Ian E. Krop, MD, PhD
Director of Clinical Research
Breast Oncology Center
Dana-Farber Cancer Institute
HER2 is a cell-surface tyrosine kinase that potently activates multiple tumorigenic cell-signaling pathways including PI3-kinase and ras/MAP kinase. Approximately 20% of primary breast cancers have amplification of the HER2
gene, leading to marked overexpression of HER2 protein, often to over 1 million copies per cell.
These cancers, termed HER2-positive, tend to be highly proliferative and, in the absence of effective adjuvant therapy, have significantly higher rates of recurrence and death than cancers without HER2 amplification. This adverse prognostic effect of HER2 is independent of other standard histopathological features.Trastuzumab Makes Mark
In the 1990s, an understanding of the tumorigenic effects of HER2 signaling and the observation that HER2 amplification was associated with a poor prognosis led to the hypothesis that agents targeting HER2 may be an effective therapeutic approach in this subtype of breast cancer. This hypothesis was first tested using trastuzumab, a humanized monoclonal antibody specific for the extracellular domain of HER2.
In a pivotal phase III trial in which patients with metastatic HER2-positive cancers were randomized to chemotherapy alone or to chemotherapy with trastuzumab, the addition of trastuzumab led to significant improvements in progression-free and overall survival.1
This study led to the FDA approval of trastuzumab in 1998. Interestingly, unlike other tyrosine kinase inhibitors such as crizotinib and erlotinib, which are highly active as single agents in their respective tumor targets, trastuzumab has only modest monotherapy activity (objective response rate 23%-35%) in HER2-positive cancers.2,3
In contrast, trastuzumab is highly synergistic with a range of chemotherapeutic agents, making the combination of trastuzumab and chemotherapy the preferred approach to using this agent in most patients.
Based on the impressive success of trastuzumab in patients with metastatic disease, trastuzumab was subsequently evaluated in the adjuvant setting in patients with early-stage HER2-positive cancers. In several large randomized trials, predominantly in patients with lymph node–positive disease, the addition of 1 year of trastuzumab therapy to combination chemotherapy (either anthracycline/taxane, or taxane/carboplatin) was associated with an approximately 40% decrease in the number of patients dying from breast cancer.4-6
The addition of trastuzumab did lead to a small incidence of symptomatic cardiomyopathy (up to 4%), predominantly in patients who received anthracycline-based therapy, but it otherwise was very well tolerated.
Based on these results, trastuzumab was approved in 2006 for use in combination with chemotherapy for patients with high-risk HER2-postive early breast cancer. A more recent study led by investigators from Dana-Farber Cancer Institute evaluated a regimen using just a single chemotherapy agent, weekly paclitaxel, with a year of trastuzumab in 406 patients with lower risk HER2-positive cancers (tumor ≤3 cm and node negative). They demonstrated that this well-tolerated regimen was associated with very favorable outcomes (3-year disease-free survival of 98.7%), suggesting that this approach is very appropriate for this patient population.7Strategies for Attacking Resistance
Although the introduction of trastuzumab has markedly improved outcomes for patients with HER2-positive cancers, resistance to this agent is a significant problem. A subset of patients with early-stage disease still develop recurrence despite adjuvant chemotherapy and trastuzumab, and patients with metastatic disease virtually all eventually develop progressive disease.Lapatinib