Patients with significant involvement of the lung, liver, or brain and those with rapidly progressive disease rarely benefit from hormonal maneuvers, and initial systemic chemotherapy is indicated in such cases. For the 25–30% of breast cancer patients whose tumors express the HER-2/neu cell surface receptor, trastuzumab, is available for therapeutic use alone or in combination with cytotoxic chemotherapy. Other agents that target HER-2/neu signaling include pertuzumab, ado-trastuzumab emtansine, and the small molecule lapatinib. Pertuzumab is a humanized IgG1 antibody that targets a different epitope on the HER-2/neu receptor than trastuzumab, and this antibody inhibits heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. This drug is used in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer in patients who have not previously received anti-HER chemotherapy for metastatic disease. Ado-trastuzumab emtansine is an antibody-drug conjugate composed of trastuzumab and the small molecule microtubule inhibitor DM1; it is approved for women with HER2-positive metastatic breast cancer who have received prior therapy with trastuzumab and taxane-based chemotherapy. Finally, lapatinib is a small molecule inhibitor of the tyrosine kinases associated with EGFR (ErbB1) and HER2 (ErbB2), resulting in inhibition of downstream signaling. This agent is used in combination with the oral fluoropyrimidine capecitabine for metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy with an anthracycline, a taxane, and trastuzumab.
About 50–60% of patients with metastatic disease respond to initial chemotherapy. A broad range of anti-cancer agents have activity in this disease, including the anthracyclines (doxorubicin, mitoxantrone, and epirubicin) and the taxanes (docetaxel, paclitaxel, and albumin-bound paclitaxel), along with the microtubule inhibitor ixabepilone, navelbine, capecitabine, gemcitabine, cyclophosphamide, methotrexate, and cisplatin. The anthracyclines and the taxanes are two of the most active classes of cytotoxic drugs. Combination chemotherapy has been found to induce higher and more durable remissions in up to 50–80% of patients, and anthracycline-containing regimens are now considered the standard of care in first-line therapy. With most combination regimens, partial remissions have a median duration of about 10 months and complete remissions have a duration of about 15 months. Unfortunately, only 10–20% of patients achieve complete remissions with any of these regimens, and as noted, complete remissions are usually not long-lasting.