REFERENCES
1. Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med 2005;353:1652-4.
2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
3. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7.
4. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-12.
5. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 2014;25:282-303.
6. Brennan PJ, Kumagai T, Berezov A, Murali R, Greene MI. HER2/neu: mechanisms of dimerization/oligomerization. Oncogene 2000;19:6093-101.
7. Brown-Glaberman U, Dayao Z, Royce M. HER2-targeted therapy for early-stage breast cancer: a comprehensive review. Oncology (Williston Park) 2014;28:281-9.
10. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 2006;3:269-80.
11. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-83.
12. Suh KJ, Sung JH, Kim JW, Han SH, Lee HS, et al. EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release. Oncotarget 2017;8:63901-10.
13. Giordano SH, Temin S, Chandarlapaty S, Crews JR, Esteva FJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:2736-40.
14. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 2018;142:1364-82.
15. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-22.
16. Daemen A, Manning G. HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res 2018;20:8.
17. Lee HJ, Kim JY, Park SY, Park IA, Song IH, et al. Clinicopathologic significance of the intratumoral heterogeneity of HER2 gene amplification in HER2-positive breast cancer patients treated with adjuvant trastuzumab. Am J Clin Pathol 2015;144:570-8.
18. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994;330:1260-6.
19. Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: national surgical adjuvant breast and bowel project protocol B-15. J Natl Cancer Inst 2000;92:1991-8.
20. Yates LR, Knappskog S, Wedge D, Farmery JHR, Gonzalez S, et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 2017;32:169-84.e7.
21. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40.
22. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, 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.
23. Wang J, Xu B. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther 2019;4:34.
24. Fink MY, Chipuk JE. Survival of HER2-positive breast cancer cells: receptor signaling to apoptotic control centers. Genes Cancer 2013;4:187-95.
25. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28:1124-30.
26. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge 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 Study. J Clin Oncol 2012;30:2585-92.
27. Bonnefoi H, Jacot W, Saghatchian M, Moldovan C, Venat-Bouvet L, et al. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. Ann Oncol 2015;26:325-32.
28. Milani A, Montemurro F, Gioeni L, Aglietta M, Valabrega G. Role of trastuzumab in the management of HER2-positive metastatic breast cancer. Breast Cancer (Dove Med Press) 2010;2:93-109.
29. Burris HA 3rd. Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 2004;9 Suppl 3:10-5.
30. Richard S, Selle F, Lotz JP, Khalil A, Gligorov J, et al. Pertuzumab and trastuzumab: the rationale way to synergy. An Acad Bras Cienc 2016;88 Suppl 1:565-77.
31. Paranjpe R, Basatneh D, Tao G, De Angelis C, Noormohammed S, et al. Neratinib in HER2-positive breast cancer patients. Ann Pharmacother 2019;53:612-20.
32. Moulder SL, Borges VF, Baetz T, McSpadden T, Fernetich G, et al. Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2(+)-advanced solid tumors, with an expansion cohort in HER2(+) metastatic breast cancer (MBC). Clin Cancer Res 2017;23:3529-36.
33. Murthy R, Borges VF, Conlin A, Chaves J, Chamberlain M, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018;19:880-8.
34. Rugo HS, Im SA, Wright GLS, Escriva-de-Romani S, DeLaurentiis M, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol 2019;37:1000.
35. Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol 2017;28:855-61.
36. Berlato C, Chan KV, Price AM, Canosa M, Scibetta AG, et al. Alternative TFAP2A isoforms have distinct activities in breast cancer. Breast Cancer Res 2011;13:R23.
37. Kojima Y, Yoshie R, Kawamoto H, Shimo A, Uejima T, et al. Trastuzumab emtansine (T-DM1) plus S-1 in patients with trastuzumab-pretreated HER2-positive advanced or metastatic breast cancer: a phase Ib study. Oncology 2019;96:309-17.
38. Peters S, Stahel R, Bubendorf L, Bonomi P, Villegas A, et al. Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers. Clin Cancer Res 2019;25:64-72.
39. Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol 2017;18:1512-22.
40. Loganzo F, Tan X, Sung M, Jin G, Myers JS, et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther 2015;14:952-63.
41. Blackwell KL, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, et al. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol 2009;20:1026-31.
42. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist 2010;15:924-34.
43. D’Amato V, Raimondo L, Formisano L, Giuliano M, De Placido S, et al. Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev 2015;41:877-83.
44. de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, 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;15:1137-46.
45. Eustace AJ, Conlon NT, McDermott MSJ, Browne BC, O’Leary P, et al. Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. BMC Cancer 2018;18:965.
46. Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31. J Clin Oncol 2015;33:1574-83.
47. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43.
48. Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol 2012;30:1989-95.
49. Liu L, Greger J, Shi H, Liu Y, Greshock J, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871-8.
50. Nahta R, Yuan LX, Du Y, Esteva FJ. Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther 2007;6:667-74.
51. Perry J, Ghazaly E, Kitromilidou C, McGrowder EH, Joel S, et al. A synergistic interaction between lapatinib and chemotherapy agents in a panel of cell lines is due to the inhibition of the efflux pump BCRP. Mol Cancer Ther 2010;9:3322-9.
52. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol 2019;11:1758835919833519.
53. Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2009;27:5838-47.
54. Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med 2015;66:111-28.
55. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57.
56. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 2005;65:11118-28.
57. Minuti G, Cappuzzo F, Duchnowska R, Jassem J, Fabi A, et al. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br J Cancer 2012;107:793-9.
58. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-27.
59. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395-402.
60. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 2007;99:628-38.
61. Chandarlapaty S, Sakr RA, Giri D, Patil S, Heguy A, et al. Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. Clin Cancer Res 2012;18:6784-91.
62. Giordano SH, Temin S, Chandarlapaty S, Crews JR, Esteva FJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:2736-40.
63. Aird KM, Ghanayem RB, Peplinski S, Lyerly HK, Devi GR. X-linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ErbB1/2 tyrosine kinase inhibitor. Mol Cancer Ther 2010;9:1432-42.
64. Martin AP, Miller A, Emad L, Rahmani M, Walker T, et al. Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation. Mol Pharmacol 2008;74:807-22.
65. Goyette MA, Duhamel S, Aubert L, Pelletier A, Savage P, et al. The receptor tyrosine kinase AXL is required at multiple steps of the metastatic cascade during HER2-positive breast cancer progression. Cell Rep 2018;23:1476-90.
66. Hafizi S, Dahlback B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev 2006;17:295-304.
68. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009;15:429-40.
69. Toomey S, Eustace AJ, Fay J, Sheehan KM, Carr A, et al. Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies. Breast Cancer Res 2017;19:87.
70. Nam HJ, Im SA, Oh DY, Elvin P, Kim HP, et al. Antitumor activity of saracatinib (AZD0530), a c-Src/Abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer. Mol Cancer Ther 2013;12:16-26.
71. Milani A, Sangiolo D, Montemurro F, Aglietta M, Valabrega G. Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol 2013;24:1740-8.
72. Ayoub NM, Al-Shami KM, Yaghan RJ. Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer (Dove Med Press) 2019;11:53-69.
73. Shah AN, Flaum LE, Rademaker A, Santa-Maria CA, Jain S, et al. A phase II study of pembrolizumab and capecitabine for triple-negative (TN) and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer (MBC). J Clin Oncol 2019;37:1096.
74. Chaganty BKR, Qiu S, Gest A, Lu Y, Ivan C, et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNgamma secretion. Cancer Lett 2018;430:47-56.
75. Griguolo G, Pascual T, Dieci MV, Guarneri V, Prat A. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer. J Immunother Cancer 2019;7:90.
76. Wargo JA, Reuben A, Cooper ZA, Oh KS, Sullivan RJ. Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin Oncol 2015;42:601-16.
77. Ryu EB, Chang JM, Seo M, Kim SA, Lim JH, et al. Tumour volume doubling time of molecular breast cancer subtypes assessed by serial breast ultrasound. Eur Radiol 2014;24:2227-35.
78. Matutino A, Amaro C, Verma S. CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease. Ther Adv Med Oncol 2018;10:1758835918818346.
79. Sobhani N, D’Angelo A, Pittacolo M, Roviello G, Miccoli A, et al. Updates on the CDK4/6 inhibitory strategy and combinations in breast cancer. Cells 2019;8.
80. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol 2018;10:1758835918786451.
81. Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer 2017;3:39-55.
82. Preusser M, De Mattos-Arruda L, Thill M, Criscitiello C, Bartsch R, et al. CDK4/6 inhibitors in the treatment of patients with breast cancer: summary of a multidisciplinary round-table discussion. ESMO Open 2018;3:e000368.
83. Zhang K, Hong R, Kaping L, Xu F, Xia W, et al. CDK4/6 inhibitor palbociclib enhances the effect of pyrotinib in HER2-positive breast cancer. Cancer Lett 2019;447:130-40.
84. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 2016;29:255-69.
