Research progress of anti-HER-2 dual targeted therapy for HER-2-positive breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XU Run ¹ ,  DU Zhenggui ²

1. Derpartment of General Surgery, The Third Hospital of Mianyang (Sichuan Provincial for Mental Health), Mianyang, Sichuan 621000, P. R. China;
2. Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

DU Zhenggui, Email: docduzg@163.com

Keywords：

breast cancer; human epidermal growth factor receptor-2; targeted therapy; review

DOI：

10.7507/1007-9424.202006041

Video：

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Objective To summarize and analyze the long-term follow-up results and the recent researches of anti-epidermal growth factor receptor-2 (HER-2) dual targeted therapy for patients with human HER-2-positive breast cancer in terms of neoadjuvant, adjuvant, and salvage treatment so as to further improve the understanding of dual targeted therapy against HER-2 in clinical practice.Method The literatures on studies of dual targeted therapy for patients with HER-2-positive breast cancer in recent years were reviewed and analyzed.Result The anti-HER-2 dual targeted therapy could achieve a higher pathological complete response rate and better prognosis in the neoadjuvant therapy, as well as in adjuvant therapy and salvage treatment.Conclusion In recent years, different combinations of targeted drugs in neoadjuvant, adjuvant, and salvage treatment of patients with HER-2-positive breast cancer have shown a benefit in clinical application, but more large sample prospective clinical researches are needed so as to find out optimal combination of targeted drugs with more benefits, less complications, and more economies.

