HER-2 GENE, RECEPTORS AND DRUG TARGET: A SYSTEMATIC REVIEW
The discovery and identification of the human epidermal growth factor receptor 2 (HER's-2) genes, have led to a better understanding of breast tumour biology. A member of the epidermal growth factor receptor family, it is a potent mediator of cellular growth and proliferation in malignant epithelial cells. Amplification or over expression of HER-2 occurs in approximately 15â€“30 % of breast cancers and 10â€“30 % of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. Treatment with HER-2 targeted monoclonal antibody, trastuzumab dramatically improved outcome in patients with breast malignancy. This promising approach led to the development of pertuzumab, ado-trastuzumab emtansine and lapatinib. The development of drug resistance and disease progression due to alternate signalling remained a real therapeutic challenge. Several research studies are currently focused on inhibition of onco-proteins, kinases and growth factors linked to HER-2 positive breast cancers. The success of immune checkpoint modulators and vaccines in preliminary studies describes the role of tumour immunity. Apart from its role in the pathogenesis of various cancers, HER-2 directed therapeutic approach has brought about a revolutionary change in terms of time to progression and survival rates in breast cancers.Keywords: ErbB-2 signalling, Targeted approach, Trastuzumab, Drug resistance
2. Moasser MM. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007;26;6469-87.
3. Kumar GL, Badve SS. Milestones in the discovery of HER2 proto-oncogene and trastuzumab. Connection 2008;13:9-14.
4. Funkhouser WK, Kaiser-Rogers K. Significance of, and optimal screening for, Her-2 gene amplification and protein over expression in breast carcinoma. Ann Clin Lab Sci 2001;31:349-58.
5. Landgraf R. HER2 (ERBB2): functional diversity from structurally conserved building blocks. Breast Cancer Res 2007;9:202-10.
6. Breuleux M. Role of neuregulin in human cancer. Cell Mol Life Sci 2007;64:2358-77.
7. Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Controlled Release 2010;146:264-75.
8. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int 2014. Doi.org/10.1155/ 2014/ 852748. [Article in Press]
9. Roskoski R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 2014;79:34-74.
10. Funkhouser WK, Kaiser-Rogers K. Significance of, and optimal screening for, Her-2 gene amplification and protein overexpression in breast carcinoma. Ann Clin Lab Sci 2001;31:349-58.
11. Cianfrocca M, Goldstein LJ. Prognostic and predictive factors in early-stage breast cancer. Oncologist 2004;9:606-16.
12. Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: Association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 2001;29:859-67.
13. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-37.
14. Cooke T, Reeves J, Lanigan A, Stanton P. HER2 as a prognostic and predictive marker for breast cancer. Annal Oncol 2001;12:23-8.
15. Ruschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F. HER2 testing in gastric cancer: a practical approach. Mod Pathol 2012;25:637-50.
16. Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Clark E, et al. HER-2/neu testing in breast cancer. Am J Clin Pathol 2003;120:53-71.
17. Goud KI, Dayakar S, Vijayalaxmi K, Babu SJ, Vijay ARP. Evaluation of HER-2/neu status in breast cancer specimens using immunohistochemistry (IHC) & fluorescence in-situ hybridization (FISH) assay. Indian J Med Res 2012;135:312-7.
18. Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, et al. HER-2 testing in breast cancer using parallel tissue-based methods. JAMA 2004;291:1972-7.
19. Taboada S, Whitney-Miller CL. Updates in HER2 testing in gastric cancer. Gastrointestinal Digestive System 2013;3:131.
20. Oâ€™Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2â€“positive early breast cancer and tumors â‰¤ 2 cm: a meta-analysis of the randomized trastuzumab trials. J Clin Oncol 2015;33:2600-8.
21. Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008;13:620-30.
22. Gunturu KS, Woo Y, Beaubier N, Remotti HE, Saif MW. Gastric cancer and trastuzumab: first biologic therapy in gastric cancer. Ther Adv Med Oncol 2013;5:143-51.
23. Nahta R. Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer. ISRN Oncology 2012. Doi:10.5402/2012/428062. [Epub 22 Nov 2012]
24. Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Annal Oncol 2007;18:977-84.
