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      Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer

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          Abstract

          Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody–drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC.

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          The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis.

          M Moasser (2007)
          The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.
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            Treatment of HER2-positive breast cancer: current status and future perspectives.

            Carlos Arteaga, Mark Sliwkowski, C Osborne … (2011)
            The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.
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              Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.

              Kimberly Blackwell, Harold J Burstein, Anna Storniolo … (2010)
              Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.
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                Author and article information

                Contributors
                Genxi Li: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 14 December 2016
                Publication date Collection: December 2016
                Volume: 17
                Issue: 12
                Electronic Location Identifier: 2095
                Affiliations
                [1 ]Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China; 15484580@ 123456life.hkbu.edu.hk (Q.L.); 15484572@ 123456life.hkbu.edu.hk (Z.M.); yu.yy01@ 123456hotmail.com (Y.Y.); jiangfenghz@ 123456163.com (F.J.); guandg2012@ 123456gmail.com (D.G.); liangchao512@ 123456163.com (C.L.); waynebo@ 123456163.com (J.Z.)
                [2 ]Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China
                [3 ]The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China
                Author notes
                [* ]Correspondence: aipinglu@ 123456hkbu.edu.hk (A.L.); zhangge@ 123456hkbu.edu.hk (G.Z.); Tel.: +86-852-3411-2456 (A.L.); +86-852-3411-2958 (G.Z.)
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: ijms-17-02095
                DOI: 10.3390/ijms17122095
                PMC ID: 5187895
                PubMed ID: 27983617
                SO-VID: 8b57cb26-2996-4359-bda4-39c5f61ed7f5
                Copyright © © 2016 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 October 2016
                Date accepted : 01 December 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: molecular mechanism,translational therapy,her2 positive breast cancer,diagnostic tests,monoclonal antibodies,small molecular inhibitors,antibody–drug conjugates
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: molecular mechanism, translational therapy, her2 positive breast cancer, diagnostic tests, monoclonal antibodies, small molecular inhibitors, antibody–drug conjugates

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