Abstract PS4-08-15: Towards Personalized Medicine - Patient-Derived Breast Tumor Grafts as Predictors of Relapse and Response to Therapy: Final Results

Abstract Background: Predicting the risk of relapse in patients with non-metastatic breast cancer is important for medical decisions. Pathologic response and especially pathologic complete response (pCR) after preoperative chemotherapy has been associated with risk of relapse; however this association is imperfect. Our work in patient-derived xenografts (PDX) indicated that tumor engraftment in mice correlated with risk of recurrence. To understand further the prognostic utility of PDX, we designed a prospective clinical trial to determine the correlation between PDX generation with residual disease and patient outcome following neoadjuvant chemotherapy. The secondary endpoint of disease-free survival (DFS) in 1 year has been published. We now present the final result of the primary endpoint, DFS in 3 years. Methods: Women with newly diagnosed non-metastatic hormone receptor low-positive (HR-low, ER and/or PR ≤ 10%) or negative breast cancer planned to receive systemic chemotherapy prior to definitive surgery were eligible. Tumor tissue at diagnosis was orthotopically implanted into NOD/SCID mice. The primary objective of the study was to correlate the ability of a tumor to engraft in mice with pathologic responses and clinical outcomes. Results: Between 12/2016 and 1/2021, 80 patients enrolled (triple negative breast cancer (TNBC), n=51; HR-low/Her2-, n=10; HR-low or negative/Her2+, n=18; mixed, n=1). Patients received uniform preoperative chemotherapy regimens per standard of care. PDXs were successfully established from 18 patients (PDX(+), 22.5%). 37 patients achieved pCR (46.3%). In the Her2- subgroup (n=62), 17 (27.4%) patients were PDX(+) and 23 (37.1%) achieved pCR. With a follow up of the last enrolled patient of 3.6 years, 14 (17.5%) patients relapsed, of whom 10 were PDX(+) and 4 PDX(-). Three patients who relapsed had achieved a pCR, all of whom were PDX(+). The PDX(+) patients who relapsed, invariably relapsed early (1 year from definitive surgery) and their overall survival (OS) following relapse did not exceed 1 year. Among the 4 PDX(-) patients who relapsed, 1 relapsed early and died of recurrent disease; 1 relapsed 2.7 years following her definitive surgery and remains alive and off treatment 5.5 years following her recurrence. One PDX(-) patient with TNBC had a new diagnosis of stage 1 contralateral HR+/Her2- breast cancer 5.4 years following her definitive surgery. PDX engraftment remains significantly associated with relapse (Hazard ratio (HR) for relapse: 12.9 (95% CI, 4.02 - 41.4, p0.001)) while the achievement of pCR has not reached statistical significance (HR for relapse: 3.5 (95% CI, 0.98 - 12.5, p 0.055)) even with longer follow-up. PDX engraftment remains significantly associated with OS and breast cancer specific survival (BCSS, HR for BCSS: 21.8 (95% CI, 4.69 - 102, p0.001)) while achievement of pCR is not (HR: 2.43 (95% CI, 0.64 - 9.15, p 0.2)). This is particularly true for the Her2- subgroup: PDX engraftment remains significantly associated with relapse (HR: 13.6 (95% CI, 3.72 - 50.1, p0.001)) while the achievement of pCR has not reached statistical significance (HR: 2.1 (95% CI, 0.58 - 7.64, p 0.3)). PDX engraftment remains significantly associated with OS and BCSS (HR for BCSS: 33.2 (95% CI, 4.19 - 263, p0.001)) while achievement of pCR is not (HR: 1.42 (95% CI, 0.37 - 5.5, p 0.6)). Conclusion. Our functional studies identify not only a patient population with a high risk of relapse with greater precision than the achievement of pCR, but also patients whose relapse has a particularly aggressive natural history. We established patient derived models that recapitulate this aggressive disease and have used these models for medium throughput drug screens. Ongoing prospective studies evaluate the impact of these functional studies on treatment selection and patient outcomes. Citation Format: C. Vaklavas, C. B. Matsen, Z. Chu, K. M. Boucher, S. D. Scherer, S. Pathi, A. Beck, K. E. Brownson, S. S. Buys, N. Chittoria, E. D'Astous, H. E. Gulbahce, N. L. Henry, S. Kimani, J. M. Porretta, R. Rosenthal, J. Ward, M. Wei, B. E. Welm, A. L. Welm. Towards Personalized Medicine - Patient-Derived Breast Tumor Grafts as Predictors of Relapse and Response to Therapy: 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 PS4-08-15.