Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.