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The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy

J S Ross 1 J A Fletcher  
  • PMID: 9831867
  •     157 citations


The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.

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Mol Imaging Biol, 2014 Jul 19; 17(1). PMID: 25034624    Free PMC article.
In vivo hyperspectral imaging of microvessel response to trastuzumab treatment in breast cancer xenografts.
Devin R McCormack, Alex J Walsh, +4 authors, Melissa C Skala.
Biomed Opt Express, 2014 Jul 30; 5(7). PMID: 25071962    Free PMC article.
Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab.
Toru Kawamoto, Kazunori Ishige, +7 authors, Junichi Shoda.
J Gastroenterol, 2014 Aug 13; 50(4). PMID: 25112701
Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer.
Nigel Fleeman, Adrian Bagust, +4 authors, Yenal Dundar.
Pharmacoeconomics, 2014 Aug 21; 33(1). PMID: 25138171
Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials.
Pernelle Lavaud, Fabrice Andre.
BMC Med, 2014 Oct 07; 12. PMID: 25285786    Free PMC article.
Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts.
Jennifer G Whisenant, Anna G Sorace, +4 authors, Thomas E Yankeelov.
Transl Oncol, 2014 Dec 17; 7(6). PMID: 25500087    Free PMC article.
Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer.
Andrew T Baker, Andrei Zlobin, Clodia Osipo.
Front Oncol, 2015 Jan 08; 4. PMID: 25566499    Free PMC article.
DNA vaccine for cancer immunotherapy.
Benjamin Yang, Jessica Jeang, +2 authors, Chien-Fu Hung.
Hum Vaccin Immunother, 2015 Jan 28; 10(11). PMID: 25625927    Free PMC article.
Association between miR-125a rs12976445 and survival in breast cancer patients.
Lianghe Jiao, Jiaxin Zhang, +5 authors, Hengjun Gao.
Am J Transl Res, 2015 Jan 30; 6(6). PMID: 25628797    Free PMC article.
Collagen density and alignment in responsive and resistant trastuzumab-treated breast cancer xenografts.
Alex J Walsh, Rebecca S Cook, +2 authors, Melissa C Skala.
J Biomed Opt, 2015 Feb 24; 20(2). PMID: 25700233    Free PMC article.
Effect of phosphorylation on EGFR dimer stability probed by single-molecule dynamics and FRET/FLIM.
Oana Coban, Laura C Zanetti-Dominguez, +14 authors, Tony Ng.
Biophys J, 2015 Mar 13; 108(5). PMID: 25762314    Free PMC article.
Mechanism of the cytotoxic action of immunophototoxin 4D5scFV-miniSOG on HER2/neu-positive cancer cells.
G M Proshkina, K E Mironova, S M Deyev, R V Petrov.
Dokl Biochem Biophys, 2015 Mar 17; 460. PMID: 25772982
t-Darpp Promotes Enhanced EGFR Activation and New Drug Synergies in Her2-Positive Breast Cancer Cells.
Erin C Denny, Susan E Kane.
PLoS One, 2015 Jun 30; 10(6). PMID: 26121470    Free PMC article.
Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co(III) -Ebox Conjugate.
Luke F Vistain, Natsuho Yamamoto, +2 authors, Thomas J Meade.
Chembiochem, 2015 Aug 26; 16(14). PMID: 26305708    Free PMC article.
Embryonic Lethality in Homozygous Human Her-2 Transgenic Mice Due to Disruption of the Pds5b Gene.
Carmen S M Yong, Janelle Sharkey, +9 authors, Michael H Kershaw.
PLoS One, 2015 Sep 04; 10(9). PMID: 26334628    Free PMC article.
Deciphering Asthma Biomarkers with Protein Profiling Technology.
Zhizhou Kuang, Jarad J Wilson, +2 authors, Ruo-Pan Huang.
Int J Inflam, 2015 Sep 09; 2015. PMID: 26346739    Free PMC article.
Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy.
Diana B Peckys, Ulrike Korf, Niels de Jonge.
Sci Adv, 2015 Nov 26; 1(6). PMID: 26601217    Free PMC article.
Comparative genomic hybridization analysis of invasive ductal breast carcinomas in the Chinese population.
Jianwei Zhang, Hongyan Zhang, +2 authors, Zhonghe Yu.
Oncol Lett, 2015 Dec 02; 10(4). PMID: 26622803    Free PMC article.
Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing.
A J García-Chequer, A Méndez-Tenorio, +17 authors, M V Ponce-Castañeda.
Cancer Genet, 2016 Feb 18; 209(3). PMID: 26883451    Free PMC article.
The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis.
Charla C Engels, Mandy Kiderlen, +8 authors, Gerrit Jan Liefers.
