P-264 - Tissue DNA methylation as a tool for clinical decision making after neo-adjuvant treatment in rectal cancer

Abstract

Introduction: Neoadjuvant chemo-radiotherapy in rectal cancer patients aims to reduce local recurrence rates following surgery. About 20% of the patients achieve complete pathological response, characterized by absence of residual primary tumor in the pathological specimen, and have excellent disease free survival rates. Several reports suggest that a selected population with this excellent response may avoid surgery. However, there is no biomarker to assist such clinical decision (“watch and wait” approach) after neoadjuvant treatment. Recently, DNA methylation alterations have been shown to be a potential predictive biomarker for response to chemotherapy and radiotherapy in solid tumors such as breast and rectal cancers. Finding highly- predictable methylation markers for chemoradiation response may alter surgical approach in a substantial proportion of the patients and may offer them conservative approach such as local excision or even non-operative approach without effecting prognosis. Methods: A retrospective cohort study. Patients who were diagnosed with rectal cancer in the years 2006-2016 and underwent chemoradiation therapy and then a resection were included in this research. Data regarding disease recurrence and clinical parameters were obtained from patients medical files. Tumor specimens were evaluated by an expert pathologist for level of tumor regression score 0-3 (TRS, 2016 guidelines of the Collage of American Pathologist) and analyzed for tissue methylation patterns (Illumina EPIC array). Results: 51 patients were enrolled to this study, 4 patients with a metastatic disease were excluded. Patients' post surgical follow up time ranged from 3 months to 10 years (median 36 months). Disease recurrence rates were higher in patients who did not respond to therapy (TRS 3) compared with patients who responded completely to moderately (TRS 0-2). The most common sites of recurrence were liver and lungs. DNA methylation profiles identified n = 638 CpG sites with differential methylation of p < 10-4 between TRS 0 + 1, 2 and 3 (Figure 1). This indicates unique methylation patterns of response allowing the discrimination of complete responder, intermediate responder and non-responder. Conclusion: Rectal cancer patients with complete pathological response to neoadjuvant therapy have a significant lower risk for disease recurrence following surgery. In this group the resected tissue has a unique DNA methylation pattern which may serve as a complimentary biomarker to clinical and imaging findings. This helpful data may support “watch and wait” approach, sparing a morbid surgery.