1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No.10 [Internet] Lyon, France: International Agency for Research on Cancer; 2010.
2. Mathew J, Perez E.A. Trastuzumab emtansine in human epidermal growth factor receptor 2-positive breast cancer: a review. Curr Opin Oncol. 2011;23:594–600. [PubMed] 3. Jemal A, Siegel R, Xu J. et al. Cancer statistics. CA Cancer J Clin. 2010;60:277–300. [PubMed] 4. Siegel R, Ward E. et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212–36. [PubMed]
5. American Cancer Society. Cancer Facts and Figures, 2011. Atlanta, GA: American Cancer Society; 2011.
6. Rugo H, Taylor D, Sanon M, Clements K, Balu S, Faria C, Teitelbaum A. Survival in US Women Following an Indication of Metastatic Breast Cancer Diagnosis and Chemotherapy Initiation: A SEER-Medicare Analysis, (P1-08-07) Poster Presentation. San Antonio Breast Cancer Symposium, San Antonio, Texas. 2012.
7. Carlson RW, Allred DC, Anderson BO, Burstein HJ. et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2009 Feb;7(2):122–92. [PubMed] 8. Buzdar AU. Role of biologic therapy and chemotherapy in hormone receptor- and HER2-positive breast cancer. Ann Oncol. 2009 Jun;20(6):993–9. [PubMed] 9. Slamon DJ, Leyland-Jones B, Shak S. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. [PubMed] 10. Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer. 2009 Jun;9(Suppl 2):S73–81. [PMC free article] [PubMed] 11. Perou CM, Sørlie T, Eisen MB. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747–52. [PubMed] 12. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360(8):790–800. [PubMed] 13. Buyse M, Loi S, van't Veer L, Viale G. et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006 Sep 6;98(17):1183–92. [PubMed] 14. Glück S, Yip AY, Ng EL. Can we replace the microscope with microarrays for diagnosis, prognosis and treatment of early breast cancer? Expert Opin Ther Targets. 2012;(Suppl 1):S17–22. [PubMed] 15. Hernandez-Aya LF, Chavez-Macgregor M, Lei X. et al. Nodal status and clinical outcomes in a large cohort of patients with triple-negative breast cancer. J Clin Oncol. 2011 Jul 1;29(19):2628–34. [PMC free article] [PubMed] 16. Ismail-Khan R, Bui MM. A review of triple-negative breast cancer. Cancer Control. 2010 Jul;17(3):173–6. [PubMed] 17. Dawood S, Broglio K, Buzdar AU. et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional based review. J Clin Oncol. 2010;28:92–98. [PMC free article] [PubMed] 18. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. [PubMed] 19. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A. et al. Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science. 1989;244:707–712. [PubMed] 20. Olson EM. et al. Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer. Ann Oncol. 2012;23(1):93–97. [PMC free article] [PubMed] 21. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol. 2001;2:127–137. [PubMed] 23. Leyland-Jones B. Trastuzumab: hopes and realities. Lancet Oncol. 2002;3(3):137–44. [PubMed] 24. Yin W. et al. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One. 2011;6(6):e21030. [PMC free article] [PubMed] 25. Baselga J, Tripathy D, Mendelsohn J. et al. Phase II study of weekly intravenous recombinant humanized antip185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14:737–744. [PubMed] 26. Vogel CL, Cobleigh MA, Tripathy D. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719–726. [PubMed] 27. Burstein HJ, Kuter I, Campos SM. et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2001;19:2722–2730. [PubMed] 28. Montemurro F, Choa G, Faggiuolo R. et al. A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer. Oncology. 2004;66:38–45. [PubMed] 29. Jahanzeb M, Mortimer JE, Yunus F. et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(þ) metastatic breast cancer. Oncologist. 2002;7:410–417. [PubMed] 30. Cobleigh MA, Vogel CL, Tripathy D. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–2648. [PubMed] 31. Romond EH, Perez EA, Bryant J. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. [PubMed] 32. Esteva FJ, Valero V, Booser D. et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:1800–1808. [PubMed] 33. Valero V, Forbes J, Pegram MD. et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011;29:149–156. [PubMed] 34. Andersson M, Lidbrink E, Bjerre K. et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264–271. [PubMed]
35. Perez EA, Suman VJ, Davidson NE. et al. Results of Chemotherapy Alone, with Sequential or Concurrent Addition of 52 Weeks of Trastuzumab in the NCCTG N9831 HER2-Positive Adjuvant Breast Cancer Trial [Abstract #80] Cancer Res. 2010;70:5640.
