What are the treatment options for recurrent metastatic HER2-positive breast cancer after trastuzumab therapy? —name withheld on request

There are now multiple agents available that target human epidermal growth factor receptor 2 (HER2)-positive breast cancers.

Trastuzumab (Herceptin) is a monoclonal antibody that binds to the HER2 receptor, triggering antibody-dependent cellular cytotoxicity and cell death.1 Trastuzumab is utilized in the neoadjuvant, adjuvant, and metastatic disease settings. It may be used as monotherapy, but is most frequently administered in combination with chemotherapy.1

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Lapatinib (Tykerb) is a tyrosine kinase inhibitor that inhibits the intracellular domains of both HER2 and epidermal growth factor receptor (EGFR), inhibiting cell growth.2 Lapatinib is used in the treatment of metastatic disease in patients who have previously received trastuzumab. Lapatinib may be used in combination with trastuzumab or capecitabine (Xeloda), and is taken orally.2

Ado-trastuzumab emtansine (Kadcyla; also known as TDM-1) is a HER2-targeted antibody-drug conjugate.3 Trastuzumab is bound to DM1, a microtubule inhibitor. The antibody portion binds to the HER2 receptor and is degraded intracellularly, releasing DM1 and resulting in cell cycle arrest and apoptosis. Ado-trastuzumab emtansine is used in the treatment of patients with metastatic disease who have previously received trastuzumab and a taxane. Ado-trastuzumab emtansine is given as monotherapy.3

Pertuzumab (Perjeta) is a monoclonal antibody that blocks heterodimerization of HER2 with other HER family receptors (EGFR, HER3, HER4).4 This inhibits intracellular signaling, causing cell growth arrest and apoptosis. Pertuzumab also mediates antibody-dependent cellular cytotoxicity. Pertuzumab is indicated for use in combination with trastuzumab and a taxane in both the neoadjuvant setting as well as for patients receiving first-line treatment for metastatic disease.4

First-line treatment options for patients with HER2-positive metastatic breast cancer include trastuzumab (with or without chemotherapy) or trastuzumab in combination with pertuzumab and a taxane (docetaxel [Taxotere] or paclitaxel [Taxol]).5 HER2-targeted treatment should be continued in patients who have disease progression on first-line therapy. When patients progress on first-line treatment regimens, subsequent HER2-targeted therapies may include ado-trastuzumb emtansine, a lapatinib-containing regimen, or continuation of trastuzumab (in combination with a new chemotherapy regimen). The HER2-targeted agent should be selected after considering patient specific factors such as disease course, comorbid conditions, organ function, and patient preference.5 The optimal sequencing of HER2-targeted treatments is not established and remains to be clarified by future studies.

Lisa A. Thompson, PharmD, BCOPClinical Pharmacy Specialist in Oncology, >Kaiser Permanente, Colorado. 


1. Herceptin [package insert]. South San Francisco, CA: Genentech Inc; 2014.

2. Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.

3. Kadcyla [package insert]. South San Francisco, CA: Genentech Inc; 2014.

4. Perjeta [package insert]. South San Francisco, CA: Genentech Inc; 2013.

5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 3.2014. Port Washington, PA: National Comprehensive Cancer Network; 2014.