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 HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.

Fig. 1. Evolution of HER2 as a biomarker and target for treatment for breast cancer.

Timeline of preclinical discovery milestones for HER2 biology and regulatory approval for anti-HER2 therapies. A, adjuvant setting; M, metastatic setting; N, neoadjuvant setting; +, approved in China only; *, M. Bishop and H. Varmus awarded Nobel Prize in 1989 for this discovery; **, S. Cohen and R. Levi-Montalcini awarded Nobel Prize in 1986 for discovery of growth factors and their receptors.

Fig. 2. Select mechanisms of HER2-targeted resistance.

a, Mutations and/or alterations in the HER family of receptors that lead to activation of downstream signalling pathways. (1) Mutations in HER2 leading to P13K–AKT and RAS–MAPK pathway activation. (2) Co-occuring mutations in HER2 and HER3 leading to PI3K–AKT pathway activation. b, Loss of HER2 extracellular domain in cells overexpressing p95^HER2 receptor. Masking of the trastuzumab-binding site on HER2 owing to overexpression of mucin 4 (MUC4) and CD44–polymeric hyaluronan complex. (3) p95^HER2 overexpression. (4) MUC4 overexpression and CD44–polymeric hyaluronan complex. c, Activation of compensatory pathways. (5) Mutations in HER2 promote MEK–ERK signalling, which activates CDK2 kinase. (6) PIK3CA mutations lead to P13K–AKT pathway activation. (7) Cyclin D1 gene overexpression leads to resistance to anti-HER2 therapies. d, Heterogeneous expression of the HER2 receptor in tumours leads to decreased sensitivity to HER2-targeted therapies that are dependent on overexpression of HER2. ER, oestrogen receptor.

Fig. 3. Immune strategies that target HER2⁺ MBC.

a, Immune-stimulating antibody conjugate (ISAC). (1) ISAC binds to cognate tumour-associated antigen (TAA). (2) Fc receptor-dependent phagocytosis of the tumour cell by myeloid antigen-presenting cell (APC). (3) Toll-like receptor (TLR)-mediated activation of the myeloid cells leads to chemokine and/or cytokine secretion and enhanced antigen presentation. (4) T cell priming by expression of major histocompatibility complex (MHC)–tumour peptide on myeloid cells and expansion of activated T cells. (5) Chemokines attract immune effector cells. Increased myeloid APC phagocytosis. Migration of activated T cells to the tumour and killing of tumour cells. b, Chimeric antigen receptor–macrophage (CAR-M). (1) Targeting of CAR-M to tumour cell expressing the antigen leads to its activation. (2) Phagocytosis of the tumour cell by CAR-M. (3) CAR-M activates the tumour microenvironment (TME) and primes T cells. (4) Primed T cells induce antitumour immune response. c, Radiation plus checkpoint inhibitor. (1) Exposure to radiation results in release of chemokines from tumour cells. (2) Migration of CXC chemokine receptor type 6 (CXCR6)-expressing T cells attracted by chemokines to tumour. (3) Addition of anti-CTLA4 antibody helps to neutralize the CTLA4-mediated inhibition of T cell activation. Activated T cells cause tumour cell lysis. d, (1) HER2-engineered toxin body (ETB) binds to HER2 receptor, followed by (2) forced internalization, (3) intracellular self-routing and (4) ribosome inactivation.

Fig. 4. Structure and mechanism of action of a HER2–CD3 bispecific antibody.

a, Structure of HER2–CD3 bispecific antibody with ‘knobs-in-hole’ technology. b, Mechanism of action of a HER2–CD3 bispecific antibody. Step 1: binding of HER2–CD3 bispecific antibody to HER2 on tumour cell and CD3 on T cell. Step 2: activation of T cell causing release of cytokines (TNF and interferon-γ (IFNγ)). Step 3: tumour cell lysis.