Abstract PS5-12-20: Synthesis-breast: a prospective early-phase trial of a synthetic lethality-focused algorithm to identify therapeutic options in metastatic breast cancer

Abstract Background: Patients with metastatic triple-negative (TNBC) or endocrine-refractory hormone receptor-positive (HR+) breast cancer have limited therapeutic options and survival benefit once reaching chemotherapy-only options. Existing precision oncology uses actionable mutations, which restrict targeted therapies to patients harboring those mutations. ENLIGHT is a computational algorithm that predicts possible treatment options via tumor transcriptomes using synthetic lethality, validated using 21 retrospective pan-cancer trial datasets with 697 total patients. This exploratory clinical trial seeks to evaluate ENLIGHT’s feasibility to prospectively identify treatment options in this population. Design: SYNTHESIS-Breast (Clinicaltrials.gov NCT number requested) is an exploratory single-institution trial that will enroll participants with advanced metastatic TNBC or endocrine-refractory HR+ breast cancer who were previously treated with approved regimens with known overall survival benefits. Tumor biopsy samples (from within 6 months before enrollment) are mailed in for screening and will undergo genomic and transcriptomic profiling using the TruSight Oncology 500 (TSO500) platform; whole-transcriptome RNA-seq will be analyzed through ENLIGHT. Participants - initially seen virtually - will be assigned to 1 of 3 arms based on TSO500 and ENLIGHT as reviewed by a molecular tumor board: Arm 1 (no treatment recommendation), Arm 2 (recommendation for an FDA on-label treatment option), or Arm 3 (ENLIGHT recommendation from 1 of 22 off-label treatment options). Participants in Arm 3 will be treated at the NIH, and those in Arms 1 and 2 will continue with their community oncologists and be followed virtually. The trial uses a Simon two-stage design with a two-part primary objective. Part A assesses feasibility through the number of participants matched to an ENLIGHT-recommended therapy. If enough participants are matched to an ENLIGHT-recommended therapy within 1 year, the trial moves to Part B, evaluating objective response in Arm 3 participants. Overall success of the trial is defined as a 40% response rate of Arm 3 participants.This study is not designed to validate ENLIGHT for routine clinical use but aims to 1) assess the feasibility of prospective use of this computational algorithm within a reasonable timeframe, and 2) guide future trials to validate clinical use of ENLIGHT. In pilot testing of 10 archival breast cancer tissue samples, all RNA-seq-evaluable samples had ≥ 1 ENLIGHT match; 6/10 were matched to immunotherapy options. Among those, 4/6 would not have been eligible under current guidelines. Implications: SYNTHESIS-Breast is a prospective trial that uses ENLIGHT, a computational algorithm based on transcriptome-based synthetic lethality, to predict off-label treatment options for participants with metastatic breast cancer who have exhausted initial-line therapies. The current mutation-based model of precision oncology leaves patients behind, requiring alternative strategies that can use multi-omic data and predictive approaches. Insights from this trial will not only inform future trials using ENLIGHT, but also early-phase trials assessing other computational algorithms. Citation Format: A. B. Warner, B. B. Solarz, M. Belyov, V. Bolanos, A. McCoy, T. Fujii, J. Lee, K. C. Conlon, G. Dinstag, R. Aharonov, T. Beker, K. Aldape, E. Ruppin, S. Lipkowitz, P. S. Rajagopal. Synthesis-breast: a prospective early-phase trial of a synthetic lethality-focused algorithm to identify therapeutic options in metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-12-20.