HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).
Trastuzumab
Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV). Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.56 Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.60,61
An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.28,57,60–63
Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).
Pertuzumab
Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2).
This dimerization is now a well-known mechanism of tumor resistance to trastuzumab; hence, co-administration of pertuzumab potentially prevents or delays such resistance.64 The use of pertuzumab alone without trastuzumab is not currently recommended and does not confer significant clinical activity. The most notable adverse effects of this drug are infusion reactions and diarrhea. As pertuzumab is always given with trastuzumab, the same caution for cardiotoxicity must be exercised, and cardiac function evaluation and monitoring, as described for trastuzumab, is recommended. However, there is no evidence of increased cardiac dysfunction when pertuzumab is added to trastuzumab.64
Ado-Trastuzumab Emtansine
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3).
In addition to the mechanisms of action of bare trastuzumab, T-DM1 adds significant cytotoxicity by way of releasing the maytansine moiety (DM1) intracellularly. It also exerts some bystander effect by disseminating locally to nearby cells that may express lower HER2 density (Figure 4).65,66
Aside from infusion reactions and cardiotoxicity that are mostly related to trastuzumab, this drug has adverse effects related to its cytotoxic component DM1. The most notable adverse effects include thrombocytopenia, which is attributable to uptake of the drug in the marrow by Fc-bearing megakaryocytes, and hepatotoxicity via drug binding to HER2 on hepatocytes and subsequent activation of cytokine-releasing Kupffer cells.67,68 Neuropathy due to DM1 has also been reported, but the overall incidence of grade 3/4 adverse effects remains very low and the agent is generally very well tolerated.66 Cardiac function monitoring follows the same principles described for trastuzumab.
Lapatinib
Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.69,70 Lapatinib is not approved for use in adjuvant settings.
Neratinib
Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.21,71 Neratinib is not FDA-approved in the metastatic settings.
