Mechanisms of Resistance to Trastuzumab in Treating HER2-Positive Breast Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 ZHOUYu-ting , TANQiu-wen ,  LÜQing

Department of Brest Surgery Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China;

Corresponding author：

LÜQing, Email: lvqingwestchina@163.com

Keywords：

Human epidermal growth factor receptor 2-positive; Breast cancer; Trastuzumab resistance; Gene profile

DOI：

10.7507/1007-9424.20160328

Video：

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Objective To summarize the progress in mechanisms of resistance to trastuzumab in treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods By searching Pubmed and CNKI, the literatures of mechanisms of resistance to trastuzumab in treating HER2-positive breast cancer were reviewed. Results The possible mechanism of resistance to trastuzumab are thought to include HER2 gene amplification and high protein expression; impaired access of trastuzumab to HER2; bidirectional crosstalk between ER and HER2; HER2 downstream signal transduction pathway activation; expansion expression of other RTKs and membrane-associated receptors; alterations in apoptosis and cell cycle control as well as multi-gene mutation, etc. Conclusions Mechanisms of trastuzumab resistance in HER2-positive breast cancer is complicated, a better understanding will be achieved by comprehensive analysis of existing possible mechanisms. The outcome of HER2-positive breast cancer patients who developed resistance to trastuzumab will be improved by appropriate multi-target regime.

Citation： ZHOU Yu-ting, TAN Qiu-wen, LÜ Qing. Mechanisms of Resistance to Trastuzumab in Treating HER2-Positive Breast Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2016, 23(10): 1280-1284. doi: 10.7507/1007-9424.20160328 Copy