36. Perez EA, Romond EH, Suman VJ. et al. Original report: 4-year follow-up of trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSAB B-31. J Clin Oncol. 2011;29:3366–3373. [PMC free article] [PubMed] 37. Saini K. et al. Beyond trastuzumab: New treatment options for HER2-positive breast cancer. The Breast. 2011;20:S20–S27. [PubMed] 39. Baselga J. Clinical trials of Herceptin(trastuzumab) Eur J Cancer. 2001;37:S18–24. [PubMed] 40. Burstein HJ, Keshaviah A, Baron AD. et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110:965–972. [PubMed] 41. Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ, Keith BR, Gilmer TM, Berger M, Podratz KC, Slamon DJ. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630–1639. [PubMed] 43. Ahn ER, Vogel CL. Dual HER2-targeted approaches in HER2-positive breast cancer. Breast Cancer Res Treat; DOI: 10.1007/s10549-011-1781-y. [PubMed] 44. Johnston S, Pippen JJr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538–5546. [PubMed] 45. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733– 2743. [PubMed] 46. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–1130. [PubMed] 47. Fang L. et al. Targeted therapy in breast cancer: what's new? Swiss Med Wkly. 2011;141:w13231. [PubMed] 48. Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene. 2007;26(25):3637–43. [PubMed] 49. 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;3:269–280. [PubMed] 50. Bartsch R, Wenzel C, Gampenrieder SP. et al. Trastuzumab and gemcitabine as salvage therapy in heavily pre-treated patients with metastatic breast cancer. Cancer Chemother Pharmacol. 2008;62:903–910. [PubMed] 51. Von Minckwitz G, du BA, Schmidt M. et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27:1999–2006. [PubMed]
52. EA Perez, Current and Emerging Targeted Therapies for Metastatic Breast Cancer. Cancer. 2011.
53. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290. [PubMed] 54. Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumour inhibitor maytansine. Science. 1975;189:1002–1005. [PubMed] 55. Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H, Kovtun Y, Chari R, Jordan MA. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther. 2010;9:2700–2713. [PMC free article] [PubMed] 56. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98–107. [PubMed] 57. Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255:232–240. [PubMed] 58. Barok et al. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Research. 2011;13:R46. [PMC free article] [PubMed] 59. LoRusso P. et al. Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive Cancer. Clin Cancer Res. 2011;17:6437–6447. [PubMed] 60. Gupta M. et al. Clinical Implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Pharmacol. 2012 May;52(5):691–703. [PubMed] 61. Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W. et al. Phase I study of trastuzumab-DM1, a HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698–704. [PubMed]
62. Miller K, Gianni L, Andre F, A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with Pertuzumab for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T) [abstract] J Clin Oncol. 2010. 28.
63. Burris HA III, Rugo HS, Vukelja SJ. et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398–405. [PubMed]
64. Perez EA, Dirix L, Kocsis J. et al. Efficacy and safety of trastuzumab- DM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G) [abstract] Ann Oncol. 2010;21:viii2.
66. A Study of Trastuzumab-Emtasine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE) NCT01120184; http://clinicaltrials.gov. 67. A Phase III Randomized, Multicenter, Two-Arm, Open-Label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician's Choice in Patients With HER2 Positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy. NCT01419197; http://clinicaltrials.gov.
