Towards personalized treatment for early stage HER2-positive breast cancer

Abstract

Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody-drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.

Fig. 1 |. Signalling by HER2 and other HER family members and the clinically approved HER2-targeted agents.

a | The HER family of receptor tyrosine kinases consists of four receptors: EGFR (HER1), HER2, HER3 and HER4. Activation of signalling through all of the HER proteins, except HER2, is induced by ligand binding. Upon ligand binding, these receptors undergo conformational changes leading to the formation of homodimers or heterodimers. HER2 lacks any known ligands but has a conformation that is conducive to dimerization and can thus be activated through homodimerization, when it is overexpressed, or heterodimerization with other ligand-bound members of the HER family. HER3 has a catalytic domain with very lower levels of intrinsic kinase activity, but is known to promote potent signalling through heterodimerization with other HER family members. Dimerization of HER protein results in transphosphorylation of specific tyrosine residues in their intracellular domains, which in turn activates downstream signalling cascades, including the PI3K−AKT and MAPK (ERK) pathways. These signalling pathways mediate diverse cellular activities, including those controlled by transcription factors that regulate the transcription of multiple genes associated with survival and proliferation. b | Five HER2-targeted agents are currently approved for the treatment of patients with HER2+ breast cancer, which are categorized as monoclonal antibodies (trastuzumab and pertuzumab), small-molecule tyrosine kinase inhibitors (lapatinib and neratinib) or antibody–drug conjugates (trastuzumab emtansine, also known as T-DM1). Trastuzumab and pertuzumab are monoclonal antibodies that bind to the extracellular domain of the HER2 receptor. These agents are often combined together or administered sequentially to more comprehensively inhibit HER signalling and counter the distinct mechanisms of resistance associated with different classes of agents.

Fig. 2 |. Major mechanisms of resistance to HER2-targeted therapy.

One of the foremost reasons for resistance of breast cancers to HER2-targeted therapy relates to the lack of complete survival dependence of all tumour cells present in the patient on HER2 signalling. This phenomenon could be attributed to intratumour HER2 heterogeneity, whereby both HER2-amplified and non-amplified tumour cell populations co-exist within a clinically HER2-positive (HER+) tumour. While the HER2-amplified and addicted cells of such heterogeneous tumours can be effectively eradicated using biological anti-HER2 agents, including antibody–drug conjugates (ADCs) that target the HER2 receptor and deliver a cytotoxic drug specifically to the HER2+ cells, the non-HER2-amplified cells will continue to thrive, ultimately manifesting as treatment resistance. For tumours with intratumour HER2 heterogeneity, continued use of chemotherapy together with anti-HER2 therapy is required, until the alternative molecular drivers are elucidated. In tumours with homogeneous HER2-amplification, resistance to HER2-targeted therapy can arise owing to alterations in the HER signalling pathway itself or the activation of alternative bypass signalling pathways supporting cell survival or proliferation. Mutations affecting HER2 itself (such as the activating L755S mutation) or the downstream kinase PI3K (encoded by PIK3CA) and/or low levels of the inhibitory protein PTEN^– provide mechanisms by which survival and proliferative signalling through the HER family receptors or their downstream pathways can be reactivated. Aberrations of HER2 that generate alternative forms of the receptor, such as the truncated protein p95HER2 and the splice variant Δ16HER2, can also mediate resistance to HER2-targeted therapies through loss of the epitopes recognized by therapeutic antibodies or by promoting dimerization and thus constitutive signalling. When the HER receptor network is effectively inhibited, however, resistance can arise owing to the emergence of several genomic and adaptive ‘escape’ mechanisms. These include crosstalk with transcription factors, such as the oestrogen receptor α (ERα)^,, activation of alternative cell-surface receptors (including other receptor tyrosine kinases (RTKs) or β-integrin)^–, amplification of signalling adapter proteins (for example, those of the insulin receptor substrate (IRS) family^,) or alterations in components of downstream signalling pathways, such as SRC and FAK. Resistance can also be caused by upregulation of membrane-associated mucin glycoproteins, which can interact with HER2–HER3 complexes and/or can mask the extracellular regions of HER2 and thus restrict the accessibility of this protein to drugs, particularly monoclonal antibodies^,. Additionally, proliferative signalling can originate from metabolic pathways, such as the fatty acid synthesis^, and mevalonate pathways^,, supporting the survival and the emergence of resistance to therapy in tumour cells. Finally, tumour immune infiltrates, including lymphocytes, natural killer (NK) cells and dendritic cells, have also been reported to modulate responses and resistance to HER2-targeted therapy^–.

Fig. 3 |. Pathological complete response rates stratified by ER status and treatment arm in clinical trials of neoadjuvant HER2-targeted therapy for HER2+ breast cancer.

a | Pathological complete response (pCR) rates observed with HER2-targeted therapy in combination with chemotherapy. b | pCR rates observed with HER2-targeted therapy, plus endocrine therapy for the oestrogen receptor-positive (ER+) patient subgroups, without chemotherapy. For some trials, ER status actually reflects the hormone receptor status (that is, positive or negative for ER and/or progesterone receptor expression). L, lapatinib; P, pertuzumab; T, trastuzumab. ^aDocetaxel and carboplatin plus T + P. ^b5-fluorouracil, epirubicin and cyclophosphamide plus T + P followed by docetaxel plus T + P. ^c5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel plus T + P, ^dChemotherapy-free arm