1.	Acharyya S, Oskarsson T, Vanharanta S, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell, 2012, 150(1):165-178.
2.	Gianni L, Eiermann W, Semiglazov V, 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(6):640-647.
3.	O'Sullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤ 2 cm:a meta-analysis of the randomized trastuzumab trials. J Clin Oncol, 2015, 33(24):2600-2608.
4.	Santa-Maria CA, Nye L, Mutonga MB, et al. Management of metastatic HER2-positive breast cancer:where are we and where do we go from here? Oncology (Williston Park), 2016, 30(2):148-155.
5.	Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA):a randomised, open-label, phase 3 trial. Lancet Oncol, 2014, 15(7):689-699.
6.	Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE):a single-group phase 2 study. Lancet Oncol, 2013, 14(1):64-71.
7.	Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med, 2012, 367(19):1783-1791.
8.	Arienti C, Zanoni M, Pignatta S, et al. Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer. Oncotarget, 2016, 7(14):18424-18439.
9.	陶云霞, 张有为,孙丽,等. 曲妥珠单抗耐药机制及耐药后的治疗策略的研究进展. 中华临床医师杂志:电子版, 2015, 9(22):4212-4215.
10.	Shi Y, Fan X, Meng W, et al. Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation. Breast Cancer Res, 2014, 16(2):R33.
11.	Scaltriti M, Nuciforo P, Bradbury I, et al. High HER2 expression correlates with response to the combination of lapatinib and trastuzumab. Clin Cancer Res, 2015, 21(3):569-576.
12.	Lipton A, Goodman L, Leitzel K, et al. HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat, 2013, 141(1):43-53.
13.	Madrid-Paredes A, Cañadas-Garre M, Sánchez-Pozo A. De novo resistance biomarkers to anti-HER2 therapies in HER2-positive breast cancer. Pharmacogenomics, 2015, 16(12):1411-1426.
14.	Tural D, Serdengecti S, Demirelli F, et al. Clinical significance of p95HER2 over expression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Br J Cancer, 2014, 110(8):1968-1976.
15.	Inoue K, Fry EA. Aberrant splicing of estrogen receptor, HER2, and CD44 genes in breast cancer. Genet Epigenet, 2015, 7:19-32.
16.	Tan M, Huynh FC, Jones FE. MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Δ16 mediated breast tumorigenesis and reverse trastuzumab resistance. PLoS ONE, 2014, 9(12):e114419.
17.	Giuliano M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer:molecular basis and clinical implications. Breast Care (Basel), 2013, 8(4):256-262.
18.	Luque-Cabal M, Garcia-Teijido P, Fernández-Pérez Y, et al. Mechanisms behind the resistance to trastuzumab in HER2-Amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol, 2016, 10(Suppl 1):21-30.
19.	Menyhárt O, Santarpia L, Győrffy B. A comprehensive outline of trastuzumab resistance biomarkers in HER2 overexpressing breast cancer. Curr Cancer Drug Targets, 2015, 15(8):665-683.
20.	Wilks ST. Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast, 2015, 24(5):548-555.
21.	Vu T, Sliwkowski MX, Claret FX. Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer. Biochim Biophys Acta, 2014, 1846(2):353-365.
22.	Gamez-Pozo A, Perez Carrion RM, Manso L, et al. The long-HER study:clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. PLoS One, 2014, 9(10):e109611.
23.	Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol, 2015, 33(12):1334-1339.
24.	Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2(her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol, 2014, 32(29):3212-3220.
25.	Pogue-Geile KL, Song N, Jeong JH, et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol, 2015, 33(12):1340-1347.
26.	José Baselga, Javier Cortés, Seock-Ah Im, et al. Biomarker analyses in CLEOPATRA:a phase Ⅲ, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol, 2014, 32(33):3753-3761.
27.	Loi S, Michiels S, Lambrechts D, et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst, 2013, 105(13):960-967.
28.	André F, O'Regan R, Ozguroglu M, 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 Oncology, 2014, 15(6):580-591.
29.	Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer, 2015, 14:43.
30.	Gagliato DM, Jardim DL, Marchesi MS, et al. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER²⁺ breast cancer. Oncotarget, 2016 Jan 27.[Epub ahead of print].
31.	Roskoski R Jr. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res, 2015, 94:9-25.
32.	Peiró G, Ortiz-Martínez F, Gallardo A, et al. Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma. Br J Cancer, 2014, 111(4):689-695.
33.	Veenstra C, Pérez-Tenorio G, Stelling A, et al. Met and its ligand HGF are associated with clinical outcome in breast cancer. Oncotarget,.
34.	Obeid EI, Conzen SD. The role of adrenergic signaling in breast cancer biology. Cancer Biomark, 2013, 13(3):161-169.
35.	Liu D, Yang Z, Wang T, et al. β2-AR signaling controls trastuzumab resistance-dependent pathway. Oncogene, 2016, 35(1):47-58.
36.	von der Heyde S, Wagner S, Czerny A, et al. mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer. PLoS One, 2015, 10(2):e0117818.·.
37.	May 10.[Epub ahead of print].

