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Revisiting HER2: Recent Research Shakes Views on Famed Marker

By Jane de Lartigue, PhD
Published Online: Wednesday, June 5, 2013

HER Receptors in Action

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.

At least 20% of patients with breast cancer have tumors that demonstrate amplification of the gene encoding the human epidermal growth factor receptor (HER)-2 protein, a receptor tyrosine kinase. The development of a monoclonal antibody targeting HER2, trastuzumab (Herceptin), has had a huge impact on the survival of this population of patients.

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 Cancer

In 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.

Table 1. Approved HER2-Targeting Therapies for Breast Cancer

Agent Breast Cancer Indicationsa
(all approved for HER+ patients)
Company Initial FDA Approval
Trastuzumab (Herceptin) • Adjuvant treatment with chemotherapy or as single agent after multimodality therapy
• MBC with chemotherapy in first line or as single agent after chemotherapy
Genentech 1998
Lapatinib (Tykerb) • Advanced BC or MBC with capecitabine after prior therapy including trastuzumab
• Postmenopausal women with HR+ MBC in combination with letrozole
GlaxoSmith- Kline 2007
Pertuzumab (Perjeta) • MBC in combination with trastuzumab and docetaxel in patients with no prior anti-HER2 or chemotherapy for metastatic disease Genentech 2012
Ado-trastuzumab emtansine, or T-DM1 (Kadcyla) • MBC as single agent after prior trastuzumab and taxane-based therapy, or disease recurrence within 6 months of adjuvant therapy Genentech 2013

aHerceptin also is indicated for HER2+ gastric cancer.
BC indicates breast cancer; HER2+, patients overexpressing HER2 based on FDA-approved testing; HR+, hormone receptor-positive; MBC, metastatic breast cancer.

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