Emerging EGFR antagonists for breast cancer

Expert Opinion on Emerging Drugs

Volumn 19, Issue 2, 2014, Pages 165-181

  Lluch, Ana ^a,b   Eroles, Pilar ^b   Perez Fidalgo, Jose Alejandro ^a,b  

^a HOSPITAL CLÍNICO UNIVERSITARIO   (Spain)

^b Instituto Universitario IVI INCLIVA   (Spain)

Author keywords

Angiogenesis; Breast cancer; Cetuximab; EGFR; Erlotinib; Gefitinib; Tyrosine kinase inhibitor

Indexed keywords

AFATINIB; ANASTROZOLE; CAPECITABINE; CARBOPLATIN; CETUXIMAB; CISPLATIN; CYCLOPHOSPHAMIDE; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; EPIRUBICIN; ERLOTINIB; EVEROLIMUS; FLUOROURACIL; FULVESTRANT; GEFITINIB; IRINOTECAN; LAPATINIB; NAVELBINE; NERATINIB; PACLITAXEL; PANITUMUMAB; TAMOXIFEN; TRASTUZUMAB; VANDETANIB; EPIDERMAL GROWTH FACTOR RECEPTOR; MONOCLONAL ANTIBODY; PROTEIN KINASE INHIBITOR; QUINAZOLINE DERIVATIVE;

BREAST CANCER; BREAST METASTASIS; CANCER STAGING; ENZYME ACTIVATION; EPITHELIAL MESENCHYMAL TRANSITION; INTERNALIZATION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; RADIOIMMUNOTHERAPY; REVIEW; TRIPLE NEGATIVE BREAST CANCER; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; DRUG DEVELOPMENT; FEMALE; HUMAN; METABOLISM;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; BREAST NEOPLASMS; DRUG DISCOVERY; EPITHELIAL-MESENCHYMAL TRANSITION; FEMALE; HUMANS; PROTEIN KINASE INHIBITORS; QUINAZOLINES; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 84901265812     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1517/14728214.2014.903919     Document Type: Review

References (113)

1. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-70 (Pubitemid 32963812
2. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787-99 (Pubitemid 46606324
3. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2-16 (Pubitemid 43199589
4. Masuda H, Zhang D, Bartholomeusz C, et al. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat 2012;136:331-45
5. Baselga J, Norton L, Masui H, et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 1993;85:1327-33 (Pubitemid 23249725
6. Hoadley KA, Weigman VJ, Fan C, et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 2007;8:258
7. Pintens S, Neven P, Drijkoningen M, et al. Triple negative breast cancer: A study from the point of view of basal CK5/6 and HER-1. J Clin Pathol 2009;62:624-8
8. Teng YH, Tan WJ, Thike AA, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: Possible implications for targeted therapy. Breast Cancer Res 2011;13:R35
9. Thike AA, Cheok PY, Jara-Lazaro AR, et al. Triple-negative breast cancer: Clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol 2010;23:123-33
10. Arpino G, Green SJ, Allred DC, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: A southwest oncology group study. Clin Cancer Res 2004;10:5670-6
11. Nicholson RI, McClelland RA, Finlay P, et al. Relationship between EGF-R, c-erbB-2 protein expression and Ki67 immunostaining in breast cancer and hormone sensitivity. Eur J Cancer 1993;29A:1018-23 (Pubitemid 23126705
12. Arpino G, De Angelis C, Giuliano M, et al. Molecular mechanism and clinical implications of endocrine therapy resistance in breast cancer. Oncology 2009;77(Suppl 1):23-37
13. Crown J, O'Shaughnessy J, Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol 2012;23(Suppl 6):vi56-65
14. Corkery B, Crown J, Clynes M, O'Donovan N. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol 2009;20:862-7
15. Buzdar A. Anastrozole as adjuvant therapy for early-stage breast cancer: Implications of the ATAC trial. Clin Breast Cancer 2003;4(Suppl 1):S42-8
16. Buzdar AU. 'Arimidex' (anastrozole) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer-efficacy overview. J Steroid Biochem Mol Biol 2003;86:399-403
17. Britten CD. Targeting ErbB receptor signaling: A pan-ErbB approach to cancer. Mol Cancer Ther 2004;3:1335-42 (Pubitemid 39440177
18. Dickler MN, Rugo HS, Eberle CA, et al. A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 2008;14:7878-83
19. Dawson SJ, Provenzano E, Caldas C. Triple negative breast cancers: Clinical and prognostic implications. Eur J Cancer 2009;45(Suppl 1):27-40
20. Sutton LM, Han JS, Molberg KH, et al. Intratumoral expression level of epidermal growth factor receptor and cytokeratin 5/6 is significantly associated with nodal and distant metastases in patients with basal-like triple-negative breast carcinoma. Am J Clin Pathol 2010;134:782-7
21. Burness ML, Grushko TA, Olopade OI. Epidermal growth factor receptor in triple-negative and basal-like breast cancer: Promising clinical target or only a marker?. Cancer J 2010;16:23-32
22. Burga LN, Hu H, Juvekar A, et al. Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptornegative cancers in BRCA1-mutant mice. Breast Cancer Res 2011;13:R30
23. Ciardiello F, Bianco R, Caputo R, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 2004;10:784-93 (Pubitemid 38174017
24. Van Laere SJ, Van der Auwera I, Van den Eynden GG, et al. NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. Br J Cancer 2007;97:659-69 (Pubitemid 47339884
25. Larsen AK, Ouaret D, El Ouadrani K, Petitprez A. Targeting EGFR and VEGF (R) pathway cross-Talk in tumor survival and angiogenesis. Pharmacol Ther 2011;131:80-90
26. Klos KS, Wyszomierski SL, Sun M, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res 2006;66:2028-37
27. Xia W, Zhao T, Lv J, et al. Celecoxib enhanced the sensitivity of cancer cells to anticancer drugs by inhibition of the expression of P-glycoprotein through a COX-2-independent manner. J Cell Biochem 2009;108:181-94
28. Dang CT, Dannenberg AJ, Subbaramaiah K, et al. Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res 2004;10:4062-7 (Pubitemid 38812482
29. Lu Y, Li X, Liang K, et al. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res 2007;67:8240-7 (Pubitemid 47395161
30. Wheeler DL, Iida M, Kruser TJ, et al. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol Ther 2009;8:696-703
31. Saxena R, Dwivedi A. ErbB family receptor inhibitors as therapeutic agents in breast cancer: Current status and future clinical perspective. Med Res Rev 2012;32:166-215
32. Fuchs BC, Fujii T, Dorfman JD, et al. Epithelial-To-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res 2008;68:2391-9 (Pubitemid 351521814
33. Basu D, Nguyen TT, Montone KT, et al. Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity. Oncogene 2010;29:4170-82
34. Kim SM, Kim JS, Kim JH, et al. Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett 2010;296:150-9
35. Dunn EF, Iida M, Myers RA, et al. Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. Oncogene 2011;30:561-74
36. Hatakeyama H, Cheng H, Wirth P, et al. Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One 2010;5:e12702
37. De Laurentiis M, Arpino G, Massarelli E, 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 (Pubitemid 41557193
38. Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 1996;15:2174-83 (Pubitemid 26141134
39. Joel PB, Smith J, Sturgill TW, et al. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol 1998;18:1978-84 (Pubitemid 28152646
40. Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-Activated protein kinase. Science 1995;270:1491-4
