title: Dual Blockade of HER-2 Provides a Greater Magnitude of Benefit in Patients With Hormone-Negative Versus Hormone-Positive Breast Cancer.
abstract: The dual small molecule tyrosine kinase inhibitor lapatinib blocks both human epidermal growth factor receptor (HER-1) and human epidermal growth factor receptor 2 (HER-2) tyrosine kinase activity by binding reversibly to the ATP-binding site of the receptor's intracellular domain. Lapatinib, in combination with capecitabine, has been approved in 2007 for the treatment of patients with advanced HER-2+breast cancer upon progressive disease following standard chemotherapy. Approval was also extended to the treatment of postmenopausal women with advanced hormone receptor (HR)-positive and HER-2-positive breast cancer in 2010. More recently, clinical trials that have investigated the efficacy of dual HER-2 blockade in both the metastatic and neoadjuvant breast cancer settings. For example, in 2013 the European Medicines Agency approved the combination of lapatinib and trastuzumab in HER-2+/HR-patients. We review the efficacy results from dual HER-2 blockade studies and present new post hoc analysis efficacy data according to HR status. We show that dual blockade of HER-2 appears to provide a greater magnitude of benefit in the HR-versus the HR+subgroup of patients. Finally, we examine the potential of molecularly subtyping HER-2+tumors using the PAM50 test as a predictor of response to treatment with the combination of trastuzumab and lapatinib.
authors.affiliation: VM Institute of Research, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Abramovitz
authors.affiliation: Avera Cancer Institute, Sioux Falls, SD.
authors.forename: Casey
authors.initials: C
authors.lastname: Williams
authors.affiliation: German Breast Group, Neu-Isenburg, Germany. Electronic address: sibylle.loibl@gbg.de.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Avera Cancer Institute, Sioux Falls, SD. Electronic address: bleylandj@aol.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000069287:Capecitabine / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant / Q000379:methods / Q000639:trends; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020360:Neoadjuvant Therapy / Q000379:methods / Q000639:trends; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000069287:Capecitabine; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: HER-2 positive; Lapatinib; Neoadjuvant; PAM50; Trastuzumab