Citation： XU Run, DU Zhenggui. Research progress of anti-HER-2 dual targeted therapy for HER-2-positive breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(4): 544-550. doi: 10.7507/1007-9424.202006041 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
2.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3.	Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist, 2009, 14(4): 320-368.
4.	Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 1987, 235(4785): 177-182.
5.	Witton CJ, Reeves JR, Going JJ, et al. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol, 2003, 200(3): 290-297.
6.	Gianni L, Eiermann W, Semiglazov V, 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(9712): 377-384.
7.	Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet, 2013, 382(9897): 1021-1028.
8.	Perez EA, Romond EH, Suman VJ, 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(33): 3744-3752.
9.	Marty M, Cognetti F, Maraninchi D, et al. Randomized phase Ⅱ trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol, 2005, 23(19): 4265-4274.
10.	江泽飞, 邵志敏, 徐兵河. 人表皮生长因子受体 2 阳性乳腺癌临床诊疗专家共识 2016. 中华医学杂志, 2016, 96(14): 1091-1096.
11.	Wong H, Leung R, Kwong A, et al. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer. Oncologist, 2011, 16(11): 1535-1546.
12.	Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
13.	Esteva FJ, Pusztai L. Optimizing outcomes in HER2-positive breast cancer: the molecular rationale. Oncology (Williston Park), 2005, 19(13 Suppl 5): 5-16.
14.	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(1): 25-32.
15.	Gianni L, Pienkowski T, Im YH, 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(6): 791-800.
16.	Shao Z, Pang D, Yang H, et al. Efficacy, safety, and tolerability of pertuzumab, trastuzumab, and docetaxel for patients with early or locally advanced ERBB2-positive breast cancer in Asia: The PEONY phase 3 randomized clinical trial. JAMA Oncol, 2020, 6(3): e193692.
17.	Hegde PS, Rusnak D, Bertiaux M, et al. Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther, 2007, 6(5): 1629-1640.
18.	Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene, 2002, 21(41): 6255-6263.
19.	de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol, 2014, 15(10): 1137-1146.
20.	Robidoux A, Tang G, Rastogi P, 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(12): 1183-1192.
21.	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(6): 542-549.
22.	Untch M, von Minckwitz G, Gerber B, et al. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol, 2018, 36(13): 1308-1316.
23.	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(1): 115-126.
24.	Bergh JC. Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: Results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard? ASCO, 2019, Abstract 501Poster Session.
25.	Chan A, Delaloge S, Holmes FA, 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.
26.	Jacobs SA, Robidoux A, et al. NSABP FB-7: a phase Ⅱ randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2(+) breast cancer. Breast Cancer Res, 2019, 21(1): 133.
27.	Nagayama A, Hayashida T, Jinno H, et al. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. J Natl Cancer Inst, 2014, 106(9): dju203.
28.	National ComprehensiveCancer Network: NCCN clinical practice guidelines in oncology: Breast cancer (Version 1.2020), 2020.
29.	Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol, 2017, 28(8): 1700-1712.
30.	von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med, 2017, 377(2): 122-131.
31.	Piccart-Gebhart M, Holmes E, Baselga J, 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(10): 1034-1042.
32.	Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol, 2020, 21(4): 519-530.
33.	Xu BH. Phase Ⅲ, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P)+trastuzumab (H)+docetaxel (D) versus Pla+H+D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN). ASCO, 2019, Abstract 1026 Poster Session.
34.	De Placido S, Giuliano M, Schettini F, et al. Human epidermal growth factor receptor 2 dual blockade with trastuzumab and pertuzumab in real life: Italian clinical practice versus the CLEOPATRA trial results. Breast, 2018, 38: 86-91.
35.	Masuda N, Ohtani S, Nagai S, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positivemetastatic breast cancer: Results of single arm phase Ⅳ COMACHI study. Ann Oncol, 2019, 30(Supplement_5).
36.	Bachelot T, Ciruelos E, Schneeweiss A, et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Ann Oncol, 2019, 30(5): 766-773.
37.	Blackwell KL, Burstein HJ, Storniolo AM, 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 Study. J Clin Oncol, 2012, 30(21): 2585-2592.
38.	Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Cancer, 2019, 125(22): 3974-3984.
39.	Rimawi M, Ferrero JM, de la Haba-Rodriguez J, et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase Ⅱ trial. J Clin Oncol, 2018, 36(28): 2826-2835.
40.	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: updated results of ALTERNATIVE. J Clin Oncol, 2020: JCO2001894.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist, 2009, 14(4): 320-368.
4. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 1987, 235(4785): 177-182.
5. Witton CJ, Reeves JR, Going JJ, et al. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol, 2003, 200(3): 290-297.
6. Gianni L, Eiermann W, Semiglazov V, 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(9712): 377-384.
7. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet, 2013, 382(9897): 1021-1028.
8. Perez EA, Romond EH, Suman VJ, 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(33): 3744-3752.
9. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase Ⅱ trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol, 2005, 23(19): 4265-4274.
10. 江泽飞, 邵志敏, 徐兵河. 人表皮生长因子受体 2 阳性乳腺癌临床诊疗专家共识 2016. 中华医学杂志, 2016, 96(14): 1091-1096.
11. Wong H, Leung R, Kwong A, et al. Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer. Oncologist, 2011, 16(11): 1535-1546.
12. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
13. Esteva FJ, Pusztai L. Optimizing outcomes in HER2-positive breast cancer: the molecular rationale. Oncology (Williston Park), 2005, 19(13 Suppl 5): 5-16.
14. 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(1): 25-32.
15. Gianni L, Pienkowski T, Im YH, 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(6): 791-800.
16. Shao Z, Pang D, Yang H, et al. Efficacy, safety, and tolerability of pertuzumab, trastuzumab, and docetaxel for patients with early or locally advanced ERBB2-positive breast cancer in Asia: The PEONY phase 3 randomized clinical trial. JAMA Oncol, 2020, 6(3): e193692.
17. Hegde PS, Rusnak D, Bertiaux M, et al. Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther, 2007, 6(5): 1629-1640.
18. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene, 2002, 21(41): 6255-6263.
19. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol, 2014, 15(10): 1137-1146.
20. Robidoux A, Tang G, Rastogi P, 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(12): 1183-1192.
21. 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(6): 542-549.
22. Untch M, von Minckwitz G, Gerber B, et al. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol, 2018, 36(13): 1308-1316.
23. 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(1): 115-126.
24. Bergh JC. Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: Results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard? ASCO, 2019, Abstract 501Poster Session.
25. Chan A, Delaloge S, Holmes FA, 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.
26. Jacobs SA, Robidoux A, et al. NSABP FB-7: a phase Ⅱ randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2(+) breast cancer. Breast Cancer Res, 2019, 21(1): 133.
27. Nagayama A, Hayashida T, Jinno H, et al. Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. J Natl Cancer Inst, 2014, 106(9): dju203.
28. National ComprehensiveCancer Network: NCCN clinical practice guidelines in oncology: Breast cancer (Version 1.2020), 2020.
29. Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol, 2017, 28(8): 1700-1712.
30. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med, 2017, 377(2): 122-131.
31. Piccart-Gebhart M, Holmes E, Baselga J, 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(10): 1034-1042.
32. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol, 2020, 21(4): 519-530.
33. Xu BH. Phase Ⅲ, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P)+trastuzumab (H)+docetaxel (D) versus Pla+H+D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN). ASCO, 2019, Abstract 1026 Poster Session.
34. De Placido S, Giuliano M, Schettini F, et al. Human epidermal growth factor receptor 2 dual blockade with trastuzumab and pertuzumab in real life: Italian clinical practice versus the CLEOPATRA trial results. Breast, 2018, 38: 86-91.
35. Masuda N, Ohtani S, Nagai S, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positivemetastatic breast cancer: Results of single arm phase Ⅳ COMACHI study. Ann Oncol, 2019, 30(Supplement_5).
36. Bachelot T, Ciruelos E, Schneeweiss A, et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Ann Oncol, 2019, 30(5): 766-773.
37. Blackwell KL, Burstein HJ, Storniolo AM, 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 Study. J Clin Oncol, 2012, 30(21): 2585-2592.
38. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE. Cancer, 2019, 125(22): 3974-3984.
39. Rimawi M, Ferrero JM, de la Haba-Rodriguez J, et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase Ⅱ trial. J Clin Oncol, 2018, 36(28): 2826-2835.
40. 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: updated results of ALTERNATIVE. J Clin Oncol, 2020: JCO2001894.

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