Targeting HER2-positive breast cancer: advances and future directions

Abstract

The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug -the monoclonal antibody trastuzumab -almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2targeted therapy and new therapeutic approaches and agents, including Nature Reviews Drug Discovery Review articlethan half of patients with metastatic HER2 + disease are diagnosed de novo, further demonstrating that most patients presenting with early disease are cured 6 .However, despite this success, metastatic HER2 + tumours inevitably develop resistance, leading to disease progression. As such, the goal of therapy in HER2 + BC is to expand the number of patients cured in the early setting and prevent recurrence. 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. 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.Advances in targeting HER2 include further exploitation of antibody-drug conjugates (ADCs), altering the linkers, payload or antibody scaffold to optimize efficacy 7,8 . Another approach is the development of bispecific antibodies, which use binding of two different HER2 epitopes to maximize efficacy 9 . As immunotherapy has shown benefit in triple-negative breast cancer (TNBC), attempts to mobilize the immune system in HER2 + disease are also ongoing. Immunotherapy is being approached from various angles including administering

Cancer of unknown primary (CUP) through the lens of precision oncology – a single institution perspective

“…Importantly, HER2 has been recognised as an important therapeutic target in various malignancies including breast, colorectal, gastric and biliary tract cancers. Targeting HER2 as a highly sensitive therapeutic agent was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer almost 25 years ago (29,30). On this basis, a variety of novel HER2-targeted drugs are under development, and related clinical trials are ongoing (31)(32)(33)(34)(35) PIK3CA is a member of the phosphoinositide-3-kinases (PI3Ks) family class I (dimers of regulatory-and catalytic subunit), which are lipid kinases that phosphorylate the inositol ring of phosphoatidylinositol (Prdlns) (36).Targeting PIK3CA mutant cancers is complex.…”

Demystifying the Role of Prognostic Biomarkers in Breast Cancer through Integrated Transcriptome and Pathway Enrichment Analyses

“…Therefore, current standard-of-care biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) provide important prognostic and predictive information in case of breast cancer [ 45 ]. For example, HER2-positive breast cancer is typically treated with targeted therapy, such as trastuzumab, while ER-positive breast cancer may be treated with endocrine therapy [ 46 ]. In addition, Oncotype DX is a widely used biomarker that provides prognostic information for patients with early-stage breast cancer and can help in guide treatment decisions [ 47 ].…”

Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling

“…Due to the high expression of HER2 in tumors such as breast cancer, several novel therapeutic strategies, including the administration of small-molecule inhibitors and monoclonal antibodies, have significantly improved patient survival. Currently, the main small-molecule drugs that effectively target HER2 are ATP-competitive inhibitors, including Tucatinib , Lapatinib, Neratinib (HKI-272), and Pyrotinib, which compete with ATP to block phosphorylation and activate downstream signaling cascades [ 78 ]. Notably, Tucatinib ( 5f ) is a selective HER2 inhibitor containing azaindole scaffold, which is also the focus of the next discussion ( Figure 5 ).…”