Abstract 3991: BRAF N486_P490del and fusions as distinctive gene alterations in pancreatic ductal adenocarcinomas: Analysis of C-CAT and AACR Project GENIE data

Abstract Backgrounds: BRAF genomic alterations (GAs) have been identified in various tumors and are categorized into three distinct classes. Based on their impact on RAS-independent kinase activity, class 1 (monomer) and class 2 (dimer) are significant treatment targets and class specific regimens are being developed. However, the distribution of these classes across different primary sites has not yet been clarified. In patients with pancreatic cancer (PC), class 2 BRAF GAs have occasionally been encountered in clinical practice. Because precision oncology is limited in PC, BRAF GAs are precious target. To elucidate the patterns of BRAF GAs in PC, we investigated two extensive databases. Methods: We analyzed the Japanese nationwide C-CAT data and the AACR Project GENIE data. BRAF GAs were annotated using OncoKB and AlphaMissense and classified into three classes based on the published literature. Results: In the C-CAT data (N=107,714), as summarized in the table, BRAF GAs (n=3559, 3.3%) were frequently observed in thyroid, skin, and colorectal cancers, but these were mainly class 1(mostly V600E). In contrast, PC showed a distinct profile: among 11,959 patients with PC, BRAF GAs were detected in 230 (1.92%), Class1 was relatively rare (15.6%) and 60.4% (139/230) were class 2. These were mainly composed of in-frame deletions (n=97), with N486_P490del (n=79) and fusions (n=28). In GENIE data (N=250,018), 1.6% (169/10,730) of patients with PC harbored BRAF GAs. Although proportion of V600E was higher than that in C-CAT (19.5%), class 2 was dominant (63%, 108/169), such as fusions(n=48) and N486_P490del (n=28). Among BRAF N486_P490del positive solid tumors, pancreas was dominant primary site in both C-CAT (82%, 79/96) and GENIE (52%, 28/53). Conclusions: Class 2 BRAF GAs, especially N486_P490del and fusions, are distinctive alterations in patients with PC, and the development of class 2 specific targeted therapies is urgently needed. Citation Format: Kiyoaki Ochi, Chigusa Morizane, Kouya Shiraishi, Takafumi Koyama, Kuniko Sunami, Rui Kitadai, Yusuke Okuma, Tetsuro Shiraishi, Eiichiro So, Yuno Goto, Shiho Hakui, Keita Fujisaki, Kazunori Onuma, Yasuhiro Komori, Daiki Yamashige, Mao Okada, Shota Harai, Yuta Maruki, Yasuyuki Kawamoto, Yoshikuni Nagashio, Susumu Hijioka, Hideki Ueno, Takushi Okusaka. BRAF N486_P490del and fusions as distinctive gene alterations in pancreatic ductal adenocarcinomas: Analysis of C-CAT and AACR Project GENIE data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3991.