H3K27me3 immunohistochemical loss predicts response to neo-adjuvant chemo-radiotherapy (CRT) in patients with locally advanced rectal adenocarcinoma

Background & objectives: Patients with locally advanced rectal cancer are treated with neo-adjuvant chemo-radiotherapy to improve resectability and decrease the probability of recurrence. This study aims to assess whether H3K27me3 immunostaining in pre-treatment biopsies of rectal adenocarcinoma may predict response to neo-adjuvant CRT. Methods: We assessed H3K27me3 immunostaining in 43 pretreatment endoscopic biopsies of locally advanced rectal carcinomas treated with neo-adjuvant CRT and correlated it with Tumour Regression Grade (TRG) measured using Dworak system in the following surgical specimen. H3K27me3 immunostain was classified: i) retained (≥ 5% stained neoplastic cells); ii) lost (> 95% stained neoplastic cells); iii) inconclusive (unstained normal and neoplastic cells). Results: H3K27me3 immunostaining was lost in 18 cases, retained in 17 and inconclusive in 8. All tumours with retained H3K27me3 expression had complete tumour regression (TRG 4/5). H3K27me3 loss was significantly associated with absent/ partial tumour regression (TRG 0/1/2) in surgical specimen (P=0.0015) Conclusion: Due to the lower probability to respond to neo-adjuvant CRT, a "watch and wait" approach to avoid side effect of surgery should be used with caution in patients with rectal carcinomas with H3K27me3 loss in the endoscopic pre-treatment biopsy.