Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Hormonal Therapy for the Treatment of Primary HER2-Positive Breast Cancer: One More Step Toward Chemotherapy-Free Therapy

Abstract

During the last decade, the introduction of agents that target the human epidermal growth factor receptor 2 (HER2), such as the monoclonal antibody trastuzumab (Herceptin; Roche, Basel, Switzerland) or the tyrosine kinase inhibitor lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC), in combination with chemotherapy, has changed the course of HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to taxanes increases progression-free survival (PFS) and overall survival (OS), whereas the addition of lapatinib to capecitabine increases PFS after treatment with regimens that include an anthracycline, a taxane, and trastuzumab. In the adjuvant setting, trastuzumab increases diseasefree survival and OS. In addition to these impressive advances, clinical research to improve the outcome in HER2-positive breast cancer is as vibrant as it has ever been. A number of important questions are being addressed at this time, including the delineation of the role of neoadjuvant (presurgical) therapy, theconceptofdualHER2receptorblockade, theidentificationof markers of sensitivity or resistance to therapy, and, finally, the study of new agents. As reported in the article that accompanies this editorial, the timely Neoadjuvant Translational Breast Cancer Research Consortium 006 (TBCRC 006) trial by Rimawi et al has addressed three of these questionsandhas identifiedonemorepiece in thepuzzle: the importance ofaddinghormonal therapyinthesubsetofpatientswithHER2-positive/ hormone receptor (HR) –positive tumors. To place this study in context, let us look at what we know today. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy and maintenance for 1 year increases pathologic complete response (pCR) rates and 3-year event-free survival (EFS). And there is increasing evidence that there is a good correlation between pCR and EFS in HER2-positive disease, which has led to the acceptance of pCR as the primary end point in a number of neoadjuvant studies. If some of these studies, such as the Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Organisation (NeoALTTO) study, further confirm that pCR is a surrogate marker of EFS, improved pCR in HER2-positive breast cancer could lead to regulatory approval of novel agents in this disease. In terms of dual HER2 blockade, laboratory studies have shown that a more complete blockage of the HER2 and/or the HER signaling pathway by combining two or three inhibitors with nonoverlapping mechanisms of action improves cell death and tumor shrinkage in HER2-positive models. These preclinical findings have now been confirmed in the clinical setting. Trastuzumab and lapatinib (or trastuzumab and pertuzumab [Perjeta; Genentech, South San Francisco, CA], a humanized monoclonal antibody binding to the HER2 dimerization domain), in combination with chemotherapy, results in pCR rates of 45.8% to 51.3% compared with pCR rates of 24.0% to 29.5% with a single anti-HER2 agent combined with the same chemotherapy schedule. Moreover, the addition of pertuzumab to trastuzumab and docetaxel increases PFS and OS in first-line metastatic HER2-positive disease. These results have led to regulatory approval of pertuzumab and have placed the dual HER2 blockade with pertuzumab and trastuzumab in combination with chemotherapy as the standard of care in first-line metastatic disease. Furthermore, dual HER2 blockade strategies could also become standard of care in other settings. For example, the ongoing Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) phase III trial is evaluating the adjuvant dual HER2 blockade with trastuzumab and lapatinib afterchemotherapy,andAStudyofPertuzumabinAdditiontoChemotherapy and Herceptin (Trastuzumab) As Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer (APHINITY), a phase III trial, is also currently evaluating adjuvant trastuzumab and pertuzumab with chemotherapy. Given that the dual HER2 blockade is more efficacious that single-agent HER2 therapy, a question that arises is whether the dual blockade may eliminate the need for chemotherapy in a subset of patients. In support of this proposal, the dual HER2 blockade without chemotherapy has shown high activity in a group of patients with metastatic and primary HER2-positive breast cancer. In HER2-positive metastatic breast cancer that was previously treated with trastuzumab, the addition of pertuzumab or lapatinib to trastuzumab showed higher clinical benefit than either pertuzumab or lapatinib alone. In treatment-naive JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 14 MAY 1