Optimal treatment of early stage HER2‐positive breast cancer

Abstract

Significant advances have occurred in the treatment of human epidermal growth factor receptor 2 (HER2)‐positive breast cancer that have changed its natural history. The addition of trastuzumab to standard therapy has dramatically improved the prognosis for patients with early stage, HER2‐positive breast cancer to unprecedented survival outcomes. Yet, long‐term follow‐up data from adjuvant pivotal trials indicate that 15‐24% of patients still develop recurrent disease. Most of the research has focused on the addition of novel anti‐HER2 drugs to standard therapy, including studies evaluating the monoclonal antibody pertuzumab; the antibody‐drug conjugate trastuzumab‐emtansine (T‐DM1); the selective, reversible HER2/epidermal growth factor receptor kinase inhibitor lapatinib; or the irreversible pan‐HER2 inhibitor neratinib. Dual HER2 blockade has improved overall survival remarkably in metastatic breast cancer; however, in patients with early stage disease, it has led to small benefits in progression‐free survival. Moreover, biologic heterogeneity within HER2‐positive disease may determine response to treatment and prognosis. Different subgroups of patients with HER2‐positive breast cancer may benefit from different therapeutic approaches. Thus, there is ongoing work to optimize and de‐escalate treatment in patients who may do just as well with less therapy and can avoid unnecessary treatments and their related toxicities. The objective of this review is to summarize the background and latest evidence on the current management of early stage, HER2‐positive breast cancer and to present novel perspectives on its management.

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

“…These subclones harbour alternative and/or collaborative drivers of carcinogenesis, which circumvent the blockade of the HER2‐driven pathways. The high prevalence of both intrinsic and acquired resistance to single‐agent treatment regimens already caused a shift towards dual HER2‐targeted therapy, such as pertuzumab or T‐DM1 (Konecny, 2013; Pernas et al , 2018).…”

“…The series of pathogenic and likely pathogenic somatic variants that we describe here yields a wide range of potential alternative drivers of cancer cell proliferation and invasion. Moreover, some genetic anomalies (such as PIK3CA and GATA3 mutations, or FGFR1 copy number gain) might drive resistance to treatment (Pernas et al , 2018; Turner et al , 2010).…”

“…These subclones harbour alternative and/or collaborative drivers of carcinogenesis, which circumvent the blockade of the HER2-driven pathways. The high prevalence of both intrinsic and acquired resistance to single-agent treatment regimens already caused a shift towards dual HER2-targeted therapy, such as pertuzumab or T-DM1 (Konecny, 2013;Pernas et al, 2018). Interestingly, 5-41% of HER2-positive breast cancers present with regional heterogeneous HER2 amplification (Cottu et al, 2008;Ng et al, 2015), although this percentage depends on the applied definition.…”

Inhibition of HER2‐Positive Breast Cancer Growth by Blocking the HER2 Signaling Pathway with HER2‐Glycan‐Imprinted Nanoparticles

“…Current clinical treatment of early stage HER2+ breast cancer mainly relies on monoclonal antibodies and tyrosine‐kinase inhibitors . For example, the monoclonal antibody pertuzumab binds the extracellular sub‐domain II, blocking the dimerization of HER2 with other EGFR family members, such as HER3, and thereby inhibiting the downstream signaling pathways .…”

Inhibition of HER2‐Positive Breast Cancer Growth by Blocking the HER2 Signaling Pathway with HER2‐Glycan‐Imprinted Nanoparticles

“…Current clinical treatment of early stage HER2 + breast cancer mainly relies on monoclonal antibodies and tyrosinekinase inhibitors. [7] Fore xample,t he monoclonal antibody pertuzumab binds the extracellular sub-domain II, blocking the dimerization of HER2 with other EGFR family members, such as HER3, and thereby inhibiting the downstream signaling pathways. [8] While tyrosine-kinase inhibitors,s uch as lapatinib and neratinib,b ind the intracellular domain, suppressing the autophosphorylation of tyrosine and leading to growth inhibition of HER2 + cancer cells.…”