Maximizing Human Epidermal Growth Factor Receptor 2 Inhibition: A New Oncologic Paradigm in the Era of Targeted Therapy

ERBB2 (HER2) amplification in breast cancer is a classic example of oncogene addiction in solid tumor oncology; most human epidermal growth factor receptor 2 (HER2) –positive tumors exhibit dependency on signaling pathways downstream of the HER2 receptor tyrosine kinase, even after developing resistance to anti-HER2 drugs. Trastuzumab is a monoclonal antibody that inhibits HER2 and demonstrates efficacy in both treatment-naive patients and those who progress after a prior trastuzumab-based regimen. Serial administration of anti-HER2 therapies in clinical practice has dramatically altered the natural course of HER2positive breast cancer. Previously considered to have a worse prognosis, women with HER2-amplified breast cancer who receive trastuzumab now experience survival outcomes similar to those with HER2-negative disease. Furthermore, recent studies suggest that dual HER2 inhibition (the administration of two anti-HER2 therapeutics simultaneously) may induce more durable tumor responses than sequential HER2-specific monotherapy. In Journal of Clinical Oncology, Cortes et al demonstrate the value of persistent HER2 blockade by reporting a clinical benefit rate of 41.2% after combined treatment with the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in patients with evidence of disease progression while receiving either of the two agents alone. This noteworthy observation suggests that the traditional oncologic paradigm—in which most drugs are used only once and discontinued permanently at the first sign of progression—may require modification in the era of targeted therapy. HER2 is a member of the HER family of transmembrane receptors, which also includes epidermal growth factor receptor, HER3 (ERBB3), and HER4 (ERBB4). In normal tissue, HER proteins mediate cell growth signals transmitted between stromal and epithelial cells. Unlike other members of the family, HER2 does not interact directly with the growth factor ligand. Instead, the receptor functions by a ligand-independent dimerization mechanism that primes HER2 for associations with both itself and other HER kinase family members. In HER2-amplified breast cancers, the overabundance of membrane HER2 further potentiates this ligand-independent mechanism, resulting in “addiction” to HER2 signaling for tumor cell survival. In particular, overexpression of HER2 results in increased HER2 homoand heterodimer formation and augmented signaling through intracellular cascades such as the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathways (Fig 1). Contrary to HER2, HER3 has an impaired intracellular kinase and lacks significant biologic activity when expressed alone. However, when HER3 undergoes heterodimerization with HER2, a potent oncogenic signal may result. The HER2:HER3 heterodimer functions as the most transforming and mitogenic receptor complex of the HER family of proteins and is a robust activator of PI3K pathway signaling. The expression of HER3 can be a rate-limiting step for HER2induced cell growth, because HER2-amplified breast tumors undergo apoptotic cell death when HER3 expression is suppressed. Clinically, patients with high levels of HER2:HER3 heterodimers and low levels of HER2 homodimers exhibit a diminished response to trastuzumab therapy. The dependence on HER2 and pathogenesis of HER2: HER3 heterodimers in HER2-amplified breast cancer provide a scientific rationale for targeting both HER2 and HER3 in the clinical setting (Fig 1). Sequential HER2 blockade aims to achieve an extended and diversified therapeutic blockade of this oncogenic receptor tyrosine kinase. However, as seen in the modest activity of singleagent treatment, demonstrated by Cortes et al and others, repetitive HER2-specific monotherapy is often insufficient to engender long-lasting responses in patients who progress while receiving trastuzumab-based regimens. Trastuzumab-DM1 and pan-HER agents are notable exceptions with reasonable singleagent activity, but these drugs are probably more synonymous to combination treatment than to monotherapy. Trastuzumab-DM1 harnesses the effects of HER2 blockade through its trastuzumab component and simultaneously delivers the cytotoxic agent DM1, and pan-HER drugs are known to affect multiple kinases. Several mechanisms of resistance to single-agent HER2 inhibition have been proposed, including alterations affecting the HER2 receptor, increased interactions with both HER proteins and other membrane-bound receptors, and alternative activation of oncogenic signaling networks such as the PI3K pathway. Dual anti-HER2 regimens, in contrast to monotherapy, show excellent synergy and improved outcome in patients previously JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 30 NUMBER 14 MAY 1