Comprehensive Genomic Profiling of Advanced Anal Adenocarcinoma in Japan

PURPOSE Anal adenocarcinoma (AD) is a rare GI malignancy with no established standard treatment. Little is known about genomic alterations (GAs) and their therapeutic implications in advanced anal AD. Here, we compared the genomic profiles of advanced anal AD and advanced rectal AD. METHODS We retrospectively extracted data from patients with advanced anal or rectal AD who underwent comprehensive genomic profiling (CGP) and were registered at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB). RESULTS From June 2019 to April 2023, 45 patients with anal AD and 1,915 patients with rectal AD were enrolled into the C-CAT database. TP53 (88.9%) and KRAS (51.1%) were the most common GAs in anal AD. Compared with rectal AD, anal AD showed significantly higher frequencies of ERBB3 (22.2% v 1.8%), MYC (20.0% v 8.4%), and BRCA2 (6.7% v 1.5%) alterations and a significantly lower frequency of APC mutations (8.9% v 84.6%). TMB-high status (≥10 mutations/Mb) was observed in 6.7% of anal AD cases, whereas no MSI-high tumors were identified in this group. At least one druggable GA (excluding RAS , BRAF V600E, ERBB2 , and MSI) was detected in 40.0% of patients with anal AD. Druggable GAs were identified in genes related to the MAPK pathway, DNA damage response pathway, and other oncogenic pathways. CONCLUSION Advanced anal AD exhibited a distinct genomic profile compared with advanced rectal AD. CGP is a useful approach for identifying druggable GAs in advanced anal AD to expand therapeutic opportunities.