Abstract Introduction: Growing evidence suggests that comprehensive genomic and molecular testing has the potential to enable more precise, effective, and individualized cancer care. However, outside of trials, testing is inconsistent, and adoption into practice is limited. The BostonGene and Exigent Genomic INsight Study (BEGIN; NCT06272864) is an ongoing, prospective, multi-site study evaluating the clinical utility and actionability of integrated DNA/RNA comprehensive genomic profiling (CGP) in community settings. Using the multimodal Tumor Portrait test, CLIA-certified whole-exome sequencing (WES), whole-transcriptome RNA-seq, and tumor microenvironment (TME) subtyping were performed in pts. with advanced tumors. Methods: We consented and prospectively enrolled adult pts. with advanced breast cancer, non-small cell lung cancer (NSCLC), melanoma, or sarcoma at six community practice sites within the Exigent Research Network. All pts. underwent WES, RNA-seq, and TME profiling using the Tumor Portrait test. Actionable findings were defined by links to FDA-approved or NCCN®-recommended therapies or eligibility for biomarker-matched clinical trials. RNA-seq expression of targetable molecules (e.g., ERBB2 HER2, CD274 PD-L1) was also classified as actionable. Absence of driver mutations were not reported. Demographics, prior therapy, treatment decisions, and clinical outcomes were collected at 6 and 12 mos. Results: We analyzed 156 pts. (breast, n = 87; NSCLC, n = 41; melanoma, n = 21; sarcoma, n = 7) with ≥6 mos. of follow-up after report delivery. The median turn around time for comprehensive testing was 8 business days. Out of 221 screened pts., the sample failure rate was 14.4% (32/221). Actionable findings were identified in 93% of pts. (145/156), with ∼10% (15/145) attributable to RNA-seq and missed by DNA-only testing. Actionable finding rates by tumor type were: breast, 95.4%; NSCLC, 87.8%; melanoma, 95.2%; and sarcoma, 71.4%. At least one NCCN®/FDA-linked CGP biomarker was identified in 71 of 156 pts. (45.5%). Post-testing follow-up was available for 138 pts.; median follow-up was 6 mos., with 68/156 (43.5%) at ≥12 mos. RNA or DNA findings directly informed or altered the clinical course through the initiation of genomically matched systemic therapy and/or referral to biomarker-selected trials in 10% of pts. Conclusions: Integrated DNA/RNA CGP identified actionable findings in 93% of pts., with 10% of actionable findings being identified by RNA expression that were missed by DNA testing. This study demonstrates the clinical utility of combined exome-transcriptome profiling for precision oncology in community practice, which directly impacts patients' therapeutic options. Continued follow-up with BEGIN will assess the impact on patient-related outcomes, including progression-free and overall survival, as well as clinical trial accrual. Citation Format: Sibel Blau, Katherine Sanchez, Eric Schaefer, Julio A. Peguero, Paul Zito, Dheeraj Kodali, Artem Tarasov, Rheanna Carter, Kayla Hendricks, Anna Love, Lile Kontselidze, Polina Turova, Viktor Smirnov, Anna Ogloblina, Konstantin Rumyantsev, Neeharika Makani, Alexander Bagaev, Nathan Fowler. Determining the benefit of comprehensive molecular testing in advanced cancers: BostonGene and Exigent Genomic INsight (BEGIN) study 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 5421.
Blau et al. (Fri,) studied this question.