Intra-tumoral genomic heterogeneity in rectal cancer: mutational status is dependent on preoperative biopsy depth and location.

Abstract

Background Neoadjuvant therapy is indicated for patients with locally advanced rectal cancer, even though a significant number of patients show minimal or no response. Adequate response prediction before the start of neoadjuvant treatment might reduce unnecessary waiting periods and therapy related toxicity in non-responders. Genomic mutational status might provide a means to predict response to neoadjuvant therapy. However, it is unclear whether predictions based on genomic mutational status in single preoperative biopsies are reliable due to intra-tumoral heterogeneity. In this study we aim to investigate the reliability of genomic mutations found in single pre-operative biopsies by comparing these genomic mutations to 4 other locations within the same tumor using next generation sequencing. Methods Rectal cancer patients undergoing primary resection, without neoadjuvant therapy, were included. Of all patients, one biopsy, two deep and two superficial samples were obtained and sequenced using a targeted next generation sequencing gene panel. Concordance between these 5 samples was assessed. Results In this feasibility study we included 11 patients. In 7 out of 11 (64%) patients, all 5 samples showed concordant mutations. In 4 out of 11 patients (36%) disconcordant mutations were observed. Conclusions Evaluation of genomic mutational status on a single pre-operative biopsy shows disconcordance in a substantial amount of patients.