H3K27me3 Immunohistochemical Loss Predicts Lower Response to Neo-Adjuvant Chemo-Radiotherapy in Rectal Carcinoma

Abstract

A watch-and-wait approach was suggested to avoid the possible complications related to surgery in patients with rectal carcinoma showing clinical complete response after neoadjuvant chemo-radiotherapy (CRT). Since clinical response may not correlate with pathological response, markers with higher accuracy are needed to identify patients who are likely responders and could be spared surgery. This study aims to assess whether H3K27me3 immunohistochemical expression in pre-treatment rectal carcinoma predicts response to neoadjuvant CRT or shows prognostic relevance. We assessed H3K27me3 immunostaining in 46 endoscopic biopsies of rectal carcinomas treated with neoadjuvant CRT and surgery. H3K27me3 immunostaining was lost in 20, retained in 19, and inconclusive (absent in neoplastic and non-neoplastic cells) in 7 cases. Retained H3K27me3 immuno-expression was significantly associated with ypTNM stage 0 (p = 0.0111) and high tumor regression, measured using either five-tiered (p = 0.0042) or two-tiered Dworak tumor regression grade (p = 0.0009). Poor differentiation, determined counting the number of poorly differentiated clusters (PDC grade) or tumor budding (TB) foci (TB grade), in the pre-treatment biopsy, was significantly associated with a shorter time to progression after surgery (p = 0.008; p = 0.0093). However, only PDC grade (p = 0.0023), together with radial margin involvement (p = 0.0001), retained prognostic significance in the multivariate analysis. The assessment of H3K27me3 immunostaining in pre-treatment endoscopic biopsy of rectal carcinoma could be useful to predict response to neo-adjuvant CRT and to identify patients who could safely undergo watch-and-wait approach. PDC and TB grade in the pre-treatment biopsy could provide additional prognostic information in patients with rectal carcinoma treated with neoadjuvant CRT and surgery.