Abstract 5735: Druggable gene alterations in Japanese patients with rare malignancy
Authors: Ohmoto Akihiro , Hayashi Naomi , Fukada Ippei , Yamazaki Masumi , Yunokawa Mayu , Kasuga Akiyoshi , Shinozaki Eiji , Ueki Arisa , Tonooka Akiko , Takeuchi Kengo , Mori Seiichi , Kiyotani Kazuma , Takahashi Shunji 
Published: June 2022

Abstract
Background: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy.
Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of &lt;6 cases per 100,000 individuals). We analyzed the genomic features in the rare malignancy cohort, including gene mutations, gene fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Gene variants, amplifications, and fusions categorized as evidence level A using Clinical Interpretations of Variants in Cancer (CIViC) and MD Anderson Knowledge Base for Precision Oncology were considered as druggable alterations. CGP testing was used to calculate overall survival (OS) to death or at the last follow-up.
Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24).
Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, &gt;20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development.
Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.