As the field evolves, it is likely that HER2-directed agents will be used to an increasing extent instead of conventional chemotherapy, further reducing toxicity.
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.7
Strategies 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.
Fortunately, the success of trastuzumab has sparked the development of a series of additional HER2-directed agents. The first of these novel agents is lapatinib, a small-molecule inhibitor of the HER2 and EGFR tyrosine kinases. Lapatinib, like trastuzumab, has limited single- agent activity, and therefore has been developed largely in combinations. In a phase III registration trial, patients with HER2-positive metastatic breast cancer (MBC) whose disease had progressed on trastuzumab, an anthracycline, and a taxane were randomized to capecitabine and lapatinib or capecitabine alone. The addition of lapatinib was associated with longer time to progression although no significant benefit in overall survival.8
Patients randomized to the combination arm did have more rash and diarrhea compared with those on capecitabine monotherapy, although lapatinib was not associated with symptomatic cardiomyopathy. Lapatinib in combination with capecitabine was approved in 2007 for use in patients with HER2-positive MBC who have had prior therapy with trastuzumab, an anthracycline, and a taxane.
More recently, there have been encouraging results using doublets of HER2-targeted agents with complementary mechanisms of action, in an effort to overcome resistance to trastuzumab.
One example of this approach is the combination of lapatinib and trastuzumab, which has shown synergism in the lab and in the clinic and can be considered for select patients who have progressed on trastuzumab-based regimens, although the combination does not have FDA approval.9
Perhaps a more successful example of this “dual blockade” approach involves the use of trastuzumab combined with the monoclonal antibody pertuzumab. Pertuzumab, like trastuzumab, binds to the HER2 extracellular domain, but pertuzumab binds to a different epitope of HER2, such that both antibodies can bind simultaneously to the same HER2 molecule.
Pertuzumab also differs from trastuzumab in that pertuzumab can block the interaction between HER2 and other homologous receptors such as HER3 and EGFR. Perhaps at least in both preclinical and clinical studies, pertuzumab and trastuzumab act synergistically.
This synergism was most clearly evident in the phase III CLEOPATRA study, in which patients with previously untreated HER2-positive MBC were randomized to docetaxel, trastuzumab, and either pertuzumab or placebo. The addition of pertuzumab was associated with an unprecedented 15.7-month improvement in overall survival,10 with only a relatively modest increase in toxicity, principally rash and diarrhea.
This study led to the approval of the pertuzumab/trastuzumab/taxane combination in the first-line setting and, based on the magnitude of the benefit, should be considered the standard of care for most such patients.
Pertuzumab/trastuzumab-based therapy has also been approved for use in the neoadjuvant setting in combination with chemotherapy. An adjuvant study evaluating the combination is under way.
A third approach to overcoming trastuzumab resistance has been through the use of the novel antibody drug conjugate trastuzumab emtansine(previously known as T-DM1). Trastuzumab emtansine consists of the trastuzumab antibody covalently linked to a highly potent antimitotic agent. Trastuzumab emtansine exploits trastuzumab’s ability to specifically bind to the overexpressed HER2 on the surface of these cancers, thus delivering large amounts of the cytotoxic agent selectively to the cancer cells. Because the cytotoxic agent is tethered to the antibody, normal tissues are largely spared from its toxicity.
Trastuzumab emtansine was definitively evaluated in the phase III EMILIA trial, in which patients with HER2-positive MBC who had previously received trastuzumab and a taxane were randomized to trastuzumab emtansine or capecitabine and lapatinib. In this population, treatment with trastuzumab emtansine was associated with longer progression-free and overall survival compared with capecitabine and lapatinib.11 In a second phase III trial, trastuzumab emtansine was superior to physician’s choice of therapy in patients with HER2-positive MBC who had progressed on both trastuzumab and lapatinib.12
In both studies, patients receiving trastuzumab emtansine had fewer significant adverse events than those on the comparator arm.
Notably, trastuzumab emtansine does not typically cause alopecia or neutropenia, and rates of nausea, neuropathy, and significant fatigue are low.13 Thrombocytopenia and transaminase elevations are the most common significant toxicities, but these are typically asymptomatic and respond to dose reductions. Based on this favorable efficacy and tolerability profile, trastuzumab emtansine was approved for use in patients with HER2-positive MBC in the secondand later-line setting and should be considered the standard of care for this population.
A better understanding of the biology of HER2-positive breast cancer has led to the development of a number of HER2-targeted agents that together have dramatically improved outcomes for patients with this disease. Because of the selectivity of these agents, their improvements in efficacy typically do not come at the cost of substantially increased toxicity.
As the field evolves, it is likely that these and other HER2-directed agents will be used to an increasing extent instead of conventional chemotherapy, further reducing toxicity. Together, these therapeutic advances have transformed a breast cancer subtype that was associated with one of the worst outcomes into one associated with a very favorable prognosis.