Abstract PS1-13-20: Functional precision oncology for metastatic breast cancer (FORESEE): a feasibility trial. Final Results

Abstract Background: Precision oncology entails identification of disease driver mutations and administering drugs that target mutated proteins. However, many breast tumors do not harbor actionable mutations. Even if an actionable mutation is identified, it is unknown if inhibition of the target will lead to clinical response. In metastatic breast cancer, mutation testing alone is insufficiently informative to make optimal treatment selections. FORESEE was a pilot study to assess the feasibility of genomic characterization and functional drug response profiling on patient-derived organoids (PDOs) to prospectively inform therapy selection in metastatic breast cancer (MBC). Methods: Women with newly diagnosed metastatic triple negative (TNBC) or hormone receptor positive/Her2 negative (HR+/Her2-) breast cancer who had exhausted endocrine therapy options were eligible. Patients had to have evaluable disease amenable to fresh biopsy. Tumor tissue was used for single cell sequencing and PDO establishment. PDOs were subjected to screening of drugs approved by the FDA or available to the patient in active clinical trials. Circulating tumor (ct) DNA was also collected. After the biopsy, patients began therapy at the discretion of the treating physician. The results from ct and tumor tissue DNA sequencing were compiled along with results from PDO drug screening in a single report that was discussed with the treating physician. The subsequent line of therapy could align with the recommendation of the report (“informed” therapy) or not (“uninformed therapy”); physicians were not required to follow the recommendations. Response assessments were conducted until documented radiographic or clinical progression. The primary objective was to assess the feasibility of comprehensive genomic characterization and functional drug screening in a clinically relevant timeframe (12 weeks). The efficacy of treatment decisions informed by functional genomic assays constituted an exploratory objective. The trial was registered at clinicaltrials.gov (NCT04450706). Results: 15 patients were enrolled (TNBC, n = 7; HR+/Her2-, n = 8; recurrent, n = 11; de novo metastatic, n = 4). Median age was 55.5 years, median number of prior therapies in the HR+/Her2- patients was 3.5. Tumor biopsies were collected successfully from 13 patients; 10 had adequate tumor content (≥20% tumor content). PDOs were successfully established in 4/10 cases (TNBC, n = 2; HR+/Her2-, n = 2). Drug profiling was successfully conducted in all 4. Functional and genomic results were returned within 12 weeks and informed subsequent therapy selection in all cases. In 3 of 4 cases, genomic testing found no mutations matching FDA approved therapies. In 1 case, actionable mutations in PIK3CA and ESR1 were identified; the treatment choice was arbitrated with PDO drug screening. The relapse-free interval (RFI) with the informed line of therapy did not exceed the RFI with the immediate prior line of therapy. In 2 cases, the informed therapy constituted the last therapy that the patients received. Conclusion: The primary endpoint that PDO-based functional drug screening and genomic characterization will identify clinically actionable outcomes in >46% of patients was not met. Although therapy selection informed by functional drug screening can be clinically meaningful, limitations of this approach included the need for a tumor biopsy with adequate tumor content, low PDO establishment rate, and limited efficacy of approved drugs in advanced MBC. Methodological refinements and generation of PDOs earlier in the natural history of the disease to inform therapy selection may overcome these limitations. Citation Format: C. Vaklavas, L. Zhao, C.-H. Yang, S. D. Scherer, X. Huang, S. S. Buys, M. Wei, P. Moos, G. Marth, B. E. Welm, A. L. Welm. Functional precision oncology for metastatic breast cancer (FORESEE): a feasibility trial. Final Results [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 PS1-13-20.