Breast Cancer Res Treat, 2016 Mar 13; 156(2). PMID: 26968397    Free PMC article.
Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines.
Jinkyoung Kim, Jiyun Lee, +3 authors, Aeree Kim.
Oncol Rep, 2016 Mar 18; 35(5). PMID: 26986571    Free PMC article.
Genetic alterations of HER genes in chromophobe renal cell carcinoma.
Wen Hui Weng, Ying Tzu Chen, +3 authors, See Tong Pang.
Oncol Lett, 2016 Mar 22; 11(3). PMID: 26998131    Free PMC article.
A Single-Nucleotide Polymorphism in 3'-Untranslated Region of Endothelin-1 Reduces Risk of Dementia After Ischemic Stroke.
Wanwan Ma, Qizhi Fu, Yanpeng Zhang, Zhen Zhang.
Med Sci Monit, 2016 Apr 24; 22. PMID: 27106952    Free PMC article.
Translation in Data Mining to Advance Personalized Medicine for Health Equity.
Estela S Estape, Mary Helen Mays, Elizabeth A Sternke.
Intell Inf Manag, 2016 May 20; 8(1). PMID: 27195185    Free PMC article.
A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors.
N Haense, A Atmaca, +8 authors, S-E Al-Batran.
BMC Cancer, 2016 Jul 09; 16. PMID: 27387446    Free PMC article.
Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer.
David N Danforth.
Breast Cancer (Auckl), 2016 Aug 26; 10. PMID: 27559297    Free PMC article.
FISH testing of HER2 immunohistochemistry 1+ invasive breast cancer with unfavorable characteristics.
Stella Petroni, Lucia Caldarola, +4 authors, Giovanni Simone.
Oncol Lett, 2016 Dec 03; 12(5). PMID: 27899970    Free PMC article.
Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing Using Multifunctional pRNA Nanoparticles.
Yijuan Zhang, Marissa Leonard, +4 authors, Xiaoting Zhang.
ACS Nano, 2016 Dec 15; 11(1). PMID: 27966906    Free PMC article.
Comparative study of Her-2, p53, Ki-67 expression and clinicopathological characteristics of breast cancer in a cohort of northern China female patients.
Li Ding, Zijin Zhang, Yan Xu, Yongqiang Zhang.
Bioengineered, 2017 Jan 12; 8(4). PMID: 28075663    Free PMC article.
Multiplexed detection of various breast cancer cells by perfluorocarbon/quantum dot nanoemulsions conjugated with antibodies.
Pan Kee Bae, Bong Hyun Chung.
Nano Converg, 2014 Jan 01; 1(1). PMID: 28191403    Free PMC article.
Expression proteomics study to determine metallodrug targets and optimal drug combinations.
Ronald F S Lee, Alexey Chernobrovkin, +5 authors, Paul J Dyson.
Sci Rep, 2017 May 10; 7(1). PMID: 28484215    Free PMC article.
Harnessing Integrative Omics to Facilitate Molecular Imaging of the Human Epidermal Growth Factor Receptor Family for Precision Medicine.
Martin Pool, H Rudolf de Boer, +2 authors, Elisabeth G E de Vries.
Theranostics, 2017 Jun 24; 7(7). PMID: 28638489    Free PMC article.
Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival.
Thomas A Werfel, Shan Wang, +12 authors, Craig L Duvall.
Cancer Res, 2018 Jan 24; 78(7). PMID: 29358172    Free PMC article.
Clinical relevance of the 21-gene Recurrence Score® assay in treatment decisions for patients with node-positive breast cancer in the genomic era.
Eleftherios P Mamounas, Christy A Russell, +2 authors, Kathy S Albain.
NPJ Breast Cancer, 2018 Aug 30; 4. PMID: 30155517    Free PMC article.
Molecular Mechanisms of Antitumor Activity of PAMAM Dendrimer Conjugates with Anticancer Drugs and a Monoclonal Antibody.
Monika Marcinkowska, Maciej Stanczyk, +4 authors, Barbara Klajnert-Maculewicz.
Polymers (Basel), 2019 Sep 01; 11(9). PMID: 31470686    Free PMC article.
Hormonal treatment combined with targeted therapies in endocrine-responsive and HER2-positive metastatic breast cancer.
Emilia Montagna, Marco Colleoni.
Ther Adv Med Oncol, 2020 Jan 04; 11. PMID: 31897091    Free PMC article.
Nanovaccines for cancer immunotherapy.
Yu Zhang, Shuibin Lin, Xiang-Yang Wang, Guizhi Zhu.
Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2019 Jun 07; 11(5). PMID: 31172659    Free PMC article.
