Abstract PS5-08-09: A Pilot, Single-Arm, Phase II Trial of Tamoxifen plus Pegylated Liposomal Doxorubicin in Patients with Metastatic Triple Negative Breast Cancer

Abstract Background: Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and disproportionately contributes to breast cancer mortality due to its aggressive clinical course, high propensity for visceral and brain metastases, and lack of targeted therapies. While TNBC lacks estrogen receptor alpha (ERα), up to 80% of tumors express estrogen receptor beta (ERβ), and a similar proportion harbor TP53 mutations. Pioneering work by our group demonstrated that ERβ directly interacts with p53, exerting tumor-suppressive effects in the presence of mutant p53 (mut-p53), but potential oncogenic effects in wild-type p53 settings (Mukhopadhyay et al., J Natl Cancer Inst, 2019). We have also showed that tamoxifen (Tam), a selective estrogen receptor modulator, stabilizes ERβ and enhances its binding to mut-p53, sequestering it away from TP73 and restoring TP73’s tumor suppressor activity. In vitro, Tam synergistically enhances the cytotoxicity of doxorubicin in ERβ/mut-p53 positive TNBC cell lines, while in vivo xenograft models demonstrate superior tumor regression with the combination. Therapeutic proof-of-concept was observed in a patient with metastatic Erβ/mut-p53 expressing TNBC who had marked tumor regression following Tam treatment (Scarpetti et al., The Oncologist, 2023). Given the frequent co-expression of ERβ and mut-p53 in TNBC and the favorable safety profile of tamoxifen and pegylated liposomal doxorubicin (PLD), we have initiated a phase II clinical trial evaluating this combination in patients with metastatic(m) or unresectable TNBC. Methods: This is an open-label, single-arm, phase II study (NCT06434064) enrolling patients(pts) ≥18 years with mTNBC characterized by ERα-low (≤10%) expression and progression on ≥2 prior lines of systemic therapy. Pts will receive Tam 20 mg orally once daily and PLD 50mg/m2 intravenously every 28 days. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. Tam is continued unless dose-limiting toxicity occurs, as no dose reductions are allowed. The primary endpoint is overall response rate (ORR) as assessed by RECIST v1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety/tolerability per CTCAE v5.0. Exploratory endpoints include changes in circulating tumor DNA (ctDNA), ERβ-mut-p53 interaction assessed by proximity ligation assay (PLA), differential gene expression analysis by RNA-seq, immune deconvolution via CIBERSORT, and peripheral immune profiling through cytokine analysis and flow cytometry. A safety lead-in will be conducted in the first 6 pts. The study uses a Simon two-stage design to detect an increase in ORR from 16% to 33%, with 80% power and α = 0.10 (n1 = 12, n2 = 18). This design ensures early stopping for futility and supports efficient evaluation of efficacy. Technical and analytic validation of ER-beta expression as a possible biomarker of response is ongoing. Significance: If successful, this study will establish a novel, mechanism-driven treatment option for previously treated mTNBC. Correlative analyses will uncover molecular and immune pathways linked to therapeutic response. Erβ and mut-p53 interaction profiling may support future patient selection for Tam based therapies. Future studies will explore potential synergy between antibody-drug conjugates that induce DNA-damage e.g. Sacituzumab govitecan and Tam as well as adding immune checkpoint inhibition to Tam and Doxil to improve patient outcomes. Status: The study is currently open to enrollment. Clinical trial information: (NCT 06434064) Citation Format: Z. Shah, C. C. Oturkar, I. Aijaz, H. Yu, M. L. Tarquini, G. M. Das, S. Kabraji. A Pilot, Single-Arm, Phase II Trial of Tamoxifen plus Pegylated Liposomal Doxorubicin in Patients with Metastatic Triple Negative 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 PS5-08-09.