Cardioprotection against Anthracycline-induced cardiotoxicity is primarily achieved through lipid-independent mechanisms, including the suppression of inflammasome-mediated injury, modulation of innate immune signaling, attenuation of myocardial fibrosis, and restoration of mitochondrial homeostasis, which are regulated by PCSK9 inhibition. The inhibition of PCSK9 has been demonstrated in preclinical models to enhance anticancer efficacy by reducing chemoresistance and increasing cardiomyocyte viability by 35-88% during anthracycline/trastuzumab exposure.

These findings enable risk stratification before trastuzumab initiation. Future research should validate a predictive model incorporating these factors and assess cardioprotective strategies, thereby translating risk assessment into actionable protocols to optimize cardiac safety without compromising oncologic outcomes.

Chemotherapy was the first-line regimen in 83 of 162 patients (51%), endocrine monotherapy in 55 of 162 (34%), and trastuzumab-pertuzumab-taxane or cyclin-dependent kinase 4 and 6 inhibitor-based regimens in eight of 162 (5%). 87534309); Center for Global Health at the United States-National Cancer Institute at the National Institutes of Health (contract award No. HHSN2612010000871/NO2-PC-2010-00087); Fogarty International Center, NIH, HHS; and Susan G. Komen for the Cure; in Argentina, Instituto Nacional del Cáncer (Ministry of Health), Fundación Argentina de Nanotecnología, Agencia Nacional de Promoción Científica y Tecnológica, CONICET (Ministry of Science, Technology, and Productive Innovation); Brazil, Ministério da Saúde (Ministry of Health); Chile, Instituto de Salud Pública (Public Health Institute) and Ministerio de Salud (Ministry of Health); and Mexico, Consejo Estatal de Ciencia y Tecnología de Jalisco (COECYTJAL) and Universidad de Sonora (University of Sonora).

P3, N=400, Recruiting, Boehringer Ingelheim

P1/2, N=129, Not yet recruiting, Medica Scientia Innovation Research S.L.

Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.

In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Conjugation of nanoparticles with Herceptin® (trastuzumab) significantly increased cellular uptake and anticancer activity, especially in clathrin-deficient SK-BR-3 cells that overexpress ERBB2. These findings establish that the easily synthesized PL-MNP-pBIRC5/As-BIRC5 and PL-MNP-pBIRC5/dN-BIRC5 nanodrugs have strong potential to overcome BIRC5- and ABCB1-related drug resistance, representing a broadly applicable strategy against various malignancies. While the size of our nanodrug (~400 nm in hydrodynamic diameter) is compatible with reported effective nanoparticle sizes in some models, the extent to which the enhanced permeability and retention (EPR) effect contributes to tumor accumulation in human cancers remains uncertain and will require validation in more clinically relevant models and imaging modalities.

P1, N=150, Recruiting, Shanghai Pharmaceuticals Holding Co., Ltd | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

These results indicate a synergistic interaction between tras tuzumab and blood serum in both groups. We also found significant differences in CI values between healthy donors and breast cancer patients: blood serum samples from patients enhance the effect of trastuzumab to a greater extent.

P2, N=54, Not yet recruiting, National Taiwan University Hospital

Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients...On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease...In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.