85. Cordera F, Jordan VC. Steroid receptors and their role in the biology and control of breast cancer growth. Semin Oncol 2006;33:631-41.
86. Mehta A, Tripathy D. Co-targeting estrogen receptor and HER2 pathways in breast cancer. Breast 2014;23:2-9.
87. Grogg A, Trippel M, Pfaltz K, Lädrach C, Droeser RA, et al. Androgen receptor status is highly conserved during tumor progression of breast cancer. BMC Cancer 2015;15:872.
88. Park S, Koo J, Park HS, Kim JH, Choi SY, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-92.
89. Barton VN, D’Amato NC, Gordon MA, Lind HT, Spoelstra NS, et al. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol Cancer Ther 2015;14:769-78.
90. D’Amato NC, Gordon MA, Babbs B, Spoelstra NS, Carson Butterfield KT, et al. Cooperative dynamics of AR and ER activity in breast cancer. Mol Cancer Res 2016;14:1054-67.
91. Krishnan AV, Swami S, Feldman D. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J Steroid Biochem Mol Biol 2010;121:343-8.
92. Mehta S, Mugusi FM, Bosch RJ, Aboud S, Urassa W, et al. Vitamin D status and TB treatment outcomes in adult patients in Tanzania: a cohort study. BMJ Open 2013;3:e003703.
93. Abduljabbar R, Negm OH, Lai CF, Jerjees DA, Al-Kaabi M, et al. Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer. Breast Cancer Res Treat 2015;150:335-46.
94. Vilasco M, Communal L, Mourra N, Courtin A, Forgez P, et al. Glucocorticoid receptor and breast cancer. Breast Cancer Res Treat 2011;130:1-10.
95. Hua S, Kittler R, White KP. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 2009;137:1259-71.
96. Ross-Innes CS, Stark R, Holmes KA, Schmidt D, Spyrou C, et al. Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev 2010;24:171-82.
97. Gao S, Ye H, Gerrin S, Wang H, Sharma A, et al. ErbB2 signaling increases androgen receptor expression in abiraterone-resistant prostate cancer. Clin Cancer Res 2016;22:3672-82.
98. Browne BC, Crown J, Venkatesan N, Duffy MJ, Clynes M, et al. Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Ann Oncol 2011;22:68-73.
99. Gordon MA, D’Amato NC, Gu H, Babbs B, Wulfkuhle J, et al. Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer. Mol Cancer Ther 2017;16:1389-400.
100. Micello D, Marando A, Sahnane N, Riva C, Capella C, et al. Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers. Virchows Arch 2010;457:467-76.
101. He L, Du Z, Xiong X, Ma H, Zhu Z, et al. Targeting androgen receptor in treating HER2 positive breast cancer. Sci Rep 2017;7:14584.
102. Trudeau ME, Winer EP, Steinberg JL, Liosatos M, Poondru S, et al. A phase 2 single-arm study to assess clinical activity, efficacy and safety of enzalutamide (ENZA) with trastuzumab in HER2+ AR+ metastatic or locally advanced breast cancer. J Clin Oncol 2015;33:tps640.
103. Lee-Bitar JS, Frankel PH, Yost SE, Synold TW, Martinez N, et al. A phase II clinical trial of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor-positive triple-negative breast cancer. J Clin Oncol 2019;37:1069.
104. Carter PR, Uppal H, Chandran S, Bainey KR, Potluri R, et al. 3106 Patients with a diagnosis of hyperlipidaemia have a reduced risk of developing breast cancer and lower mortality rates: a large retrospective longitudinal cohort study from the UK ACALM registry. Eur Heart J 2017;38.
106. Sezgin E, Levental I, Mayor S, Eggeling C. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat Rev Mol Cell Biol 2017;18:361-74.
107. Chen X, Resh MD. Cholesterol depletion from the plasma membrane triggers ligand-independent activation of the epidermal growth factor receptor. J Biol Chem 2002;277:49631-7.
108. Borgquist S, Bjarnadottir O, Kimbung S, Ahern TP. Statins: a role in breast cancer therapy? J Intern Med 2018;284:346-57.
109. Gobel A, Breining D, Rauner M, Hofbauer LC, Rachner TD. Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells. Cell Death Dis 2019;10:91.
110. Zhao Z, Cao X, Pan Y, Sha S, Zhao T, et al. Simvastatin downregulates HER2 via upregulation of PEA3 to induce cell death in HER2-positive breast cancer cells. Oncol Res 2012;20:187-95.
111. Adam RM, Mukhopadhyay NK, Kim J, Di Vizio D, Cinar B, et al. Cholesterol sensitivity of endogenous and myristoylated Akt. Cancer Res 2007;67:6238-46.