68. Blackwell KL, Miles D, Gianni L. et al. Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. 2012 ASCO Annual Meeting. J Clin Oncol. 2012;30:abstrLBA1.
69. Baselga J, Gelmon KA, Verma S. et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–1144. [PubMed] 70. Baselga J. et al. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist. 2011;16(Suppl 1):12–19. [PubMed] 71. Baselga J, Cortés J, Sung-Bae K. et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med. 2012;366:109–119. [PubMed]
72. Gianni L, Pienkowski T, Im YH, Neoadjuvant pertuzumab (P) and trastuzumab (H): antitumor and safety analysis of a randomized phase II study ('NeoSphere') San Antonio: Thirty-Third Annual San Antonio Breast Cancer Symposium; December 8-12. 2010: Abstract.
73. Geretti E, Abstract C90: HER2-targeted liposomal doxorubicin MM-302 has a favorable cardio safety profile in preclinical models. Molecular Cancer Therapeutics. 2011. 10(11)
74. A Phase 1, Multi-Center, Open-Label, Dose-Escalation, Safety, and Pharmacokinetic Clinical Study of Intravenously Administered MM-302 in Patients With Advanced Breast Cancer. NCT01304797; http://clinicaltrials.gov. 75. Kiewe P, Thiel E. Phase I Trial of the Trifunctional Anti-HER2 × Anti-CD3 Antibody Ertumaxomab in Metastatic Breast Cancer. Clin Cancer Res. 2006 May 15;12(10):3085–91. [PubMed] 76. Phase II Study Of The Trifunctional Bispecific Anti-HER-2/Neu x Anti-CD3 Antibody Ertumaxomab In Patients With HER-2/Neu Overexpressing (3+ Or 2+/FISH+) Metastatic Breast Cancer Progressing After Trastuzumab Treatment. NCT00522457; http://clinicaltrials.gov.
77. Denlinger CS. et al. A phase I/II and pharmacologic study of MM-111 in patients with advanced, refractory HER2-positive (HER2+) cancers. J Clin Oncol. 2010;28:abstrTPS169.
78. McDonagh CF, Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther. 2012. [PubMed] 79. Yap TA, Vidal L, Adam J. et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010;28:3965–72. [PubMed] 80. Stopfer P, Marzin K, Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother Pharmacol. 2011. [PubMed]
81. Hickish T, Wheatley D, Lin N. et al. Use of BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor (TKI), to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab. J Clin Oncol. 2009;27(15S):Abstract1023.
82. Gunzer K. et al. Addition of BIBW 2992, an irreversible inhibitor of EGFR/HER1 and HER2, to letrozole in estrogen receptor (ER)-positive metastatic breast cancer (mBC) progressing on letrozole monotherapy. Cancer Res. 2009;69(24 Suppl):Abstract4098.
83. Schuler MH. et al. BIBW 2992, a novel irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor, for the treatment of patients with HER2-negative metastatic breast cancer after failure of no more than two prior chemotherapies. J Clin Oncol. 2010;28:abstr1065.
84. Harbeck N, Schmidt M, Harter P. et al. BIBW 2992, a novel irreversible EGFR/HER1 and 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. 2009;69(24 Suppl):Abstract5062.
85. 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. [PubMed] 86. Doi T. Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients et al. British Journal of Cancer. 2012;106:666– 672. [PMC free article] [PubMed] 87. A multicenter, open-label, non comparative phase I clinical and pharmacokinetic study of oral TAK-285 in patients with advanced cancer. NCT00535522; http://clinicaltrials.gov.
88. Lee P, in Vivo Activity of ARRY-380, a Potent, Small Molecule Inhibitor of ErbB2 in Combination with Trastuzumab, Docetaxel or Bevacizumab. Cancer Research. 2009. 69(24)
89. Moulder SL, A phase I study to assess the safety, tolerability, and PK of ARRY-380, an oral HER2 inhibitor. Poster ASCO Breast Cancer Symposium. 2010.
