Multiomics Identifies Potential Molecular Profiles Associated With Outcomes After BRAF-Targeted Therapy in Patients With BRAF V600E-Mutated Advanced Solid Tumors.

Abstract

It is a clinical challenge to select patients for BRAF-targeted therapy because of the lack of predictive biomarkers besides the BRAF V600E mutation. By analyzing the genome, transcriptome, and proteome, this study investigated the association between baseline molecular alterations and outcomes of BRAF-targeted therapy. Fresh tumor tissue from patients enrolled in the Copenhagen Prospective Personalized Oncology study was collected and underwent comprehensive molecular profiling. <i>TP53</i> comutations were most frequently detected. Patients with a <i>TP53</i> wild-type tumor had a significantly longer median progression-free survival than those with <i>TP53</i> comutations (hazard ratio, 2.8 [95% CI, 1.13 to 7.08]; <i>P</i> = .02). RNAseq revealed a distinct gene expression signature for patients with long-term disease control (LDC), including hallmarks of cell cycle arrest and proliferation in the p53 pathway. The protein analysis demonstrated that ubiquitin-conjugating enzyme EK2 was significantly downregulated in patients with LDC. Using a multiomic approach, we identified molecular alterations associated with treatment outcomes. The potential of analyzing multiomic data is promising and should be prioritized in translational cancer research to uncover the full potential within precision oncology.