1. Acharyya S, Oskarsson T, Vanharanta S, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell, 2012, 150(1):165-178.
2. Gianni L, Eiermann W, Semiglazov V, 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(6):640-647.
3. O'Sullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤ 2 cm:a meta-analysis of the randomized trastuzumab trials. J Clin Oncol, 2015, 33(24):2600-2608.
4. Santa-Maria CA, Nye L, Mutonga MB, et al. Management of metastatic HER2-positive breast cancer:where are we and where do we go from here? Oncology (Williston Park), 2016, 30(2):148-155.
5. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA):a randomised, open-label, phase 3 trial. Lancet Oncol, 2014, 15(7):689-699.
6. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE):a single-group phase 2 study. Lancet Oncol, 2013, 14(1):64-71.
7. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med, 2012, 367(19):1783-1791.
8. Arienti C, Zanoni M, Pignatta S, et al. Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer. Oncotarget, 2016, 7(14):18424-18439.
9. 陶云霞, 张有为,孙丽,等. 曲妥珠单抗耐药机制及耐药后的治疗策略的研究进展. 中华临床医师杂志:电子版, 2015, 9(22):4212-4215.
10. Shi Y, Fan X, Meng W, et al. Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation. Breast Cancer Res, 2014, 16(2):R33.
11. Scaltriti M, Nuciforo P, Bradbury I, et al. High HER2 expression correlates with response to the combination of lapatinib and trastuzumab. Clin Cancer Res, 2015, 21(3):569-576.
12. Lipton A, Goodman L, Leitzel K, et al. HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat, 2013, 141(1):43-53.
13. Madrid-Paredes A, Cañadas-Garre M, Sánchez-Pozo A. De novo resistance biomarkers to anti-HER2 therapies in HER2-positive breast cancer. Pharmacogenomics, 2015, 16(12):1411-1426.
14. Tural D, Serdengecti S, Demirelli F, et al. Clinical significance of p95HER2 over expression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Br J Cancer, 2014, 110(8):1968-1976.
15. Inoue K, Fry EA. Aberrant splicing of estrogen receptor, HER2, and CD44 genes in breast cancer. Genet Epigenet, 2015, 7:19-32.
16. Tan M, Huynh FC, Jones FE. MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Δ16 mediated breast tumorigenesis and reverse trastuzumab resistance. PLoS ONE, 2014, 9(12):e114419.
17. Giuliano M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer:molecular basis and clinical implications. Breast Care (Basel), 2013, 8(4):256-262.
18. Luque-Cabal M, Garcia-Teijido P, Fernández-Pérez Y, et al. Mechanisms behind the resistance to trastuzumab in HER2-Amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol, 2016, 10(Suppl 1):21-30.
19. Menyhárt O, Santarpia L, Győrffy B. A comprehensive outline of trastuzumab resistance biomarkers in HER2 overexpressing breast cancer. Curr Cancer Drug Targets, 2015, 15(8):665-683.
20. Wilks ST. Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast, 2015, 24(5):548-555.
21. Vu T, Sliwkowski MX, Claret FX. Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer. Biochim Biophys Acta, 2014, 1846(2):353-365.
22. Gamez-Pozo A, Perez Carrion RM, Manso L, et al. The long-HER study:clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy. PLoS One, 2014, 9(10):e109611.
23. Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol, 2015, 33(12):1334-1339.
24. Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2(her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol, 2014, 32(29):3212-3220.
25. Pogue-Geile KL, Song N, Jeong JH, et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol, 2015, 33(12):1340-1347.
26. José Baselga, Javier Cortés, Seock-Ah Im, et al. Biomarker analyses in CLEOPATRA:a phase Ⅲ, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol, 2014, 32(33):3753-3761.
27. Loi S, Michiels S, Lambrechts D, et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst, 2013, 105(13):960-967.
28. André F, O'Regan R, Ozguroglu M, 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 Oncology, 2014, 15(6):580-591.
29. Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer, 2015, 14:43.
30. Gagliato DM, Jardim DL, Marchesi MS, et al. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER²⁺ breast cancer. Oncotarget, 2016 Jan 27.[Epub ahead of print].
31. Roskoski R Jr. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res, 2015, 94:9-25.
32. Peiró G, Ortiz-Martínez F, Gallardo A, et al. Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma. Br J Cancer, 2014, 111(4):689-695.
33. Veenstra C, Pérez-Tenorio G, Stelling A, et al. Met and its ligand HGF are associated with clinical outcome in breast cancer. Oncotarget,.
34. Obeid EI, Conzen SD. The role of adrenergic signaling in breast cancer biology. Cancer Biomark, 2013, 13(3):161-169.
35. Liu D, Yang Z, Wang T, et al. β2-AR signaling controls trastuzumab resistance-dependent pathway. Oncogene, 2016, 35(1):47-58.
36. von der Heyde S, Wagner S, Czerny A, et al. mRNA profiling reveals determinants of trastuzumab efficiency in HER2-positive breast cancer. PLoS One, 2015, 10(2):e0117818.·.
37. May 10.[Epub ahead of print].

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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Mechanisms of Resistance to Trastuzumab in Treating HER2-Positive Breast Cancer

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