title: ERBB2 juxtamembrane domain (trastuzumab binding site) gene mutation is a rare event in invasive breast cancers overexpressing the ERBB2 gene.
abstract: The recent development of targeted therapies using monoclonal antibodies has added new dimensions to breast cancer treatment. Trastuzumab has been added to the regimens that contain chemotherapeutic agents, which has improved the clinical outcomes of patients in both the adjuvant and metastatic settings. However, trastuzumab resistance, both de novo and acquired, continues to be problematic. There have been scattered studies reporting ERBB2 gene mutation, but nothing is currently known about the ERBB2 binding site mutations. In the current study, we examined the ERBB2 juxtamembrane domain trastuzumab binding site for mutations in invasive breast cancers overexpressing ERBB2. Pure tumor cells of 54 breast cancer patients were procured using laser capture microdissection. Two polymerase chain reaction primer pairs were designed to amplify the trastuzumab binding site sequence. The polymerase chain reaction product was sequenced. Standard clinicopathological data were recorded. For the 54 patients, there was one (2%) case that showed missense point mutation in exon 17 (H559A). There were nine patients treated with trastuzumab in the metastatic setting, none of which had gene mutation. Therefore, we conclude that ERBB2 juxtamembrane domain (trastuzumab binding site) gene mutation is a rare event in breast cancer. Although it is unclear whether this substitution would result in trastuzumab target therapy resistance, this would not account for the relatively high frequency of this resistance encountered clinically.
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. thaer.khoury@roswellpark.org
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.forename: Wilfrido
authors.initials: W
authors.lastname: Mojica
authors.forename: David
authors.initials: D
authors.lastname: Hicks
authors.forename: Petr
authors.initials: P
authors.lastname: Starostik
authors.forename: Foluso
authors.initials: F
authors.lastname: Ademuyiwa
authors.forename: Bagirathan
authors.initials: B
authors.lastname: Janarthanan
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cheney
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007834:Lasers; D042282:Microdissection; D008875:Middle Aged; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human