Current treatment approaches for breast cancer patients with HER2-positive disease in the adjuvant, and neo-adjuvant setting


  • Rashmi Purushottam Surti Maharashtra University of Health Sciences, Maharashtra, India



Breast cancer, HER2


Breast cancer (BC) is the second most common cancer and the leading cause of mortality among women globally. Approximately 20% to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2- therapies (trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM 1) has changed the natural history of HER2-positive BC and improved the prognosis and survival in HER2-positive BC patients. The approval of trastuzumab and pertuzumab linked with a taxane as a first-line treatment and follow-up treatment with the antibody-drug conjugate T-DM1 has undeniably contributed to attaining these outcomes. The Tyrosine Kinase Inhibitor lapatinib is another commonly used treatment in combination with capecitabine, approved on the basis of an improvement in progression-free survival. The superiority of combination anti-HER2 therapy to achieve more complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. Nonetheless, studies have also suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only a single chemotherapy agent or in the absence of any chemotherapy. However, despite therapeutic advances, tumors expressing estrogen receptor (ER) have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. The aim of this review is to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant, and neoadjuvant setting.


Cancer Fact Sheet. Last accessed on 21st December, 2019.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.

Breast cancer. Last accessed on 21st December, 2019.

Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol. 2017;13:289-295.

Mahtani R, Hineman L. Advances in HER2-Positive Breast Cancer: Novel Therapies and Adverse Event Management. J Adv Pract Oncol. 2019;10:136-153.

Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med. 2005;353:1652-4.

Figueroa-Magalhães MC, Jelovac D, Connolly R, Wolff AC. Treatment of HER2-positive Breast Cancer. Breast. 2014;23:128-136.

Baselga J, Coleman RE, Cortés J, Janni W. Advances in the management of HER2-positive early breast cancer. Crit Rev Oncol Hematol. 2017;119:113-122.

Zurawska U, Baribeau DA, Giilck S, Victor C, Gandhi S, Florescu A, et al. Outcomes of HER2-positive early-stage breast cancer in the trastuzumab era: a population-based study of Canadian patients.Curr Oncol. 2013;20:e539-45.

Ahmed S, Sami A, Xiang J. HER2-directed therapy: current treatment options for HER2-positive breast cancer. Breast Cancer. 2015;22:101-16.

Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1758835919833519.

Pondé N, Brandão M, El-Hachem G, Werbrouck E, Piccart M. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev. 2018;67:10-20.

Wuerstlein R, Harbeck N. Neoadjuvant Therapy for HER2-positive Breast Cancer. Rev Recent Clin Trials. 2017;12:81-92.

Sharp A, Johnston SR. Dose-reduced trastuzumab emtansine: active and safe in acute hepatic dysfunction. Case Rep Oncol. 2015;8:113-21.

Larionov AA. Current Therapies for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients. Front Oncol. 2018;8:89.

Lv Q, Meng Z, Yu Y, Jiang F, Guan D, Liang C et al. Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer. Int J Mol Sci. 2016;17:2095.

Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog. 2012;17:1-16.

Meric-Bernstam F, Johnson AM, Dumbrava EEI, Raghav K, Balaji K, Bhatt M, et al. Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer. Clin Cancer Res. 2019;25:2033-41.

Brufsky AM. Current Approaches and Emerging Directions in HER2-resistant Breast Cancer. Breast Cancer (Auckl). 2014;8:109-18.

Baselga J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand-dependent ErbB2 receptor heterodimerization. Cancer Cell. 2002;2:93-5.

Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16:5276-87.

Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, HoeflichKP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-87.

Menendez JA, Schroeder B, Peirce SK, Vellon L, Papadimitropoulou A, Espinoza I, et al. Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling. J Natl Cancer Inst. 2015;107:djv090.

Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317-28.

Baselga J, Cortés J, Kim SB, Im SA, Hegg R, ImYH, et al. CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M et al. CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-34.

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomized, open-label, multicenter, phase 3 trial. Lancet. 2012b;379:633-40.

Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900. J Clin Oncol. 2012;30:2585-92.

Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224-37.

Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER2 tyrosine kinase. Cancer Res. 2004;64:3958-3965.

Sánchez-Martín M, Pandiella A. Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: therapeutic implications. Int J Cancer. 2012;131:244-252.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer. N Engl J Med 2005;353:1659-1672.

Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al, Herceptin Adjuvant (HERA) Trial Study Team. 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.

Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744-52.

Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15:640-7.

Goss PE, Smith IE, O’Shaughnessy J, Ejlertsen B, Kaufmann M, Boyle F, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomized, controlled, phase 3 trial. Lancet Oncol. 2013;14:88-96.

Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016;34:1034-42.

Moreno-Aspitia A, Holmes E, Jackisch C, de Azambuja E, Boyle F, Hillman DW, et al. Updated results from the phase III ALTTO trial (BIG NCCTG/Alliance N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L) or their combination (L + T) in the adjuvant treatment of HER2-positive early breast cance. J Clin Oncol. 2017;35(suppl):2-06.

Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ et al. ExteNET Study Group. 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;17:367-77.

Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, et al. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer: 5-year analysis of the phase III ExteNET trial. Ann Oncol. 2017;28(5).

von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G et al. APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-31.

Lambert JM, Chari RV. Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014;57:6949-64.

von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M et al. KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380:617-628.

Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008;34:539-57.

Arnould L, Arveux P, Couturier J, Gelly-Marty M, Loustalot C, Ettore F et al. Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification. Clin Cancer Res. 2007;13:6404-9.

Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676-3685.

Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84.

Untch M, Fasching PA, Konecny GE, Hasmüller S, Lebeau A, Kreienberg R et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol. 2011;29:3351-7.

Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1317-25.

Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28:2024-31.

Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB. et al. Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012;13:869-78.

Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;13:135-44.

Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1183-92.

Gianni L, Pienkowski T, ImYH, Roman L, Tseng LM, Liu MC et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomisedmulticentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

Gianni L, Pienkowski T, ImYH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17:791-800.

Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R 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;24:2278-84.

Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design. Pharmacol Ther. 2018;181:126-42.

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;367:1783-1791.

Iwata H, Tamura K, Doi T, Tsurutani J, Modi S, Park H et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol. 2018;36:2501.

Saura C, Thistlethwaite F, Banerji U, Lord S, Moreno V, MacPherson I, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer [abstract]. J Clin Oncol. 2018;36:1014.

Yurkovetskiy A, Gumerov D, Ter-Ovanesyan E, Conlon P, Devit M, Bu C, et al. Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate [abstract]. Proc Am Assoc Cancer Res Annual Meeting 2017. Cancer Res. 2017;77(13):48.

Escrivá-de-Romaní S, Arumí M, Bellet M, Saura C. HER2-positive breast cancer: Current and new therapeutic strategies. Breast. 2018;39:80-88.

Esposito A, Viale G, Criscitiello C, Curigliano G. A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer. Expert Rev Clin Pharmacol. 2019;12:9-16.

Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009;27:5685-5692.

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-1283.

Guarneri V, Frassoldati A, Bruzzi P, D'Amico R, Belfiglio M, Molino A. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer. 2008;8:453-6.

Conte PF, Bisagni G, Frassoldati A, Brandes AA, Anselmi E, Giotta F et al. 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian study Short-HER [abstract]. J Clin Oncol. 2017;35:501.

Earl HM, Cameron DA, Miles D, Wardley AM, Ogburn E, Vallier AL et al. The PERSEPHONE trial: Duration of Trastuzumab with Chemotherapy in women with HER-2 positive early breast cancer[abstract]. J Clin Oncol. 2012;30:660.

Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393:2599-612.

Tolaney S, Guo H, Pernas S, Barry W, Dillon D, Ritterhouse L, et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. Journal of Clinical Oncology. 2019;37(22):1868-75.

U.S. Food & Drugs Administration, Prescribing Information for Nerlynx. Last accessed on 30th December, 2019.

André 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;15:580-91.

De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11:4741-8.

Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A. 2006;103:7795-800.

Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.Sci Transl Med. 2015;7:283ra51.

Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538-46.

Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529-37.

Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013;31:1726-31.

Nitz UA, Gluz O, Christgen M, Grischke EM, Augustin D, Kuemmel S et al; West-German Study Group (WSG)-ADAPT Investigators. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phases II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol. 2017;28:2768-2772.




How to Cite

Surti, R. P. (2021). Current treatment approaches for breast cancer patients with HER2-positive disease in the adjuvant, and neo-adjuvant setting. International Journal of Basic & Clinical Pharmacology, 10(5), 596–608.



Review Articles