Expression of Histo-blood Group Antigens in Tumor and Adjacent Normal Breast Tissues as Prognostic Markers of Breast Carcinoma.
Soukaina Zouine, Farida Marnissi, +6 authors, Norddine Habti.
J Breast Cancer, 2020 Mar 07; 23(1). PMID: 32140271    Free PMC article.
Visualisation of HER2 homodimers in single cells from HER2 overexpressing primary formalin fixed paraffin embedded tumour tissue.
Diana B Peckys, Daniela Hirsch, Timo Gaiser, Niels de Jonge.
Mol Med, 2019 Aug 29; 25(1). PMID: 31455202    Free PMC article.
Extracellular Matrix Features Discriminate Aggressive HER2-Positive Breast Cancer Patients Who Benefit from Trastuzumab Treatment.
Ilona Rybinska, Marco Sandri, +8 authors, Tiziana Triulzi.
Cells, 2020 Feb 20; 9(2). PMID: 32069815    Free PMC article.
Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer.
Hannelore Denys, Corina L Martinez-Mena, +7 authors, Mona M Van Steenberghe.
Breast Cancer Res Treat, 2020 Apr 03; 181(1). PMID: 32240454    Free PMC article.
A case of advanced gastric cancer showing HER2 positivity after chemotherapy.
Suguru Hirose, Toshikazu Moriwaki, +8 authors, Ichinosuke Hyodo.
Int Cancer Conf J, 2020 Jun 26; 9(3). PMID: 32582513    Free PMC article.
Predictive factors affecting axillary lymph node involvement in patients with breast cancer in Duhok: Cross-sectional study.
Ayad Ahmad Mohammed.
Ann Med Surg (Lond), 2019 Jul 26; 44. PMID: 31341618    Free PMC article.
Leveraging TCGA gene expression data to build predictive models for cancer drug response.
Evan A Clayton, Toyya A Pujol, John F McDonald, Peng Qiu.
BMC Bioinformatics, 2020 Oct 02; 21(Suppl 14). PMID: 32998700    Free PMC article.
SETDB1 regulates SMAD7 expression for breast cancer metastasis.
Tae Young Ryu, Kwangho Kim, +6 authors, Hyun-Soo Cho.
BMB Rep, 2018 Dec 14; 52(2). PMID: 30545440    Free PMC article.
Anticancer therapeutics: a brief account on wide refinements.
Fiza Ur Rehman, Mansoor Al-Waeel, Syeda Sohaila Naz, Kifayat Ullah Shah.
Am J Cancer Res, 2020 Dec 10; 10(11). PMID: 33294257    Free PMC article.
Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial.
Alexandra Maria Rüger, Andreas Schneeweiss, +17 authors, Stephan von Haehling.
J Am Heart Assoc, 2020 Nov 17; 9(23). PMID: 33191846    Free PMC article.
Biomarkers in Her2- Positive Disease.
Eva Valentina Klocker, Christoph Suppan.
Breast Care (Basel), 2021 Jan 16; 15(6). PMID: 33447232    Free PMC article.
Cancer Vaccines, Treatment of the Future: With Emphasis on HER2-Positive Breast Cancer.
Sandeep Pallerla, Ata Ur Rahman Mohammed Abdul, Jill Comeau, Seetharama Jois.
Int J Mol Sci, 2021 Jan 21; 22(2). PMID: 33466691    Free PMC article.
The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer.
Christopher E Eyermann, John D Haley, Evguenia M Alexandrova.
Cell Death Dis, 2021 Jan 28; 12(1). PMID: 33500390    Free PMC article.
Inhibition of HER Receptors Reveals Distinct Mechanisms of Compensatory Upregulation of Other HER Family Members: Basis for Acquired Resistance and for Combination Therapy.
Daniela Gutsch, Robert Jenke, Thomas Büch, Achim Aigner.
Cells, 2021 Feb 13; 10(2). PMID: 33572976    Free PMC article.
Assessment of CPS + EG, Neo-Bioscore and Modified Neo-Bioscore in Breast Cancer Patients Treated With Preoperative Systemic Therapy: A Multicenter Cohort Study.
Ling Xu, Yinhua Liu, +31 authors, Yimin Cui.
Front Oncol, 2021 Apr 03; 11. PMID: 33796452    Free PMC article.
The Exciting New Field of HER2-Low Breast Cancer Treatment.
Daniel Eiger, Elisa Agostinetto, Rita Saúde-Conde, Evandro de Azambuja.
Cancers (Basel), 2021 Apr 04; 13(5). PMID: 33804398    Free PMC article.
Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer.
Ming Zhao, Stephen Scott, +13 authors, Funda Meric-Bernstam.
Clin Cancer Res, 2021 Jan 09; 27(6). PMID: 33414137    Free PMC article.