Statins enhance trastuzumab deruxtecan efficacy: preclinical synergy in HER2-negative models and clinical benefit in HER2-positive metastatic breast cancer
EXPERIMENTAL HEMATOLOGY & ONCOLOGY, cilt.15, sa.1, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 15 Sayı: 1
- Basım Tarihi: 2026
- Doi Numarası: 10.1186/s40164-026-00787-z
- Dergi Adı: EXPERIMENTAL HEMATOLOGY & ONCOLOGY
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, Directory of Open Access Journals, Academic Search Ultimate (EBSCO), Health Research Premium Collection (ProQuest)
- Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
- Gazi Üniversitesi Adresli: Evet
Özet
Trastuzumab deruxtecan (T-DXd) has demonstrated significant efficacy in metastatic breast cancer (mBC) with varying HER2 expression. Statins have been shown to increase HER2 membrane localization and stability, potentially enhancing responses to HER2-targeted therapies. We investigated whether statins enhance T-DXd activity through a translational approach combining a preclinical HER2-negative model and a real-world HER2-positive mBC cohort. In the preclinical arm, 60 female Wistar albino rats were induced with 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. In the clinical arm, 109 patients with HER2-positive mBC who received T-DXd were retrospectively analyzed. The combination of T-DXd and statin significantly reduced tumor volume compared to either monotherapy (p < 0.0001) in a preclinical rat model. HER2 protein levels were found to be elevated in the statin and combination groups, as demonstrated by both IHC and Western blot analyses. 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 median progression-free survival (mPFS) and median overall survival (mOS). Our findings revealed that statin use significantly enhanced the efficacy of T-DXd in both a preclinical HER2-negative rat model and patients with HER2-positive mBC. Prospective clinical trials are warranted to validate these observations.