41. Russell KS, Hung MC. Transcriptional repression of the neu protooncogene by estrogen stimulated estrogen receptor. Cancer Res 1992;52:6624-9
42. Wilson MA, Chrysogelos SA. Identification and characterization of a negative regulatory element within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer cells. J Cell Biochem 2002;85:601-14 (Pubitemid 34465140
43. Eccles SA. The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology. Int J Dev Biol 2011;55:685-96
44. Eccles SA, Massey A, Raynaud FI, et al. NVP-AUY922: A novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 2008;68:2850-60 (Pubitemid 351556284
45. Modi S, Stopeck A, Linden H, et al. HSP90 inhibition is effective in breast cancer: A phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011;17:5132-9
46. Lenz HJ. Cetuximab in the management of colorectal cancer. Biologics 2007;1:77-91
47. Oliveras-Ferraros C, Vazquez-Martin A, Lopez-Bonet E, et al. Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: New prospects in the treatment of triple-negative/basal-like breast cancer. Int J Oncol 2008;33:1165-76
48. O'Shaughnessy J, Weckstein DJ, Vukelja SJ, et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer. Cancer Res Treat 2007;106:abstract 308
49. Khambata-Ford S, O'Shaughnessy J, Brickman D, et al. Candidate predictive biomarkers of cetuximab benefit in triple-negative breast cancer. J Clin Oncol 2010;28:15s (Suppl):abstract 1056
50. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012;30:2615-23
51. Baselga J, Gomez P, Greil R, et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 2013;31:2586-92
52. Available from: Http://clinicaltrials.gov/ct2/show/results/NCT00633464?. term=cetuximab+breast+cancer & rank=2§=X0125clinicaltrials.gov
53. Available from: Http://clinicaltrials.gov/ct2/show/results/NCT01097642?. term=ixabepilone+cetuximab&rank=3
54. Carteni G, Fiorentino R, Vecchione L, et al. Panitumumab a novel drug in cancer treatment. Ann Oncol 2007;18(Suppl 6):vi16-21
55. Nabholtz J, Weber B, Mouret-Reynier M, et al. Panitumumab in combination with FEC 100 (5-fluorouracil, epidoxorubicin, cyclophosphamide) followed by docetaxel (T) in patients with operable, triplenegative breast cancer (TNBC): Preliminary results of a multicenter neoadjuvant pilot phase II study. J Clin Oncol 2011;29:abstract e11574
56. Nabholtz J-MA, Dauplat M-M, Abrial C, et al. Impact of biomarkers in predictivity of the efficacy and toxicity of a combination of panitumumab plus FEC 100 followed by docetaxel in a phase II neoadjuvant trial for triple-negative breast cancer (TNBC) patients. J Clin Oncol 2012;30:abstract 1051
57. Penault-Llorca F, Dauplat M-D, Abrial C, et al. Response to the anti-EGFR antibody panitumumab combined with standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC): The immune and IGFR pathways. J Clin Oncol 2013;15(Suppl):abstract 1058
58. Dickler MN, Cobleigh MA, Miller KD, et al. Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2009;115:115-21
59. Bruns CJ, Solorzano CC, Harbison MT, et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000;60:2926-35 (Pubitemid 30395817
60. Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001;7:1459-65 (Pubitemid 32708703
61. Hirata A, Ogawa S, Kometani T, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002;62:2554-60 (Pubitemid 34462734
62. Perrotte P, Matsumoto T, Inoue K, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 1999;5:257-65 (Pubitemid 29085177
63. Jung YD, Mansfield PF, Akagi M, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 2002;38:1133-40 (Pubitemid 34468020
64. Li M, Ye C, Feng C, et al. Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin and epidermal growth factor receptor-Antisense therapy. Clin Cancer Res 2002;8:3570-8 (Pubitemid 35340735
65. Montagna E, Cancello G, Bagnardi V, et al. Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: Clinical and biological activity. Clin Breast Cancer 2012;12:207-14
66. Twelves C, Trigo JM, Jones R, et al. Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: A dose-escalation study. Eur J Cancer 2008;44:419-26
67. Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-Associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005;10:345-56 (Pubitemid 40647253
68. Tan AR, Steinberg SM, Parr AL, et al. Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment. Ann Oncol 2008;19:185-90
69. Gee JM, Harper ME, Hutcheson IR, et al. The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 2003;144:5105-17 (Pubitemid 37378426
70. Britton DJ, Hutcheson IR, Knowlden JM, et al. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 2006;96:131-46
71. Gutteridge E, Agrawal A, Nicholson R, et al. The effects of gefitinib in tamoxifen-resistant and hormoneinsensitive breast cancer: A phase II study. Int J Cancer 2010;126:1806-16
72. Meric JB, Faivre S, Monnerat C, et al. [Zd 1839 "Iressa"]. Bulletin du Cancer 2000;87:873-6
73. von Minckwitz G, Jonat W, Fasching P, et al. A multicentre phase II study on gefitinib in taxane-And anthracyclinepretreated metastatic breast cancer. Breast Cancer Res Treat 2005;89:165-72 (Pubitemid 40249050
74. Arteaga CL, O'Neill A, Moulder SL, et al. A phase I-II study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer. Clin Cancer Res 2008;14:6277-83
75. Polychronis A, Sinnett HD, Hadjiminas D, et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: A double-blind placebo-controlled phase II randomised trial. Lancet Oncol 2005;6:383-91 (Pubitemid 40753744
