Real-world clinical utility of comprehensive genomic and transcriptomic profiling in metastatic breast cancer (mBC).

e13080 Background: Integrated DNA/RNA comprehensive genomic profiling (CGP) may expand therapeutic opportunities and support decision-making in metastatic breast cancer (mBC), yet real-world evidence for its clinical utility remains limited. We evaluated the impact of CGP-guided care on treatment decisions and outcomes in a heterogeneous mBC cohort. Methods: A retrospective, single-center analysis of 207 patients with mBC who underwent BostonGene’s Tumor Portrait test. Actionable alterations were defined per NCCN/FDA guidelines or clinical trial eligibility. Clinical utility is defined as CGP-driven treatment initiation or identification of guideline-supported future options was assessed in patients with ≥60 days of follow-up (n = 160). Subgroup analyses evaluated outcomes with trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), or immune checkpoint inhibitors using RNA-seq-based ADC biomarker thresholds, breast cancer classifier (BCC/PAM50), and tumor microenvironment subtypes. Progression-free survival (PFS) was analyzed using Kaplan–Meier methods and Cox regression. Results: The cohort included HR+/HER2− (58%), TNBC (35%), and HER2+ (7%) mBC, with a median of 2 prior therapy (range: 1–11). Overall, 65.5% of patients had actionable molecular alterations, of which 33.9% were supported by NCCN/FDA-approved indications, while the remaining alterations were potentially targetable within clinical trial settings. CGP directly informed treatment initiation in 10% of patients and identified potential future targeted therapy options in an additional 15%. Luminal B and Basal BCC subtypes were consistently associated with inferior PFS outcomes across the cohort. Among patients treated with T-DXd (n = 45), higher HER2 RNA expression was associated with reduced progression risk, whereas Basal and Luminal B subtypes demonstrated worse PFS (p = 0.006). Among patients receiving SG (n = 55), those with TNBC had longer PFS than those with HR-positive mBC, whereas TROP2 RNA expression was uniformly high and not predictive of outcome. Among patients treated with immunotherapy (n = 25), PD-L1 expression was not significantly associated with PFS. Conclusions: Integrated DNA and RNA CGP identified actionable alterations in most patients in our study cohort. It also either directly informed treatment decisions or identified new guideline-supported treatment options in 25% (total) of cases. Transcriptomic subtyping provided further prognostic insights, particularly among patients receiving T-DXd, that contextualize treatment selection and sequence when multiple therapeutic options are available, including scenarios in which more potent ADC-based regimens may be favored over alternative targeted approaches.