Statins enhance trastuzumab deruxtecan efficacy: preclinical synergy in HER2-negative models and clinical benefit in HER2-positive metastatic breast cancer

Creative Commons License

Sahin T. K., Orhan C., Ozercan I. H., Muglu H., Er B., Akyildiz A., ...Daha Fazla

Experimental Hematology and Oncology, cilt.15, sa.1, 2026 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Kısa Makale
  • Cilt numarası: 15 Sayı: 1
  • Basım Tarihi: 2026
  • Doi Numarası: 10.1186/s40164-026-00787-z
  • Dergi Adı: Experimental Hematology and 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)
  • Anahtar Kelimeler: Apoptosis, Breast cancer, HER2-low, Statin, Synergistic effect, Trastuzumab deruxtecan
  • Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
  • Hacettepe 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.