76. Osborne CK, Neven P, Dirix LY, et al. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: A randomized phase II study. Clin Cancer Res 2011;17:1147-59
77. Baselga J, Albanell J, Ruiz A, et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 2005;23:5323-33 (Pubitemid 46206986
78. Engebraaten O, Edvardsen H, Lokkevik E, et al. Gefitinib in combination with weekly docetaxel in patients with metastatic breast cancer caused unexpected Toxicity: Results from a randomized phase II clinical trial. ISRN Oncol 2012;2012:176789
79. Opdam FL, Guchelaar HJ, Beijnen JH, Schellens JH. Lapatinib for advanced or metastatic breast cancer. Oncologist 2012;17:536-42
80. Di Leo A, Gomez HL, Aziz Z, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 2008;26:5544-52
81. Finn RS, Press MF, Dering J, et al. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol 2009;27:3908-15
82. Amir E, Ocana A, Seruga B, et al. Lapatinib and HER2 status: Results of a meta-Analysis of randomized phase III trials in metastatic breast cancer. Cancer Treat Rev 2010;36:410-15
83. Pestrin M, Bessi S, Puglisi F, et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-Agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat 2012;134:283-9
84. Hsia TC, Tu CY, Chen YJ, et al. Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells. Mol Pharmacol 2013;83:857-69
85. Reis-Filho JS, Tutt AN. Triple negative tumours: A critical review. Histopathology 2008;52:108-18 (Pubitemid 350265179
86. Liu T, Yacoub R, Taliaferro-Smith LD, et al. Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. Mol Cancer Ther 2011;10:1460-9
87. Wong KK, Fracasso PM, Bukowski RM, et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 2009;15:2552-8
88. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010;28:1301-7
89. Awada A, Dirix L, Manso Sanchez L, et al. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol 2013;24:109-16
90. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013;3:224-37
91. Lin NU, Winer EP, Wheatley D, et al. A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 2012;133:1057-65
92. Harbeck N, Schmidt M, Harter P, et al. BIBW 2992, a novel irreversible EGFR/ HER1and HER2 tyrosine kinase inhibitor for the treatment of patients with HER2-negative metastatic breast cancer after failure of no more than two prior chemotherapies. Cancer Res 2010;69:5062; doi:10.1158/0008-5472. SABCS-09-5062
93. Willmarth NE, Ethier SP. Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells. J Biol Chem 2006;281:37728-37 (Pubitemid 46042076
94. Schuler M, Awada A, Harter P, et al. A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 2012;134:1149-59
95. Morabito A, Piccirillo MC, Falasconi F, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: Current status and future directions. Oncologist 2009;14:378-90
96. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): A double-blind, randomised, phase 3 trial. Lancet Oncol 2010;11:619-26
97. Miller KD, Trigo JM, Wheeler C, et al. A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 2005;11:3369-76 (Pubitemid 40627889
98. Boer K, Lang I, Llombart-Cussac A, et al. Vandetanib with docetaxel as second-line treatment for advanced breast cancer: A double-blind, placebo-controlled, randomized Phase II study. Invest New Drugs 2012;30:681-7
99. Rosen AC, Wu S, Damse A, et al. Risk of rash in cancer patients treated with vandetanib: Systematic review and meta-Analysis. J Clin Endocrinol Metab 2012;97:1125-33
100. Goldenberg DM. Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med 2002;43:693-713 (Pubitemid 34507123
101. Song H, Hedayati M, Hobbs RF, et al. Targeting aberrant DNA double strand break repair in triple negative breast cancer with alpha particle emitter radiolabeled anti-EGFR antibody. Mol Cancer Ther 2013;12(10):2043-54
102. M'Kacher R, Bennaceur A, Farace F, et al. Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma. Oncogene 2003;22:7905-12 (Pubitemid 37175855
103. Al-Ejeh F, Shi W, Miranda M, et al. Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor. J Nucl Med 2013;54:913-21
104. Castoria G, Migliaccio A, Bilancio A, et al. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J 2001;20:6050-9 (Pubitemid 33049280
105. Hiscox S, Morgan L, Green TP, et al. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat 2006;97:263-74 (Pubitemid 43945756
106. Tilch E, Seidens T, Cocciardi S, et al. Mutations in EGFR, BRAF and RAS are rare in triple-negative and basal-like breast cancers from Caucasian women. Breast Cancer Res Treat 2014;143:385-92
107. Jacot W, Lopez-Crapez E, Thezenas S, et al. Lack of EGFR-Activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles. Breast Cancer Res 2011;13:R133
108. Park HS, JangMH, Kim EJ, et al. High EGFR gene copy number predicts poor outcome in triple-negative breast cancer. Mod Pathol 2014. [Epub ahead of print]
109. Ciardiello F, Troiani T, Caputo F, et al. Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer. Br J Cancer 2006;94:1604-9 (Pubitemid 43924921
110. Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol 2007;25:3816-22 (Pubitemid 47477255
111. Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010;16:1904-14
112. Bernsdorf M, Ingvar C, Jorgensen L, et al. Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial. Breast Cancer Res Treat 2011;126:463-70
113. Carlson RW, O'Neill A, Vidaurre T, et al. A randomized trial of combination anastrozole plus gefitinib and of combination fulvestrant plus gefitinib in the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer. Breast Cancer Res Treat 2012;133:1049-56