90. 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. [PubMed] 91. I-SPY 2 Trial (Investigation of Serial Studies to Predict Your therapeutic Response With Imaging And moLecular Analysis 2) NCT01042379; http://clinicaltrials.gov.
92. Gajria D, King TA, Pannu H, Combined inhibition of mTORC1 with temsirolimus and HER2 with neratinib: a phase I study in patients with metastatic HER2-amplified breast cancer. Abstract ASCO Annual Meeting. 2011.
93. Schoeberl B. et al. An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation. Cancer Res. 2010;70(6):2485–2494. [PMC free article] [PubMed]
94. Moyo V. A. A randomized, double-blind phase II trial of exemestane with or without MM-121 in postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+), HER2-negative breast cancer. J Clin Oncol 29. 2011;(suppl):abstrTPS112.
95. Fong PC, Boss DS, Yap TA. et al. Inhibition of poly(ADPribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34. [PubMed] 96. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell. 2010;39:8–24. [PMC free article] [PubMed] 97. Amir E, Seruga B, Serrano R, Ocana A. Targeting DNA repair in breast cancer: a clinical and translational update. Cancer Treat Rev. 2010;36:557–565. [PubMed] 98. Amé J-C. Spenlehauer C, de Murcia G. The PARP superfamily. BioEssays. 2004;26:88293. [PubMed] 99. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nature Rev Cancer. 2008;8:193–204. [PubMed] 100. Burstein H.J. Novel Agents and Future Directions for Refractory Breast Cancer. Semin Oncol. 2011;38(Suppl 2):S17–S24. [PubMed] 101. Farmer H, McCabe N, Lord CJ. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21. [PubMed] 102. Carey L.A. et al. PARP and Cancer — If It's Broke, Don't Fix It. N Engl J Med. 2011;364:277–279. [PMC free article] [PubMed] 103. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48. [PubMed] 104. Liu X. et al. Iniparib non-selectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res. 2011 [Epub ahead of print] [PubMed] 105. O'Shaughnessy J. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205–14. [PubMed] 106. A phase 3, multi-center study of gemcitabine/carboplatin, with or without BSI-201, in patients with ER-, PR-, and Her2-negative metastatic breast cancer. NCT00938652; http://www.clinicaltrials.gov. 107. Tutt A, Robson M, Garber JE. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of concept trial. Lancet. 2010;376:235–244. [PubMed] 108. Gelmon KA. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011 Sep;12(9):852–61. [PubMed] 109. Yang SX, Kummar S, Steinberg SM, Murgo AJ, Gutierrez M. et al. Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumor lymphomas. Cancer Biol Ther. 2009;8:2004–9. [PubMed] 110. Donawho CK, Luo Y, Penning TD. et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728–37. [PubMed] 111. Kummar S. et al. Phase I Study of ABT-888, a PARP Inhibitor, in Combination with Topotecan Hydrochloride in Adults with Refractory Solid Tumors and Lymphomas. Cancer Res. 2011 Sep 1;71(17):5626–34. [PMC free article] [PubMed]
112. Isakoff SJ, Overmoyer B, Tung NM. et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer [abstract 1019] J Clin Oncol. 2009;28(15S):118s.
113. Ali M. et al. Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo? Clin Cancer Res. 2009;15(19):6106–12. [PMC free article] [PubMed]
114. Plummer R. et al. First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors. Journal of Clinical Oncology. 2005;23(16S):3065.
115. A Phase I/II, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral Rucaparib in Patients With BRCA Mutation Breast Cancer or Other Solid Tumor. NCT01482715; http://clinicaltrials.gov.
116. Sandhu S. K, et al. First-in-human trial of a poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers. J Clin Oncol. 2010;28:15s.
117. A Phase I Study of MK-4827 in Patients With Advanced Solid Tumors or Hematologic Malignancies. NCT00749502; http://clinicaltrials.gov.
118. Moulder S. et al. A Phase 1b Study To Assess the Safety and Tolerability of the PARP Inhibitor Iniparib (BSI-201) in Combination with Irinotecan for the Treatment of Patients with Metastatic Breast Cancer (MBC) Proc SABCS. 2010:AbstractP6. ~15~01.
119. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011 Apr;121(4):1231–41. [PMC free article] [PubMed] 120. Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975 Oct;28(10):721–6. [PubMed] 121. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med. 2007 Oct;13(10):433–42. [PubMed] 122. Hudes G, Carducci M. et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal Cell. N Engl J Med. 2007;356:2271–2281. [PubMed] 123. Motzer RJ, Escudier B, Oudard S. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56. [PubMed] 124. Stoica GE, Franke TF, Moroni M. et al. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene. 2003;22(39):7998–8011. [PubMed] 125. Boulay A, Rudloff J, Ye J. et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11(14):5319–28. [PubMed] 126. Baselga J, Semiglazov V, van Dam P. et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009 Jun 1;27(16):2630–7. [PubMed] 127. Ellard SL, Clemons M, Gelmon KA. et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol. 2009 Sep 20;27(27):4536–41. [PubMed] 128. Baselga J, Campone M. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520–9. [PubMed]
129. Hortobagyi GN, Piccart M, Rugo H, Burris H, Campone M, Noguchi S, Gnant M, Pritchard KI, Vittori L, Mukhopadhyay P, Sahmoud T, Lebwohl D, Baselga J. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial (S3-7) Cancer Res. 2011:105–106s.
130. Nahta R, O'Regan RM. Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway. Clin Breast Cancer. 2010 Nov;10(Suppl 3):S72–8. [PubMed] 131. Miller TW, Forbes JT, Shah C, Wyatt SK. et al. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res. 2009 Dec 1;15(23):7266–76. [PMC free article] [PubMed] 132. Morrow PK, Wulf GM, Ensor J. et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011 Aug 10;29(23):3126–32. [PMC free article] [PubMed]
133. Dalenc F. et al. Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial. J Clin Oncol. 2010;28:abstr1013.
134. Jerusalem G, Fasolo A, Dieras V. et al. Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat. 2011 Jan;125(2):447–55. [PubMed]
135. Jerusalem G. et al. Maintenance with everolimus (RAD001) and trastuzumab (T) after discontinuation of chemotherapy in patients (pts) with heavily pretreated HER2-positive metastatic breast cancer (MBC): Pooled data of extension cohorts of phase Ib/II studies. J Clin Oncol. 2010;28:abstr1041.
136. Everolimus in combination with trastuzumab and paclitaxel in the treatment of HER2 positive locally advanced or metastatic breast cancer (BOLERO 1) NCT00876395; http://clinicaltrials.gov. 137. Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (BOLERO-3) NCT01007942; http://clinicaltrials.gov. 138. Fleming GF, Ma CX, Huo D, Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat. 2012. [PMC free article] [PubMed]
139. Gajria D, King T, Pannu H, Sakr R, Seidman AD, Modi S, Dickler M, Drullinsky P, Syldor A, Sujata P, Majid M, Norton L, Rosen N, Chandarlapaty S. Combined Inhibition of mTORC1 with Temsirolimus and HER2 with Neratinib: A Phase I/II Study in Patients with Metastatic HER2-Amplified or Triple-Negative Breast Cancer (PD09-08) Cancer Res 2011:113s.
140. Dumont AG, Dumont SN, Trent JC. The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chin J Cancer. 2012 Jul;31(7):327–34. [PMC free article] [PubMed] 141. Miller TW, Balko JM, Arteaga CL. et al. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011 Nov 20;29(33):4452–61. [PMC free article] [PubMed] 142. Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012 Jan;16(1):121–30. [PubMed] 143. Campbell RA, Bhat-Nakshatri P, Patel NM. et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001 Mar 30;276(13):9817–24. [PubMed]
144. Tolaney S. et al. A Phase 1/2 Study of SAR245408 (S08) in Combination with Trastuzumab (T) or Paclitaxel (P) and T in Patients with HER2+ Metastatic Breast Cancer (MBC) Who Progressed on a Previous T-Based Regimen. (P1-17-02) Cancer Res. 2011;71:240s.
145. Baselga J, Tolaney S, Hart L, Gomez P, Gartner E, DeCillis A, Ruiz-Soto R, Lager J, Burris H. A Phase 1/2 Dose-Escalation Study of SAR245408 (S08) or SAR245409 (S09) in Combination with Letrozole (L) in Subjects with Hormone Receptor-Positive and HER2-Negative (HR+/HER2-) Breast Cancer (BC) Refractory to a Nonsteroidal Aromatase Inhibitor (AI) (P1-17-09) Cancer Res. 2011:243s.
146. Krop IE, Wolff AC, Winer EP, Miller KD, Park BH, Ware J, Holden S, Levy GG, Derynck M, Storniolo AM. A Phase Ib Study Evaluating Safety, Tolerability, Pharmacokinetics (PK), and Activity of the Phosphoinositide-3 Kinase (PI3K) Inhibitor GDC-0941 in Combination with Trastuzumab-MCC-DM1 (T-DM1) in Patients with Advanced HER2-Positive Breast Cancer (P6-15-02) Presentated at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 12. 2010.
147. Schöffski P, De Benedictis E, Gendreau S, Gianni L, Krop IE, Levy G, Ware J, Wildiers H, Winer EP. A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of the PI3-Kinase Inhibitor GDC-0941 in Combination with Paclitaxel and Bevacizumab in Patients with Locally Recurrent or Metastatic Breast Cancer (PD09-04) Cancer Res. 2011:150–151s.
148. Maki RG, Small is beautiful. insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010 Nov 20;28(33):4985–95. [PMC free article] [PubMed] 149. Pollak M. The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res. 2012 Jan 1;18(1):40–50. [PubMed] 150. Gao J, Chang YS, Jallal B, Viner J. Targeting the insulin-like growth factor axis for the development of novel therapeutics in oncology. Cancer Res. 2012 Jan 1;72(1):3–12. [PubMed]
151. Jassem J. et al. Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC) J Clin Oncol. 2010;28:abstr7500.
152. Kaufman PA, Ferrero JM, Bourgeois H, Kennecke H, De Boer R, Jacot W, McGreivy J, Suzuki S, Loh E, Robertson J. A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of AMG 479 With Exemestane (E) or Fulvestrant (F) in Postmenopausal Women With Hormone-Receptor Positive (HR+) Metastatic (M) or Locally Advanced (LA) Breast Cancer (BC) (S1-4) Presentated at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 9. 2010.
153. Ryan PD, Neven P, Blackwell KL, Dirix LY, Barrios CH, Miller Jr WH, Fein LE, Fenton D, Benner RJ, Meech SJ, Paccagnella L, Sleight B, Yee D, Goss PE. Figitumumab Plus Exemestane Versus Exemestane as First-Line Treatment of Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer: A Randomized, Open-Label Phase II Trial (P1-17-01) Cancer Res. 2011:239–240s. [PubMed]
154. Ebbinghaus S. et al. A phase II study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor-positive (ER+) breast cancer. J Clin Oncol. 2011;29:abstrTPS110.
155. NCT00684983. Capecitabine and Lapatinib with or without Cixutumumab in treating patients with previously treated HER2-Positive stage IIIB, Stage IIIC, or Stage IV breast cancer.
156. NCT00728949. A Study for Safety and Effectiveness of IMC-A12 by Itself or Combined With Antiestrogens to Treat Breast Cancer.
157. Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T, Atadja P, Pili R. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res. 2008;14(11):3589–97. [PubMed]
158. Haluska P. et al. Phase II trial of the dual IGF-1R/IR inhibitor BMS-754807 with or without letrozole in aromatase inhibitor-resistant breast cancer. J Clin Oncol. 2011;29:abstrTPS111.
159. Peyton J.D. et al. A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors (Abstract No: 3066) J Clin Oncol. 2011;29:abstr3066.
160. Banerji U. Heat shock protein 90 as a drug target: some like it hot. Clin Cancer Res. 2009 Jan 1;15(1):9–14. [PubMed] 161. Pick E, Kluger Y, Giltnane JM. et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007 Apr 1;67(7):2932–7. [PubMed] 162. Modi S, Stopeck A, Linden H, Solit D. 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 Aug 1;17(15):5132–9. [PubMed]
163. Modi S. et al. Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) J Clin Oncol. 2008;26:abstr1027.
164. Modi et al. Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer. J Clin Oncol. 2011;29:abstr590.
165. Jhaveri K, Chandarlapaty S, Lake D, Gilewski T, Drullinsky P, Sugarman S, Wasserheit-Leiblich C, Moynahan ME, D'Andrea G, Haque S, Patil S, Bauman L, Vukovic V, El-Hariry I, Hudis C, Modi S. A Phase II Trial of Ganetespib: Efficacy and Safety in Patients (pts) with Metastatic Breast Cancer (MBC) (P1-17-08) Cancer Res. 2011:242–243s.
166. Quintero M, Mackenzie N, Brennan PA. Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol. 2004 Jun;30(5):465–8. [PubMed] 167. Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol. 2006 Mar;26(6):2019–28. [PMC free article] [PubMed] 168. Kim SH, Kim KW, Jeong JW. et al. Inhibition of hypoxia-induced angiogenesis by sodium butyrate, a histone deacetylase inhibitor, through hypoxia-inducible factor-1alpha suppression. Oncol Rep. 2007 Apr;17(4):793–7. [PubMed] 169. Munster P, Marchion D. et al. Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC. Clin Cancer Res. 2009;15:2488–2496. [PubMed]
170. Munster P.N. et al. Phase II trial of vorinostat, a histone deacetylase inhibitor to restore the hormone sensitivity to the anti-estrogen tamoxifen in patients with advanced breast cancer having failed prior aromatase inhibitor therapy. J Clin Oncol. 2008;26:abstr3501.
171. Wardley AM. Phase II data for entinostat, a class 1 selective histone deacetylase inhibitor, in patients whose breast cancer is progressing on aromatase inhibitor therapy. J Clin Oncol. 2010;26:abstr1052.
172. Yardley DA. et al. A double-blind, randomized, placebo-controlled phase II study of the steroidal aromatase inhibitor exemestane with and without the isoform selective histone deacetylase inhibitor (HDACi) entinostat in metastatic breast cancer (MBC) J Clin Oncol. 2010;28:abstrTPS128.
173. Peacock NW. A phase I study of panobinostat (LBH589) with capecitabine with or without lapatinib. J Clin Oncol. 2010;28:abstr1115.
174. Mahalingam D. Challenges in developing targeted therapy for pancreatic adenocarcinoma. Expert Opin Ther Targets. 2008 Nov;12(11):1389–401. [PubMed] 175. Glück S, Arteaga CL, Osborne CK. Optimizing Chemotherapy-Free Survival for the ER/HER2-Positive Metastatic Breast Cancer Patient. Clinical Cancer Research. 2011;17(17):1–3. [PubMed]
176. Sandoval-Sus J, Mahtani R, Glück S. HER2-Positive Metastatic Breast Cancer: A Double-Edged Sword. Breast Cancer Management. 2012 in press.