ANTI-HER2 ANTIBODIES IN COMBINATION WITH CHEMOTHERAPY OR CHEMOTHERAPY-FREE REGIMENS TARGETING HER2-POSITIVE BREAST CANCER: A SYSTEMATIC REVIEW
Keywords:Breast cancer, HER2-positive, trastuzumab, pertuzumab, T-DM1
Breast cancer is the leading cause of cancer-related death in female worldwide. Human epidermal growth factor receptor 2 (HER2) amplification is observed in approximately 20% of breast cancer cases and is associated with poor clinical outcomes. Dual HER2 blockade without chemotherapy represents an attractive therapeutic approach, and it remains unresolved if anti-HER2 therapeutic antibodies are sufficient to replace chemotherapy regimens. In this review, we discuss the approved therapeutic monoclonal antibodies (pertuzumab and trastuzumab) and antibody-drug conjugate (trastuzumab emtansine or T-DM1) for the treatment of HER2-positive breast cancer patients. In summary, phase II and III clinical trials have demonstrated that dual HER2 blockade (pertuzumab and trastuzumab) plus chemotherapy regimens confer better efficacy compared with dual HER2 blockade alone, or anti-HER2 antibody monotherapy, in HER2-positive breast cancer patients. Dual HER2 blockade (pertuzumab and trastuzumab) combined with chemotherapies (5-fluorouracil, epirubicin, cyclophosphamide and docetaxel) yield superior response. Moreover, dual HER2 blockade (T-DM1 and pertuzumab) in combination with docetaxel represents a promising treatment regimen containing T-DM1. Ongoing clinical trials are assessing the optimal chemotherapy of choice with anti-HER2 antibodies combinations. In conclusion, improved outcomes are attributable to selection for the optimal chemotherapy regimen in combination with anti-HER2 antibodies instead of replacing chemotherapy altogether with the current line of anti-HER2 therapeutic antibodies.
Torre LA, Siegel RL, Ward EM, et al. Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol Biomarkers Prev 2016; 25: 16-27. DOI: 10.1158/1055-9965.EPI-15-0578.
Global Burden of Disease Cancer C, Fitzmaurice C, Dicker D, et al. The Global Burden of Cancer 2013. JAMA Oncol 2015; 1: 505-527. DOI: 10.1001/jamaoncol.2015.0735.
Siegel RL, Miller KD and Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7-30. DOI: 10.3322/caac.21442.
Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 2008; 14: 1368-1376. DOI: 10.1158/1078-0432.CCR-07-1658.
Blows FM, Driver KE, Schmidt MK, et al. Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies. PLoS Med 2010; 7. DOI: https://doi.org/10.1371/journal.pmed.1000279.
Rakha EA, Pinder SE, Bartlett JM, et al. Updated UK Recommendations for HER2 assessment in breast cancer. Journal of clinical pathology 2015; 68: 93-99. DOI: 10.1136/jclinpath-2014-202571.
Press MF, and C-CC and DJ S. Expression of the HER-2/neu protooncogene
in normal human adult and fetal tissues. Oncogene 1990; 5: 953–962.
Tse C, Gauchez A, Jacot Wa, et al. HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer. cancer Treat Rev 2011; 38: 133-142.
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707-712.
Owens MA, Horten BC and Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer 2004; 5: 63-69.
Vu T and Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2012; 2: 62. DOI: 10.3389/fonc.2012.00062.
Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007; 357: 39-51. DOI: 10.1056/NEJMra043186.
Boekhout AH, Beijnen JH and Schellens JH. Trastuzumab. Oncologist 2011; 16: 800-810. DOI: 10.1634/theoncologist.2010-0035.
Tai W, Mahato R and Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release 2010; 146: 264-275. DOI: 10.1016/j.jconrel.2010.04.009.
Shak S. Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group. Semin Oncol 1999; 26: 71-77.
Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996; 14: 737-744. DOI: 10.1200/JCO.19220.127.116.117.
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: 2639-2648. DOI: 10.1200/JCO.1918.104.22.16839.
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20: 719-726. DOI: 10.1200/JCO.2002.20.3.719.
Baselga J, Carbonell X, Castaneda-Soto NJ, et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 2005; 23: 2162-2171. DOI: 10.1200/JCO.2005.01.014.
Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389: 1195-1205. DOI: 10.1016/S0140-6736(16)32616-2.
Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015; 372: 134-141. DOI: 10.1056/NEJMoa1406281.
Awada A, Colomer R, Inoue K, 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: 1557-1564. DOI: 10.1001/jamaoncol.2016.0237.
Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006; 24: 2786-2792. DOI: 10.1200/JCO.2005.04.1764.
Carey LA, Berry DA, Cirrincione CT, et al. Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 2016; 34: 542-549. DOI: 10.1200/JCO.2015.62.1268.
Harbeck N, Huang CS, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol 2016; 17: 357-366. DOI: 10.1016/S1470-2045(15)00540-9.
Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19: 880-888. DOI: 10.1016/S1470-2045(18)30256-0.
Pistilli B, Pluard T, Urruticoechea A, et al. Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. Breast cancer research and treatment 2018; 168: 357-364. DOI: 10.1007/s10549-017-4596-7.
Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012; 379: 633-640. DOI: 10.1016/S0140-6736(11)61847-3.
Johnston SRD, Hegg R, Im SA, et al. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol 2018; 36: 741-748. DOI: 10.1200/JCO.2017.74.7824.
Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. The Lancet Oncology 2019; 20: 371-382. DOI: 10.1016/S1470-2045(18)30812-X.
Bighin C, Pronzato P and Del Mastro L. Trastuzumab emtansine in the treatment of HER-2-positive metastatic breast cancer patients. Future Oncol 2013; 9: 955-957. DOI: 10.2217/fon.13.74.
McCormack PL. Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer. Drugs 2013; 73: 1491-1502. DOI: 10.1007/s40265-013-0109-0.
Pedersen MW, Jacobsen HJ, Koefoed K, et al. Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance. Mol Cancer Ther 2015; 14: 669-680. DOI: 10.1158/1535-7163.MCT-14-0697.
Chung C and Lam MS. Pertuzumab for the treatment of human epidermal growth factor receptor type 2-positive metastatic breast cancer. Am J Health Syst Pharm 2013; 70: 1579-1587. DOI: 10.2146/ajhp120735.
Cortes J, Fumoleau P, Bianchi GV, 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: 1594-1600. DOI: 10.1200/JCO.2011.37.4207.
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25-32. DOI: 10.1016/S1470-2045(11)70336-9.
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013; 24: 2278-2284. DOI: 10.1093/annonc/mdt182.
Smyth LM, Iyengar NM, Chen MF, et al. Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study. Breast Cancer Res Treat 2016; 158: 91-97. DOI: 10.1007/s10549-016-3851-7.
Perez EA, Lopez-Vega JM, Petit T, et al. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res 2016; 18: 126. DOI: 10.1186/s13058-016-0773-6.
Araki K, Fukada I, Yanagi H, et al. First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer. Breast 2017; 35: 78-84. DOI: 10.1016/j.breast.2017.06.015.
Wildiers H, Tryfonidis K, Dal Lago L, et al. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group. The Lancet Oncology 2018; 19: 323-336. DOI: 10.1016/S1470-2045(18)30083-4.
Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724-734. DOI: 10.1056/NEJMoa1413513.
Urruticoechea A, Rizwanullah M, Im SA, et al. Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy. J Clin Oncol 2017; 35: 3030-3038. DOI: 10.1200/JCO.2016.70.6267.
Urruticoechea A, Rizwanullah M, Im S-A, et al. Final overall survival (OS) analysis of PHEREXA: A randomized phase III trial of trastuzumab (H) + capecitabine (X) ± pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) who experienced disease progression during or after H-based therapy. Journal of Clinical Oncology 2018; 36: 1013-1013. DOI: 10.1200/JCO.2018.36.15_suppl.1013.
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. The New England journal of medicine 2017; 377: 122-131. DOI: 10.1056/NEJMoa1703643.
Beitsch P, Whitworth P, Baron P, et al. Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST). Ann Surg Oncol 2017; 24: 2539-2546. DOI: 10.1245/s10434-017-5863-x.
Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010; 28: 1138-1144. DOI: 10.1200/JCO.2009.24.2024.
Beaver JA, Amiri-Kordestani L, Charlab R, et al. FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Clin Cancer Res 2015; 21: 4760-4766. DOI: 10.1158/1078-0432.CCR-15-1185.
Nur Husna SM, Tan HT, Mohamud R, et al. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol 2018; 10: 1758835918808509. DOI: 10.1177/1758835918808509.
Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol 2018; 19: 249-256. DOI: 10.1016/S1470-2045(18)30001-9.
Li C, Wang B, Chen SC, et al. Exposure-response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Cancer Chemother Pharmacol 2017; 80: 1079-1090. DOI: 10.1007/s00280-017-3440-4.
Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008; 68: 9280-9290. DOI: 10.1158/0008-5472.CAN-08-1776.
