Clinical utility of whole transcriptome sequencing for fusion detection in advanced solid tumors: SCRUM-Japan MONSTAR-SCREEN-2.

Abstract

3127 Background: Fusion variants represent established therapeutic targets in precision oncology yet are incompletely captured by conventional targeted DNA panel sequencing. Recent studies have reported that RNA sequencing enables detection of oncogenic fusions and structural variants that escape conventional DNA panel sequencing, particularly complex rearrangements occurring in intergenic regions. Herein, we evaluated the landscape of fusion variant detection by whole transcriptome sequencing (WTS) in advanced solid tumors from the SCRUM-Japan MONSTAR-SCREEN-2, a nationwide molecular profiling project. Methods: Patients with advanced solid tumors were enrolled; tumor tissues were profiled using whole exome/transcriptome sequencing (MI CancerSeek, Caris Life Sciences, Phoenix, AZ, USA). For fusion detection comparison, we performed an in silico analysis cross-referencing each fusion detected by WTS against publicly available information from conventional DNA panels including both target gene lists and breakpoint information where available, to evaluate theoretical detectability. Results: Among 2,768 patients enrolled as of March 2024, WTS data from baseline tissue samples were available in 2,253 pts across 33 cancer subtypes: the most common subtypes were colorectal adenocarcinoma (n=520), gastric adenocarcinoma (n=306), breast cancer (n = 198), prostate cancer (n=177) and pancreatic cancer (n=156). Pathogenic gene fusions and structural variants were detected by WTS in 122 of the 2,253 patients (5.4%), with a total of 126 pathogenic fusions identified. Among 126 pathogenic fusions, 75 (59.5%) represented variants that would theoretically have escaped detection by targeted panel DNA sequencing methodologies, including druggable kinase fusions (FGFR2, FGFR3, and BRAF). Among 18 patients treated with kinase fusion-targeted therapy with evaluable response data, 1 (5.6%) showed complete response, 3 (16.7%) showed partial response and 11 (61.1%) showed stable disease. WTS identified a MYO5A-BRAF fusion in a patient with melanoma that was undetectable by conventional DNA panel sequencing. Based on this finding, the patient received combination BRAF and MEK inhibitor therapy, achieving stable disease for four months, demonstrating the therapeutic relevance of WTS-guided treatment selection. Conclusions: WTS detected fusion variants at a high frequency, highlighting the importance of WTS in precision oncology. Clinical trial information: UMIN000043899.