![]() ![]() ![]() Subsequently, in 1986 Cohen and Rita Levi-Montalcini were jointly awarded the Nobel Prize in Physiology or Medicine for the discovery of growth factors (see Related links: ). Demonstration that the EGF receptor (EGFR) formed complexes after EGF binding was postulated to be the initial step for cell growth 1. In 1962, Stanley Cohen discovered the protein responsible for incisor and eyelid opening in mice, termed epidermal growth factor (EGF), thus beginning the journey from bench to bedside for HER2-targeted therapy 237, 238. As HER2 is such a sensitive target, continued investigation to advance therapeutic benefit will undoubtedly lead to improvements in survival. ![]() A survey of the landscape of platforms being used to maximize HER2-targeted therapeutic efficacy are enumerated, which includes mAbs, tyrosine kinase inhibitors (TKIs), ADCs, bispecific antibodies, immune system targeting agents, cellular therapy and targeted protein degraders. This Review summarizes the successful therapeutic approaches approved for treatment of HER2 + BC, which are essential to understanding ensuing developments, exploring the potential areas of drug resistance that are the foundation for future drug development. Immunotherapy is being approached from various angles including administering checkpoint inhibitors, linking effector T cells to HER2 antibodies, cellular therapy and vaccines 9, 10, 11, 12. As immunotherapy has shown benefit in triple-negative breast cancer (TNBC), attempts to mobilize the immune system in HER2 + disease are also ongoing. Another approach is the development of bispecific antibodies, which use binding of two different HER2 epitopes to maximize efficacy 9. Therefore, extensive research is ongoing in the preclinical, translational and clinical arenas to develop original and more potent therapies for this exceptionally sensitive target, HER2.Īdvances in targeting HER2 include further exploitation of antibody–drug conjugates (ADCs), altering the linkers, payload or antibody scaffold to optimize efficacy 7, 8. In those HER2 + cancers that do present with de novo stage IV disease or ultimately recur, development of novel therapies is needed as these tumours continue to be dependent on HER2 signalling. As such, the goal of therapy in HER2 + BC is to expand the number of patients cured in the early setting and prevent recurrence. However, despite this success, metastatic HER2 + tumours inevitably develop resistance, leading to disease progression. More than half of patients with metastatic HER2 + disease are diagnosed de novo, further demonstrating that most patients presenting with early disease are cured 6. Currently, survival rates exceed 90% in HER2 + early breast cancer (EBC) treated with chemotherapy and dual antibody therapy 5. The dependence of the tumour on HER2, coupled with effective HER2-targeted drugs such as trastuzumab, pertuzumab and most recently, tucatinib and trastuzumab deruxtecan (T-DXd), have contributed to these survival improvements in patients with HER2-positive (HER2 +) BC 4. However, newer and novel therapeutic strategies have led to markedly improved survival outcomes. Advanced BC was considered incurable, and treatment was purely palliative. Until this point, triple-negative and HER2-overexpressing disease were widely regarded as the most aggressive BC histologies, with unfavourable prognoses. The discovery that amplification or overexpression of HER2 was associated with extremely poor survival in BC ultimately led to the development of a monoclonal antibody (mAb) to HER2, trastuzumab 3 (Box 1). The field was energized in 1978 when the first tyrosine kinase, epidermal growth factor receptor (EGFR), was discovered followed by the identification of the neu or HER2 (also known as ERBB2) gene in 1984 1, 2. Innovations in pathology, molecular biology and drug development have enabled HER2-positive breast cancer (BC), a historically aggressive subtype, to become one with impressive outcomes. ![]()
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