Hong E a and R C. Linker Design for Antibody–Drug Conjugates. Springer, Cham, 2015.
Krop IE, Kim SB, Martin AG, 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. The Lancet Oncology 2017; 18: 743-754. DOI: 10.1016/S1470-2045(17)30313-3.
Barok M, Joensuu H and Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast cancer research : BCR 2014; 16: 209. DOI: 10.1186/bcr3621.
Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011; 128: 347-356. DOI: 10.1007/s10549-010-1090-x.
Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010; 28: 2698-2704. DOI: 10.1200/JCO.2009.26.2071.
Beeram M, Krop IE, Burris HA, et al. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 2012; 118: 5733-5740. DOI: 10.1002/cncr.27622.
Yamamoto H, Ando M, Aogi K, et al. Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer. Jpn J Clin Oncol 2015; 45: 12-18. DOI: 10.1093/jjco/hyu160.
Burris HA, 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011; 29: 398-405. DOI: 10.1200/JCO.2010.29.5865.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-1791. DOI: 10.1056/NEJMoa1209124.
Krop IE, Modi S, LoRusso PM, et al. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res 2016; 18: 34. DOI: 10.1186/s13058-016-0691-7.
Martin M, Fumoleau P, Dewar JA, et al. Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2016; 27: 1249-1256. DOI: 10.1093/annonc/mdw157.
Miller KD, Dieras V, Harbeck N, et al. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol 2014; 32: 1437-1444. DOI: 10.1200/JCO.2013.52.6590.
Perez EA, Barrios C, Eiermann W, 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: 141-148. DOI: 10.1200/JCO.2016.67.4887.
Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2018; 19: 115-126. DOI: 10.1016/S1470-2045(17)30716-7.
Efficacy and Safety of Trastuzumab Emtansine in Chinese Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer, https://clinicaltrials.gov/ct2/show/NCT03084939 (2018, accessed 27 April 2019).
A Study of Trastuzumab Emtansine (Kadcyla) Plus Pertuzumab (Perjeta) Following Anthracyclines in Comparison With Trastuzumab (Herceptin) Plus Pertuzumab and a Taxane Following Anthracyclines as Adjuvant Therapy in Participants With Operable HER2-Positive Primary Breast Cancer, https://clinicaltrials.gov/ct2/show/NCT01966471 (2019, accessed 27 April 2019 2019).
Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013; 31: 1157-1163. DOI: 10.1200/JCO.2012.44.9694.
Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30: 3234-3241. DOI: 10.1200/JCO.2011.40.5902.
Kashiwaba M, Ito Y, Takao S, et al. A multicenter Phase II study evaluating the efficacy, safety and pharmacokinetics of trastuzumab emtansine in Japanese patients with heavily pretreated HER2-positive locally recurrent or metastatic breast cancer. Jpn J Clin Oncol 2016; 46: 407-414. DOI: 10.1093/jjco/hyw013.
Harbeck N, Gluz O, Christgen M, et al. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017; 35: 3046-3054. DOI: 10.1200/JCO.2016.71.9815.
Phase 2 Study of Tucatinib vs Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB), https://clinicaltrials.gov/ct2/results?cond=&term=NCT02614794 (2018, accessed August 15 2018).
Adjuvant Trastuzumab, Pertuzumab Plus Docetaxel in the Treatment of Early HER2-positive Breast Cancer (BOLD-1), https://clinicaltrials.gov/ct2/show/NCT02625441?term=NCT02625441&rank=1 (2018, accessed Mei 14 2018).
A Study to Assess Preference for Subcutaneous Trastuzumab Treatment in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Metastatic Breast Cancer Responding to First-Line Intravenous Trastuzumab for at Least 3 Years, https://clinicaltrials.gov/ct2/show/NCT01810393 (2018, accessed 14 May 2018).
Pre Operative Trastuzumab in Operable Breast Cancer, https://clinicaltrials.gov/ct2/show/NCT01785420 (2018, accessed 14 May 2018).
Pertuzumab With High-Dose Trastuzumab in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (MBC) With Central Nervous System (CNS) Progression Post-Radiotherapy, https://clinicaltrials.gov/ct2/show/NCT02536339 (2018, accessed 14 May 2018).
A Phase III Trial of Pertuzumab Retreatment in Previously Pertuzumab Treated Her2-Positive Advanced Breast Cancer (PRECIOUS), https://clinicaltrials.gov/ct2/show/NCT02514681 (2018, accessed 14 May 2018).
A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE), https://clinicaltrials.gov/ct2/show/NCT01772472 (2018, accessed 14 May 2018).