HER2-positive breast cancer – Available anti-HER2 therapies and new agents under investigation
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Students’ Scientific Association, Oncological Surgery Department, Medical University, Lublin, Poland
Oncological Surgery Department, Independent Public Teaching Hospital No. 1, Lublin; Medical University, Lublin, Poland
Corresponding author
Martyna Zielińska   

Scientific Association, Oncological Surgery Department, Medical University, Lublin, Poland
J Pre Clin Clin Res. 2020;14(2):44-48
Introduction and objectives:
Breast cancer (BC) is the most common malignancy and the leading cause of cancer death among women. About 15–20% of all BCs are HER2-positive. Proper assessment of HER2 status is crucial to choose appropriate treatment. The review summarizes data on anti-HER2 drugs used to treat HER2-positive BC and provides basic information on new agents under investigation.

Brief description of the state of knowledge.:
Specific HER2-targeting drugs are available or are being evaluated in clinical trials. Anti-HER2 agents include: monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates, bispecific antibodies, PI3K/AKT/mTOR inhibitors and heat shock protein 90 inhibitors, HER2-targeting vaccines and CDK4/6 inhibitors. The advent of anti-HER2 therapies increased the time of progression free survival and overall survival in BC patients.

Final analysis of the CLEOPATRA trial shows that the combination of trastuzumab, pertuzumab and taxane significantly improved outcomes in metastatic HER2-positive BC and it is currently preferred first-line treatment. The recommended second-line treatment is based on trastuzumab emtansine or on the combination of lapatinib and capecitabine. Some promising agents such as margetuximab or trastuzumab deruxtecan are still under investigation.

Anti-HER2 directed treatment undoubtedly improves outcomes among patients with HER2-positive BC. Access to drugs such as trastuzumab, pertuzumab, lapatinib and T-DM1 improves prognosis even in patients with advanced disease. Further studies and clinical trials on novel anti-HER2 therapies are required. Nevertheless, BC treatment is becoming more effective and, hopefully, one day it may be possible to cure patients even with metastases.

1. assesed at January 6th, 2020.
Krishnamurti U, Silverman JF. HER2 in Breast Cancer: A Review and Update. Adv Anat Pathol. 2014; 21(2): 100–107. doi: 10.1097/PAP.0000000000000015.
Escriva-de-Romaní S, Arumí M, Bellet M, Saura C. HER2-positive breast cancer: Current and new therapeutic strategies. Breast. 2018; 39: 80–88. doi: 10.1016/j.breast.2018.03.006.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013; 31(31): 3997–4013. doi: 10.1200/JCO.2013.50.9984.
Veeraraghavan J, De Angelis C, Reis-Filho JS, Pascual T, Prat A, Rimawi MF, et al. De-escalation of treatment in HER2-positive breast cancer: determinants of response and mechanisms of resistance. Breast. 2017; 34(1): 19–26. doi: 10.1016/j.breast.2017.06.022.
Yao M, Fu P. Advances in anti-HER2 therapy in metastatic breast cancer. Chin Clin Oncol. 2018; 7(3): 27. doi: 10.21037/cco.2018.05.04.
Albanell J, Baselga J. Trastuzumab, a humanized anti-HER2 monoclonal antibody, for the treatment of breast cancer. Drugs Today (Barc). 1999; 35(12): 931–946.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344(11): 783–792.
von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009; 27(12): 1999–2006. doi: 10.1200/JCO.2008.19.6618.
Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019; 11: 1–16. doi: 10.1177/1758835919833519.
Cortés J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012; 30(14): 1594–1600. doi: 10.1200/JCO.2011.37.4207.
Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366(2): 109–119. doi: 10.1056/NEJMoa1113216.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi: 10.1056/NEJMoa1413513.
Helwick C. CLEOPATRA End-of-Study Analysis in Metastatic Breast Cancer: 37% Alive at 8 Years.
Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nordstrom JL et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;28(4):855-861. doi: 10.1093/annonc/mdx002.
16. Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in the Treatment of HER2+ Metastatic Breast Cancer (SOPHIA).
Segovia-Mendoza M, Gonzalez-Gonzalez ME, Barrera D, Diaz L, Garcia-Becerra R. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence. Am J Cancer Res. 2015;5(9):2531-2561.
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743.
Gligorov J, Richard S, Todorovic V. New anti-HER2 agents: from second-generation tyrosine kinases inhibitors to bifunctional antibodies. Curr Opin Oncol. 2017;29(6):405-410. doi: 10.1097/CCO.0000000000000412.
Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301-1307. doi: 10.1200/JCO.2009.25.8707.
Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T et al. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2014;32(32):3626-3633. doi: 10.1200/JCO.2014.56.3809.
Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G et al. Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial. JAMA Oncol. 2016;2(12):1557-1564. doi: 10.1001/jamaoncol.2016.0237.
Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367–377. doi: 10.1016/S1470-2045(15)00551-3.
24. A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA).
Cortés J, Dieras V, Ro J, Berriere J, Bachelot T, Hurvitz S et al. Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol. 2015;16(16):1700-1710. doi: 10.1016/S1470-2045(15)00373-3.
26. A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB).
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. doi: 10.1056/NEJMoa1209124.
Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742. doi: 10.1016/S1470-2045(17)30312-1.
Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badowinac-Crnjevic T et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi: 10.1016/S1470-2045(17)30313-3.
Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017;35(2):141-148.
Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastrooesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18(11):1512–1522. doi: 10.1016/S1470-2045(17)30604-6.
32. DS-8201a in Pre-treated HER2 Breast Cancer That Cannot be Surgically Removed or Has Spread [DESTINY Breast02].
33. DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03].
34. SYD985 vs. Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP).
35. Study of RC48-ADC in Patients With HER2-Positive Advanced Malignant Solid Tumors.
36. PF-06804103 Dose Escalation in HER2 Positive Solid Tumors.
37. A Dose-escalation Study of ARX788, IV Administered in Subjects With Advanced Cancers With HER2 Expression.
38. A Phase 1/2 Study of MEDI4276 in Adults Subjects With Select HER2-expressing Advanced Solid Tumors. (MEDI4276).
39. Study of Antibody Drug Conjugate in Patients With Advanced Breast Cancer Expressing HER2.
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi: 10.1038/nature11412.
Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double blind, multicentre trial. Lancet Oncol. 2015;16(7):816–829. doi: 10.1016/S1470-2045(15)00051-0.
Andre´F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G et al. Everolimus for women with trastuzumab-resistant, HER2 positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580–591. doi: 10.1016/S1470-2045(14)70138-X.
Andre´ F, Hurvitz S, Fasolo A, Tseng LM, Jerusalem G, Wilks S et al. Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2016;34(18):2115–2124. doi: 10.1200/JCO.2015.63.9161.
44. Open-Label Study Evaluating the Safety and Tolerability of LJM716, BYL719 and Trastuzumab in Patients With Metastatic HER2+ Breast Cancer.
45. Phase Ib/II Trial of coPANlisib in Combination With Trastuzumab in HER2-positive Breast Cancer. (Panther Study) (Panther).
46. Phase Ib Dose-escalation Trial of Taselisib (GDC-0032) in Combination With Anti-HER2 Therapies in Participants With Advanced HER2+ Breast Cancer.
Jhaveri K, Wang R, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K et al. A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res. 2017;19(1):89. doi: 10.1186/s13058-017-0879-5.
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 2016;29(3):255-269. doi: 10.1016/j.ccell.2016.02.006.
49., Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer (PATINA),
50., A Study of Abemaciclib (LY2835219) in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer (monarcHER),
51., Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients (HER3+),
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