Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab. Patients treated with chemotherapy plus trastuzumab had an OS advantage as compared with those receiving chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity. Consequently, patients with metastatic breast cancer with substantial overexpression of HER2/neu are candidates for treatment with the combination of trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with taxanes and other chemotherapeutic agents.
Clinical trials comparing multiagent chemotherapy plus trastuzumab versus single-agent chemotherapy have yielded conflicting results. In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time-to-progression, compared with trastuzumab and paclitaxel alone.[Level of evidence: 1iDiii] However, a phase III Breast Cancer International Research Group (BCIRG) trial (BCIRG-007 [NCT00047255]) comparing carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer showed no difference in OS, time to progression, or response rate.[Level of evidence: 1iiA] Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer should consist of single-agent chemotherapy plus trastuzumab.
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.
Lapatinib plus capecitabine
Lapatinib has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded, randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab. At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34-0.71; P < .001). There was no difference in OS (HR, 0.92; 95% CI, 0.58-1.46; P = .72).[Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (Refer to the PDQ summary on Gastrointestinal Complications for more information on diarrhea.)