Tailoring Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer: Recent Advances and Strategies
Francisco J. Esteva, MD, PhD and Elena Katz, MD
JCO Oncology Practice 2024

Amplification of the human epidermal growth factor receptor 2 (HER2, ErbB2) gene leads to persistent activation of signaling pathways that enhance cell proliferation, resistance to apoptosis signals, heightened cell motility, and the induction of angiogenesis.1-3 HER2-positive breast cancer is known for its aggressive behavior and tendency to metastasize. The approval of trastuzumab, the first humanized anti-HER2 monoclonal antibody, revolutionized the treatment and prognosis of this subtype.4 As our understanding of tumor biology and HER2 signaling has improved, additional therapies targeting HER2 have been approved, including monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors.5 Neoadjuvant HER2-targeted therapy, also known as preoperative treatment, is now the preferred approach for patients with locally advanced breast cancer (clinical stage IIB-IIIC according to American Joint Committee on Cancer eighth edition criteria) and for operable tumors larger than 2 cm.6,7 The neoadjuvant approach in operable breast cancer is particularly attractive because of the high probability of pathological complete response (pCR) and the opportunity to tailor postoperative treatment on the basis of the pathological response at the time of surgery.8 It also increases the utilization of breast-conserving surgery and limits treatment to the axilla in patients who achieve clinical response.9 Moreover, the neoadjuvant setting allows for adaptive de-escalation strategies in the research realm.10 In addition to HER2, the estrogen receptor (ER) and progesterone receptor (PR) status of the tumor affects decision making in the neoadjuvant setting because ER/PR-negative tumors are more likely to achieve pCR.11,12 In this review, we provide a concise overview of neoadjuvant systemic therapy in early-stage HER2-positive breast cancer, with a focus on various chemotherapy backbones and deescalation strategies.