113. Gao X, Zhang J. Spatiotemporal analysis of differential Akt regulation in plasma membrane microdomains. Mol Biol Cell 2008;19:4366-73.
114. Wahdan-Alaswad RS, Edgerton SM, Salem HS, Thor AD. Metformin targets cholesterol biosynthesis pathway,GM1 lipid raft stabilization, EGFR signaling and proliferation in triple negative breast cancers. Cancer Therapy Oncol Int J 2018;9:555765.
115. Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, et al. Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget 2012;3:395-8.
116. Wahdan-Alaswad R, Fan Z, Edgerton SM, Liu B, Deng XS, et al. Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle 2013;12:3759-69.
117. Wahdan-Alaswad RS, Edgerton SM, Salem HS, Thor AD. Metformin targets glucose metabolism in triple negative breast cancer. J Oncol Transl Res 2018;4.
118. McIlhinney RA. Membrane targeting via protein N-myristoylation. Methods Mol Biol 1998;88:211-25.
119. Sethunath V, Hu H, De Angelis C, Veeraraghavan J, Qin L, et al. Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer. Mol Cancer Res 2019;17:2318-30.
120. Brown DN, Caffa I, Cirmena G, Piras D, Garuti A, et al. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer. Sci Rep 2016;6:19435.
121. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009;8:909-15.
122. Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 2009;8:2031-40.
123. Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, et al. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle 2011;10:2959-66.
124. Kim HJ, Kwon H, Lee JW, Kim HJ, Lee SB, et al. Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes. Breast Cancer Res 2015;17:64.
125. Sonnenblick A, Agbor-Tarh D, Bradbury I, Di Cosimo S, Azim Jr HA, et al. Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2-positive primary breast cancer: analysis from the ALTTO phase III randomized trial. J Clin Oncol 2017;35:1421-9.
126. Martin-Castillo B, Pernas S, Dorca J, Alvarez I, Martinez S, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget 2018;9:35687-704.
127. Berstein LM. New developments of metformin in the clinical cancer area. Oncotarget 2018;9:36820-1.
128. McCullough AE, Dell’orto P, Reinholz MM, Gelber RD, Dueck AC, et al. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res Treat 2014;143:485-92.
129. Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, 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.
130. Holmes EM, Bradbury I, Williams LS, Korde L, de Azambuja E, et al. Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial. Ann Oncol 2019;30:1507-13.
131. Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, 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;34:542-9.
132. Goss PE, Smith IE, O’Shaughnessy J, Ejlertsen B, Kaufmann M, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol 2013;14:88-96.
133. Robidoux A, Tang G, Rastogi P, Geyer CE, Jr., Azar CA, 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.
134. Hurvitz S, Singh R, Adams B, Taguchi JA, Chan D, et al. Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09). Ther Adv Med Oncol 2018;10:1758835918807339.
135. Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, 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.
136. Trowe T, Boukouvala S, Calkins K, Cutler RE Jr., Fong R, et al. EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. Clin Cancer Res 2008;14:2465-75.
137. Xia W, Petricoin EF 3rd, Zhao S, Liu L, Osada T, et al. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res 2013;15:R85.
138. Rexer BN, Ham AJ, Rinehart C, Hill S, Granja-Ingram Nde M, et al. Phosphoproteomic mass spectrometry profiling links Src family kinases to escape from HER2 tyrosine kinase inhibition. Oncogene 2011;30:4163-74.
139. Formisano L, Nappi L, Rosa R, Marciano R, D’Amato C, et al. Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res 2014;16:R45.
140. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;68:9221-30.
141. Brady SW, Zhang J, Tsai MH, Yu D. PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition. Cancer Biol Ther 2015;16:402-11.
142. Vazquez-Martin A, Oliveras-Ferraros C, Colomer R, Brunet J, Menendez JA. Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb) in human breast carcinoma cells. Ann Oncol 2008;19:1097-109.
143. Gayle SS, Arnold SL, O’Regan RM, Nahta R. Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 2012;12:151-62.
144. Wurz GT, Kao CJ, DeGregorio MW. Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential. Ther Adv Med Oncol 2016;8:4-31.
145. Li BT, Shen R, Buonocore D, Olah ZT, Ni A, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol 2018;36:2532-7.
146. Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res 2016;22:1499-509.
147. Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol 2019;20:371-82.
148. Giuliano M, Schettini F, Rognoni C, Milani M, Jerusalem G, et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol 2019;20:1360-9.
149. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation. Breast Cancer Res 2011;13:R121.
150. Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19:5505-12.