25. Kyi C, Shah MA. A case report of trastuzumab dose in gastric cancer. J Gastrointest Oncol 2013;4;19-22.
26. Gonzalez-Angulo AM, Hortobagyi GN, Esteva FJ. Adjuvant therapy with trastuzumab for HER-2/neu-positive breast cancer. Oncologist 2006;11:857-67.
27. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910-6.
28. Paul B, Trovato JA, Thompson J. Lapatinib: a dual tyrosine kinase inhibitor for metastatic breast cancer. Am J Health Syst Pharm 2008;65:1703-10.
29. Rana P, Sridhar SS. Efficacy and tolerability of lapatinib in the management of breast cancer. Breast Cancer: Basic Clin Res 2012;6:67-77.
30. Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations. Oncologist 2007;12:756-65.
31. Untch M, Luck HJ. Lapatinibâ€“member of a new generation of ErbB-targeting drugs. Breast Care 2010;5:8-12.
32. Capelan M, Pugliano L, De Azambuja E, Bozovic I, Saini KS, Sotiriou C, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Annal Oncol 2013;24:273-82.
33. Metzger-Filho O, Winer EP, Krop I. Pertuzumab: optimizing HER2 blockade. Clin Cancer Res 2013;19:5552-6.
34. Harbeck N, Beckmann MW, Rody A, Schneeweiss A, Muller V, Fehm T, et al. HER2 dimerization inhibitor pertuzumab-mode of action and clinical data in breast cancer. Breast Care 2013;8:49-55.
35. Amiri-Kordestani L, Blumenthal GM, Xu QC, Zhang L, Tang SW, Ha L, et al. FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res 2014;20:4436-41.
36. Peddi PF, Hurvitz SA. Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Ther Adv Med Oncol 2014;6:202-9.
37. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted antiâ€“HER-2 therapy and personalized medicine. Oncologist 2009;14:320-68.
38. Chung A, Cui X, Audeh W, Giuliano A. Current status of antiâ€“human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. Clin Breast Cancer 2013;13:223-32.
39. Nahta R, Esteva FJ. Molecular mechanisms of trastuzumab resistance. Breast Cancer Res 2006;8:667-74.
40. Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 2012;2:62-8.
41. Lavaud P, Andre F. Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials. BMC Med 2014;12:132-3.
42. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer 2012;106:6-13.
43. Incorvati JA, Shah S, Mu Y, Lu J. Targeted therapy for HER2 positive breast cancer. J Hematol Oncol 2013;6:38.
44. Drakaki A, Hurvitz SA. HER2-Positive breast cancer: update on new and emerging agents. Am J Haematol Oncol 2015;11:17-23.
45. Wilks ST. Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast 2015;24:548-55.
46. Zagouri F, Bournakis E, Koutsoukos K, Papadimitriou CA. Heat shock protein 90 (hsp90) expression and breast cancer. Pharmaceuticals 2012;5:1008-20.
47. Parimi S, Tsang RY. Hsp90 inhibitors in oncology: ready for prime time? Curr Oncol 2014;21:663-7.
48. Wehland M, Bauer J, Infanger M, Grimm D. Target-based anti-angiogenic therapy in breast cancer. Curr Pharm Des 2012;18:4244-57.
49. Rugo HS. Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J Clin Oncol 2012;30:898-901.
50. Weroha SJ, Haluska P. IGF-1 receptor inhibitors in clinical trialsâ€”early lessons. J Mammary Gland Biol Neoplasia 2008;13:471-83.
51. McKian KP, Haluska P. Cixutumumab. Expert Opin Investig Drugs 2009;18:1025-33.
52. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.
53. Kyi C, Postow MA. Checkpoint is blocking antibodies in cancer immunotherapy. FEBS Lett 2014;588;368-76.
54. Ladjemi MZ, Jacot W, Chardes T, Pelegrin A, Navarro-Teulon I. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother 2010;59:1295-312.
55. Singh JC, Jhaveri K, Esteva FJ. HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer 2014;111:1888-98.