HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers. Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers.
To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family. The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation.
Amplification of the HER2 gene and/or overexpression at the messenger RNA or protein level occurs in about 20% of patients with early stage breast cancer. Before the advent of HER2-directed therapies, this increased level of HER2 was associated with high recurrence rates and increased mortality in patients. The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing now.
The monoclonal antibody trastuzumab is currently the only approved adjuvant treatment specifically for patients with HER2-positive early stage breast cancer. Trastuzumab is recommended by both US (National Comprehensive Cancer Network[NCCN]) and European (St Gallen) guidelines for use as monotherapy after completion of chemotherapy, and in combination with paclitaxel or docetaxel after completion of doxorubicin plus cyclophosphamide, or given concurrently with carboplatin and docetaxel. These recommendations are based on results of four large ongoing trials, in addition to several smaller trials. Results of individual studies are supported by a recent meta-analysis that included six randomized clinical trials and showed that the combination of trastuzumab with adjuvant chemotherapy produced a significant benefit in disease-free survival (DFS; odds ratio [OR] = 0.69), overall survival (OR = 0.78), locoregional recurrence (OR = 0.53), and distant recurrence (OR = 0.62), as compared to chemotherapy alone.
Lapatinib is the only treatment, other than trastuzumab, approved specifically for patients with HER2-positive advanced-stage breast cancer. Lapatinib reversibly inhibits the intracellular tyrosine kinase activity of both HER2 and EGFR (also known as HER1), suppressing tyrosine autophosphorylation and thereby downstream pathways, such as the MAPK/Erk1/2 and PI3K/Akt pathways.
Importantly, preclinical studies showed that lapatinib could inhibit the growth of HER2-positive breast cancer cells that were resistant to trastuzumab (including those with truncated HER2 receptors), and that lapatinib could enhance the apoptotic effect of anti-HER2 antibodies. These findings suggested that lapatinib might have additive or even synergistic activity if combined with trastuzumab, and that it might have activity in patients with disease resistant to trastuzumab.
Early clinical trials indicated modest clinical activity (response rates <10%) for single-agent lapatinib in patients whose disease had progressed when receiving trastuzumab, but the combination of lapatinib and capecitabine showed significantly superior efficacy compared to capecitabine alone in such patients.
Although chemotherapy has shown to be an efficient strategy for adjuvant therapy in colorectal cancer, it is still not capable of preventing recurrence in all patients. Therefore there is numerous ongoing research for alternative compounds to be used as adjuvant therapy. Monoclonal antibodies and other biologicals, targeting tumor-associated proteins and blocking essential processes of the tumor, are extensively studied. A crucial step in this process is the identification of tumor specific proteins that can be targeted by these compounds. One of these targets is HER2, which is primarily associated with breast cancer.
Several studies evaluating HER2 in colorectal cancer resulted in a large debate at the end of the last century because overexpression rates varied between zero and 84%.15 Also the clinical significance of HER2 in these publications was not consistent, with some publications associating HER2 overexpression to survival, while others failed to find such a correlation. Most researchers agreed that the differences in expression were likely due to differences in technical approaches, antibodies, and scoring protocols, but conclusive data were never presented. Since then a large number of immunohistochemical studies have emerged about HER2 in colorectal cancer. The majority showed membranous overexpression rates between zero and 15%. Remarkably, some studies reported both membranous and cytoplasmic overexpression with much higher rates up to 60%. Up to now, there is no consistency about the proportion o HER2-overexpression in colorectal tumors.
Because symptoms are usually absent, 70 to 80% of patients with ovarian cancer will have advanced disease at the time of diagnosis. Despite an initial good response to first-line combination chemotherapy (taxane/platinum), relapses are frequent because of acquired chemoresistance. The use of new targeted therapies that are potentially effective in a subset of patients may be of great value.
Trastuzumab (Herceptin®, F. Hoffmann-La Roche, Basel, Switzerland) is a humanized monoclonal antibody that targets the HER2 extracellular domain and inhibits HER2-positive tumor cell proliferation. It is effective alone and in combination with chemotherapy in patients with breast cancer whose tumors express high levels of HER2 protein. The benefits of trastuzumab have been demonstrated in both metastatic and adjuvant treatment settings.
Observed rates of HER2 overexpression/amplification in ovarian carcinomas show considerable variation between studies, ranging from 8% to 66%. Single-agent trastuzumab therapy was associated with a low response rate (7%) in a series of heavily pretreated patients with ovarian cancer, but the efficacy of trastuzumab in combination with chemotherapy has not been tested in this setting.
1. Arteaga C L et al. Treatment of HER2-positive breast cancer: current status and future perspectives[J]. Nature reviews Clinical oncology, 2012, 9(1): 16-32.
2. Blok E J et al. Cytoplasmic overexpression of HER2: a key factor in colorectal cancer[J]. Clinical Medicine Insights. Oncology, 2013, 7: 41.
3. Tuefferd M et al. HER2 Status in Ovarian Carcinomas: A Multicenter GINECO Study of 320 Patients. Huang S, ed. PLoS ONE. 2007;2(11):e1138.