery). Twenty–four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05–1.03, P=0.055).Conclusions:This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

“…Spatial and temporal intratumour molecular heterogeneity is a landmark of many malignancies including colorectal cancer . Studies addressing this phenomenon in nonmetastatic rectal cancer are limited and results not always consistent . By analysing a relatively large number of paired tumour tissues from pretreatment biopsies and posttreatment resection samples, we found a high concordance (≥95%) for NRAS , BRAF and PIK3CA while the concordance for KRAS and TP53 was lower at 82 and 63%, respectively.…”

“…42,43 Studies addressing this phenomenon in nonmetastatic rectal cancer are limited and results not always consistent. [44][45][46][47][48] By analysing a relatively large number of paired tumour tissues from pretreatment biopsies and posttreatment resection samples, we found a high concordance (≥95%) for NRAS, BRAF and PIK3CA while the concordance for KRAS and TP53 was lower at 82 and 63%, respectively. Notably, the vast majority of discordant cases in our series were due to the detection at baseline of mutant clones which were not subsequently detectable on the resection specimens, this likely reflecting an artefact secondary to the reduced tumour cellularity after neoadjuvant treatment.…”

Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

“…Spatial and temporal intra-tumour genomic heterogeneity (ITGH) is a common feature of many cancers [25]. Studies investigating ITGH in non-metastatic rectal cancers are limited with varying results [26][27][28]. We found a high concordance of driver mutations between pre-, on-and post-NACRT treatment samples.…”

The effect of radiotherapy on rectal cancer: a histopathological appraisal and prognostic indicators

“…Some modalities of preoperative CRT further showed disappearance of mutations which could be related to the effect of CRT as well as the emergence of new resection mutations which were thought that may be due to either treatment-driven selection or expansion of pre-existing clones which were undetectable due to their low levels. Thus, evidence of intramural heterogeneity in rectal cancer was reported [38].…”