Revisiting HER2: Recent Research Shakes Views on Famed Marker
HER Receptors in Action
Genomic analyses have shed new light on the molecular drivers of HER activity that can activate cancer-causing pathways. Examples are illustrated above.
AR indicates amphiregulin; EGF, epidermal growth factor; HER, human epidermal growth factor receptor; HRG, heregulin; TGFα, transforming growth factor alpha; TK, tyrosine kinase.
Source: Recreated from Chang JC. Dual HER2 blockade: with and without chemotherapy. Presented at: 29th Annual Miami Breast Cancer Conference; March 14-17, 2012; Miami Beach, FL.
Currently, HER2 gene amplification guides clinical decision-making in breast cancer, and HER2-targeted drugs are only approved for use in patients designated HER2-positive. Yet new research suggests that these drugs may actually have much broader applications, benefiting patients who are not designated HER2-positive by routine testing, with far-reaching implications not just for the diagnosis and treatment of breast cancer, but for the understanding of the molecular drivers of cancers as a whole and the development of targeted therapies in general.
HER2 and Breast CancerIn 1998, trastuzumab became the first HER2-targeted therapy to be approved by the FDA for the treatment of advanced, metastatic, HER2-overexpressing breast cancer in combination with chemotherapy or as a single agent, based on pivotal clinical trials showing overall response rates of 45% and 14%, respectively. This was followed in 2006 by approval to treat early-stage HER2-positive breast cancer in combination with a chemotherapeutic regimen containing doxorubicin, cyclophosphamide, and paclitaxel, following studies demonstrating greater than 50% reduction in the risk of recurrence, second primary cancer, or death among patients treated with trastuzumab plus chemotherapy, compared with chemotherapy alone.
In the years that followed its approval, trastuzumab has been joined by several other FDA-approved HER2-targeted agents (Table 1). The clinical trials that were instrumental in gaining approval for these HER2-targeted agents indicated that their benefits were restricted to patients whose tumors exhibited overexpression of the HER2 protein or amplification of the HER2 gene. As such, administration of these drugs is dependent on the demonstration of a patient’s HER2-positive status, typically using the standard FDA-approved assays⎯fluorescence in situ hybridization, to evaluate the number of HER2 genes in a cancer cell (gene amplification), and immunohistochemistry, to examine the level of HER2 protein present on the cancer cell surface (protein overexpression) (Table 2). A third method, chromogenic in situ hybridization, also has been approved to evaluate gene expression.