Abstract Background: Trastuzumab deruxtecan (T-DXd) has demonstrated significant clinical efficacy in metastatic breast cancer (mBC) with varying HER2 expression, including HER2-low and HER2-ultralow. Statins have been shown to increase HER2 membrane localization and stability, potentially enhancing responsiveness to HER2-targeted therapies. Given this mechanistic rationale, we investigated the potential of statins to enhance T-DXd activity through a translational approach combining a preclinical HER2-negative breast cancer model and a real-world clinical cohort of patients with HER2-positive mBC treated with T-DXd. Methods: In the preclinical arm, 60 female Wistar albino rats were induced with hormone receptor-positive, HER2-negative mammary tumors using N-methyl-N-nitrosourea (MNU). Animals were randomized into five groups: Control, MNU-only, MNU+T-DXd, MNU+statin, and MNU+T-DXd+statin. Tumor volume, number, and survival were monitored. HER2 expression, apoptotic markers (Bax, Bcl-2, Caspase-3/9), and proliferative signaling pathways (p-AKT, p-ERK) were assessed via immunohistochemistry (IHC) and Western blotting. In the clinical arm, 109 patients with HER2-positive mBC who received T-DXd were retrospectively analyzed. Patients were stratified based on concomitant statin use. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis and log-rank testing. Results: The combination of T-DXd and statin significantly reduced tumor volume compared to either monotherapy (p 0.0001), with a strong trend toward reduced tumor count (p = 0.051). HER2 protein levels were elevated in the statin and combination groups, as demonstrated by both IHC and Western blot analyses. The combination group exhibited significantly higher levels of pro-apoptotic markers (↑Bax, ↑Caspase-3), decreased anti-apoptotic Bcl-2, and stronger suppression of p-AKT and p-ERK (p 0.0001 for all vs. T-DXd). In a real-world cohort of 109 heavily pretreated patients with HER2-positive mBC receiving T-DXd, concomitant statin use was associated with significantly improved mPFS (21.83 months vs. 14.02 months; p = 0.049) and median OS (not reached vs. 19.68 months; p = 0.023) compared to non-users. Conclusions: Our findings revealed that statin use significantly enhanced the efficacy of T-DXd in both preclinical and clinical settings. These results support the potential role of statins as cost-effective and widely available agents to potentiate HER2-targeted therapies. Prospective clinical trials are warranted to validate these observations. Citation Format: T. Sahin, C. Orhan, I. Ozercan, H. Muglu, B. Er, A. Akyildiz, S. Tunbekici, A. Oruc, M. Aykan, B. Koylu, O. Akdogan, I. Deliktas Onur, O. Ates, O. Yazici, F. Selcukbiricik, N. Karadurmus, M. Araz, D. Erdem, E. Goker, A. Bilici, S. Aksoy, D. Guven. Statins enhance trastuzumab deruxtecan efficacy: Preclinical synergy in HER2-negative models and clinical benefit in HER2-positive 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 PS4-04-11.
Sahin et al. (Tue,) studied this question.