Overcoming Trastuzumab–Pertuzumab Resistance and Optimizing Sequential Anti-HER2 Therapy in HER2-Positive Metastatic Breast Cancer

HER2-positive breast cancer accounts for 15–20% of all breast cancers. The introduction of anti-HER2 therapies has markedly improved the clinical outcomes; however, overcoming drug resistance in metastatic disease remains a major challenge. This review summarizes the multilayered mechanisms of resistance to trastuzumab and pertuzumab and outlines the rationale for sequential treatment strategies based on the emerging evidence. Resistance arises through diverse and often coexisting mechanisms, including structural alterations in the HER2 receptor (e.g., p95HER2 and HER2 mutations), constitutive activation of the PI3K–AKT–mTOR pathway, and engagement of bypass signaling through receptors such as HER3 and IGF-1R, as well as immune evasion and metabolic reprogramming. Given this complexity, the strategic sequencing of agents with distinct mechanisms of action is critical beyond first-line therapy. Trastuzumab deruxtecan demonstrates substantial antitumor activity through potent cytotoxic effects and a bystander effect, supporting its efficacy in tumors with intratumoral heterogeneity or downstream pathway activation. In contrast, tucatinib-based regimens represent an important option for patients with brain metastases and tumors expressing p95HER2. The ongoing development of novel antibody–drug conjugates and bispecific antibodies is expected to further advance personalized sequential therapy targeting composite resistance mechanisms.