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. Increasingly, management decisions regarding whether oncologists should prescribe adjuvant treatment are being based on the biology of the patient's tumor, with a consideration of the hormone receptor status, 4 and more recently, with the assessment of ERBB2. 5 The identification of the amplification of ERBB2 gene and the overexpression of its protein product has resulted in targeted monoclonal antibody-based therapy. 6,7 Preclinical studies indicate synergistic anti-tumor activity when trastuzumab is combined with a number of anti-cancer drugs. Additive cytotoxic interactions between trastuzumab and other agents, including paclitaxel,

Human Breast Cancer Cells Harboring a Gatekeeper T798M Mutation in HER2 Overexpress EGFR Ligands and Are Sensitive to Dual Inhibition of EGFR and HER2

“…1E). Trastuzumab binds to domain IV of HER2 (36) and induces receptor internalization and downregulation from the cell surface thus attenuating downstream signal transduction (37). Since trastuzumab did not inhibit downstream signaling in cells expressing T798M (Fig 1E), we investigated if this mutation would impair trastuzumab-induced receptor internalization.…”

Phase II study to investigate the efficacy of trastuzumab biosimilar (Herzuma®) plus treatment of physician's choice (TPC) in patients with heavily pretreated HER-2+ metastatic breast cancer (KCSG BR 18–14/KM10B)

“…Now, it is being tested in HER2 positive MBC with PIK3CA mutations in multiple clinical trials and emerging results will guide us to deal with HER2 positive breast cancer with PIK3CA mutations (ClinicalTrials.gov Identifier: NCT05063786, NCT05230810, NCT04208178). ERBB2 somatic mutations are observed in 2-5% of primary breast cancers and most have been reported in HER2-negative breast cancers [23][24][25]. However, in a recent study evaluating ERBB2 mutations using ctDNA in patients with advanced breast cancer, the frequency of ERBB2 mutations was 8.9% and this was higher in HER2-positive tumors than in HER2-negative tumors [26].…”

Selection and Evaluation of Human Recombinant Antibodies against ErbB2 Antigen for Breast Cancer Immunotherapy

“…In the present study, we selected 2 specific anti-ErBb2 scFv antibodies against ErbB2 peptides (amino acids 557 -567; ARHCLPCHPEC), which include the loop 1 of ErbB2 targeted by trastuzumab; this region is introduced as a proper site for anticancer immunotherapy (32,33). The second peptide, used for the selection of scFvs, contained amino acids 377 -392 (LPESFDGDPASNTAPL), as the first target of pertuzumab in the epitope; also, it is considered as a novel recombinant monoclonal antibody against ERbB2.…”