Dual HER2 blockade: preclinical and clinical data.
The estrogen receptor and human epidermal growth factor receptor (HER) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, targeting these pathways provides the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and understand some of the mechanisms of resistance to HER2-targeted treatments. Recent studies have demonstrated an increased effectiveness of dual targeted HER2 therapies against HER2-amplified breast cancer as compared with single blockade. These studies have resulted in the recent US Food and Drug Administration approval of the combination of taxane chemotherapy with pertuzumab and trastuzumab in the first-line metastatic setting as well as an accelerated approval in the neoadjuvant setting. Another mechanism for overcoming resistance to HER2 targeted therapies is the antibody-drug conjugate trastuzumab-emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule agent mertansine, allowing for intracellular release of the cytotoxic drug. Studies evaluating the efficacy of dual blockade with antibody-drug conjugate are currently ongoing. This article reviews recent data on different combinations of anti-HER2 treatments as well as ongoing and future research in this area.
Houston Methodist Cancer Center, 6445 Main Street, P21-34, Houston, TX, 77030, USA. tapatel@houstonmethodist.org.|Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. tapatel@houstonmethodist.org.
Tejal A
TA
Patel
Houston Methodist Cancer Center, 6445 Main Street, P21-34, Houston, TX, 77030, USA. BDave@houstonmethodist.org.
Bhuvanesh
B
Dave
Houston Methodist Cancer Center, 6445 Main Street, P21-34, Houston, TX, 77030, USA. AARodriguez@houstonmethodist.org.|Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. AARodriguez@houstonmethodist.org.
Angel A
AA
Rodriguez
Houston Methodist Cancer Center, 6445 Main Street, P21-34, Houston, TX, 77030, USA. jcchang@houstonmethodist.org.|Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. jcchang@houstonmethodist.org.
Jenny C
JC
Chang
Division of Hemotology and Oncology, College of Medicine, Mayo Clinic, 4500 San Pablo Rd S., Jacksonville, FL, 32224, USA. perez.edith@mayo.edu.
Edith A
EA
Perez
Division of Hemotology and Oncology, College of Medicine, Mayo Clinic, 4500 San Pablo Rd S., Jacksonville, FL, 32224, USA. gcolonotero@mayo.edu.
Gerardo
G
Colon-Otero
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D058990:Molecular Targeted Therapy; D011799:Quinazolines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000077156:Gefitinib; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab