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International Journal of Breast Cancer
Volume 2013 (2013), Article ID 137414, 15 pages
http://dx.doi.org/10.1155/2013/137414
Review Article

Drug Resistance and the Role of Combination Chemotherapy in Improving Patient Outcomes

Breast Cancer Research, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203, USA

Received 26 February 2013; Accepted 1 May 2013

Academic Editor: Ian S. Fentiman

Copyright © 2013 Denise A. Yardley. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Kamangar, G. M. Dores, and W. F. Anderson, “Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world,” Journal of Clinical Oncology, vol. 24, no. 14, pp. 2137–2150, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Tripathy, “Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer: underlying rationale and results of clinical trials,” Oncologist, vol. 12, no. 4, pp. 375–389, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. C. M. Perou, T. Sørlie, M. B. Eisen, et al., “Molecular portraits of human breast tumours,” Nature, vol. 406, no. 6797, pp. 747–752, 2000.
  4. T. Sørlie, C. M. Perou, R. Tibshirani, et al., “Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 19, pp. 10869–10874, 2001.
  5. T. Sørlie, R. Tibshirani, J. Parker, et al., “Repeated observation of breast tumor subtypes in independent gene expression data sets,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8418–8423, 2003.
  6. S. J. L. Payne, R. L. Bowen, J. L. Jones, and C. A. Wells, “Predictive markers in breast cancer—the present,” Histopathology, vol. 52, no. 1, pp. 82–90, 2008.
  7. V. Ossovskaya, I. C. Koo, E. P. Kaldjian, C. Alvares, and B. M. Sherman, “Upregulation of poly (ADP-Ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types,” Genes and Cancer, vol. 1, no. 8, pp. 812–821, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. F. Kassam, K. Enright, R. Dent et al., “Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design,” Clinical Breast Cancer, vol. 9, no. 1, pp. 29–33, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. K. D. Voduc, M. C. Cheang, S. Tyldesley, K. Gelmon, T. O. Nielsen, and H. Kennecke, “Breast cancer subtypes and the risk of local and regional relapse,” Journal of Clinical Oncology, vol. 28, no. 10, pp. 1684–1691, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Goldhirsch, W. C. Wood, A. S. Coates, R. D. Gelber, B. Thürlimann, and H. J. Senn, “Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011,” Annals of Oncology, vol. 22, no. 8, pp. 1736–1747, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. G. Peiró, E. Adrover, L. Sánchez-Tejada, et al., “Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma,” Modern Pathology, vol. 24, no. 2, pp. 201–208, 2011.
  12. J. M. Gee, J. F. Robertson, E. Gutteridge et al., “Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer,” Endocrine-Related Cancer, vol. 12, supplement 1, pp. S99–S111, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. R. Nahta and F. J. Esteva, “HER2 therapy: molecular mechanisms of trastuzumab resistance,” Breast Cancer Research, vol. 8, no. 6, article 215, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. R. Nahta and R. O'Regan, “Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway,” Clinical Breast Cancer, vol. 10, supplement 3, pp. S72–S78, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. NCCN.org, NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, version 2, 2011, http://www.nccn.com/.
  16. L. A. Carey, “Directed therapy of subtypes of triple-negative breast cancer,” The Oncologist, vol. 15, supplement 5, pp. 49–56, 2010. View at Scopus
  17. M. Stenger, “Multiparameter breast cancer gene profiling assays,” ASCO Post, vol. 1, no. 2, July 2010, http://www.ascopost.com/articles/july-2010/multiparameter-breast-cancer-gene-profiling-assays.
  18. J. Jassem, T. Pienkowski, A. Pluzanska et al., “Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial,” Journal of Clinical Oncology, vol. 19, no. 6, pp. 1707–1715, 2001. View at Scopus
  19. L. Biganzoli, T. Cufer, P. Bruning et al., “Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: the European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial,” Journal of Clinical Oncology, vol. 20, no. 14, pp. 3114–3121, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. J. M. Nabholtz, C. Falkson, D. Campos et al., “Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial,” Journal of Clinical Oncology, vol. 21, no. 6, pp. 968–975, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. G. W. Sledge, D. Neuberg, P. Bernardo et al., “Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an Intergroup trial (E1193),” Journal of Clinical Oncology, vol. 21, no. 4, pp. 588–592, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. R. E. Langley, J. Carmichael, A. L. Jones et al., “Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute Trial AB01,” Journal of Clinical Oncology, vol. 23, no. 33, pp. 8322–8330, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Gligorov and J. P. Lotz, “Optimal treatment strategies in postmenopausal women with hormone-receptor-positive and HER2-negative metastatic breast cancer,” Breast Cancer Research and Treatment, vol. 112, supplement 1, pp. 53–66, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Chan, K. Friedrichs, D. Noel, et al., “Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer,” Journal of Clinical Oncology, vol. 17, no. 8, pp. 2341–2354, 1999.
  25. D. J. Slamon, B. Leyland-Jones, S. Shak et al., “Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2,” New England Journal of Medicine, vol. 344, no. 11, pp. 783–792, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Miller, M. Wang, J. Gralow et al., “Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer,” New England Journal of Medicine, vol. 357, no. 26, pp. 2666–2676, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. D. Miles, A. Chan, G. Romieu, et al., “Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (MBC): AVADO,” Journal of Clinical Oncology, vol. 26, supplement 15, abstract LBA1011, p. 43s, 2008.
  28. N. J. Robert, V. Diéras, J. Glaspy et al., “RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer,” Journal of Clinical Oncology, vol. 29, no. 10, pp. 1252–1260, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. D. B. Longley and P. G. Johnston, “Molecular mechanisms of drug resistance,” Journal of Pathology, vol. 205, no. 2, pp. 275–292, 2005.
  30. V. Valero and G. N. Hortobagyi, “Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer?” Journal of Clinical Oncology, vol. 21, no. 6, pp. 959–962, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. P. Conte, V. Guarneri, and C. Bengala, “Evolving nonendocrine therapeutic options for metastatic breast cancer: how adjuvant chemotherapy influences treatment,” Clinical Breast Cancer, vol. 7, no. 11, pp. 841–849, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. S. H. Giordano, A. U. Buzdar, T. L. Smith, S. W. Kau, Y. Yang, and G. N. Hortobagyi, “Is breast cancer survival improving? Trends in survival for patients with recurrent breast cancer diagnosed from 1974 through 2000,” Cancer, vol. 100, no. 1, pp. 44–52, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. M. M. Gottesman, T. Fojo, and S. E. Bates, “Multidrug resistance in cancer: role of ATP-dependent transporters,” Nature Reviews Cancer, vol. 2, no. 1, pp. 48–58, 2002. View at Scopus
  34. E. A. Perez, “Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer,” Breast Cancer Research and Treatment, vol. 114, no. 2, pp. 195–201, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. S. T. Wong and S. Goodin, “Overcoming drug resistance in patients with metastatic breast cancer,” Pharmacotherapy, vol. 29, no. 8, pp. 954–965, 2009.
  36. B. J. Trock, F. Leonessa, and R. Clarke, “Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance,” Journal of the National Cancer Institute, vol. 89, no. 13, pp. 917–931, 1997. View at Scopus
  37. K. Kamath, L. Wilson, F. Cabral, and M. A. Jordan, “βIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability,” Journal of Biological Chemistry, vol. 280, no. 13, pp. 12902–12907, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. A. Paradiso, A. Mangia, A. Chiriatti et al., “Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer,” Annals of Oncology, vol. 16, supplement 4, pp. iv14–iv19, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. C. E. Horak, F. Y. Lee, L. Xu, S. Galbraith, and J. Baselga, “High β-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: a retrospective analysis,” Journal of Clinical Oncology, vol. 27, supplement 15, abstract 3587, p. 167s, 2009.
  40. K. M. Bhat and V. Setaluri, “Microtubule-associated proteins as targets in cancer chemotherapy,” Clinical Cancer Research, vol. 13, no. 10, pp. 2849–2854, 2007.
  41. R. Rouzier, R. Rajan, P. Wagner, et al., “Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 23, pp. 8315–8320, 2005.
  42. S. Tanaka, T. Nohara, M. Iwamoto et al., “Tau expression and efficacy of paclitaxel treatment in metastatic breast cancer,” Cancer Chemotherapy and Pharmacology, vol. 64, no. 2, pp. 341–346, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Baselga, M. Zambetti, A. Llombart-Cussac et al., “Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer,” Journal of Clinical Oncology, vol. 27, no. 4, pp. 526–534, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Dumontet, M. A. Jordan, and F. F. Y. Lee, “Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies,” Molecular Cancer Therapeutics, vol. 8, no. 1, pp. 17–25, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. G. Kadra, P. Finetti, Y. Toiron et al., “Gene expression profiling of breast tumor cell lines to predict for therapeutic response to microtubule-stabilizing agents,” Breast Cancer Research and Treatment, vol. 132, no. 3, pp. 1035–1047, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. J. M. Teodoridis, G. Strathdee, and R. Brown, “Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker,” Drug Resistance Updates, vol. 7, no. 4-5, pp. 267–278, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. E. K. Baker, R. W. Johnstone, J. R. Zalcberg, and A. El-Osta, “Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs,” Oncogene, vol. 24, no. 54, pp. 8061–8075, 2005. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Nyce, S. Leonard, D. Canupp, S. Schulz, and S. Wong, “Epigenetic mechanisms of drug resistance: drug-induced DNA hypermethylation and drug resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 7, pp. 2960–2964, 1993. View at Scopus
  49. V. F. Chekhun, N. Y. Lukyanova, O. Kovalchuk, V. P. Tryndyak, and I. P. Pogribny, “Epigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets,” Molecular Cancer Therapeutics, vol. 6, no. 3, pp. 1089–1098, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. G. Valabrega, F. Montemurro, and M. Aglietta, “Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer,” Annals of Oncology, vol. 18, no. 6, pp. 977–984, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. I. Helfrich, I. Scheffrahn, S. Bartling et al., “Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma,” Journal of Experimental Medicine, vol. 207, no. 3, pp. 491–503, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. E. A. Musgrove and R. L. Sutherland, “Biological determinants of endocrine resistance in breast cancer,” Nature Reviews Cancer, vol. 9, no. 9, pp. 631–643, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. V. Roy and E. A. Perez, “Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer,” Oncologist, vol. 14, no. 11, pp. 1061–1069, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. A. F. Leary, S. Drury, S. Detre et al., “Lapatinib restores hormone sensitivity with differential effects on estrogen receptor signaling in cell models of human epidermal growth factor receptor 2-negative breast cancer with acquired endocrine resistance,” Clinical Cancer Research, vol. 16, no. 5, pp. 1486–1497, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Vallabhaneni, B. C. Nair, V. Cortez, et al., “Significance of ER-Src axis in hormonal therapy resistance,” Breast Cancer Research and Treatment, vol. 130, no. 2, pp. 377–385, 2011.
  56. R. Sáez, M. A. Molina, E. E. Ramsey, et al., “p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer,” Clinical Cancer Research, vol. 12, no. 2, pp. 424–431, 2006.
  57. L. S. Steelman, P. Navolanic, W. H. Chappell, et al., “Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells,” Cell Cycle, vol. 10, no. 17, pp. 3003–3015, 2011.
  58. P. M. Fracasso, P. Westervelt, C. L. Fears, et al., “Phase I study of paclitaxel in combination with a multidrug resistance modulator, PSC 833 (Valspodar), in refractory malignancies,” Journal of Clinical Oncology, vol. 18, no. 5, pp. 1124–1134, 2000.
  59. L. Pusztai, P. Wagner, N. Ibrahim et al., “Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma,” Cancer, vol. 104, no. 4, pp. 682–691, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. W. H. Dragowska, S. A. Weppler, M. A. Qadir, et al., “The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity,” BMC Cancer, vol. 11, article 420, 2011.
  61. D. A. Yardley, R. Ismail-Khan, P. Klein, et al., “Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI),” Journal of Clinical Oncology, vol. 29, supplement 27, abstract 268, 2011.
  62. J. Baselga, M. Campone, M. Piccart, et al., “Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer,” New England Journal of Medicine, vol. 366, no. 6, pp. 520–529, 2012.
  63. T. Bachelot, C. Bourgier, C. Cropet, et al., “Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study,” Journal of Clinical Oncology, vol. 30, no. 22, pp. 2718–2724, 2012.
  64. W. Y. Hu, W. R. Zhong, F. H. Wang, L. Li, and Y. Z. Shao, “In silico synergism and antagonism of an anti-tumour system intervened by coupling immunotherapy and chemotherapy: a mathematical modelling approach,” Bulletin of Mathematical Biology, vol. 74, no. 2, pp. 434–452, 2012.
  65. P. A. C. Greenberg, G. N. Hortobagyi, T. L. Smith, L. D. Ziegler, D. K. Frye, and A. U. Buzdar, “Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer,” Journal of Clinical Oncology, vol. 14, no. 8, pp. 2197–2205, 1996. View at Scopus
  66. J. O'Shaughnessy, D. Miles, S. Vukelja, et al., “Superior survival with capecitabine plus docetaxel in combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results,” Journal of Clinical Oncology, vol. 20, no. 12, pp. 2812–2823, 2002.
  67. D. Miles, S. Vukelja, V. Moiseyenko et al., “Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial,” Clinical Breast Cancer, vol. 5, no. 4, pp. 273–278, 2004. View at Scopus
  68. N. Batista, G. Perez-Manga, M. Constenla et al., “Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer,” British Journal of Cancer, vol. 90, no. 9, pp. 1740–1746, 2004. View at Scopus
  69. J. L. Blum, E. C. Dees, S. J. Vukelja et al., “Phase II trial of capecitabine and weekly paclitaxel in patients with metastatic breast cancer previously treated with every-3-week taxane therapy,” Clinical Breast Cancer, vol. 7, no. 6, pp. 465–470, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. K. S. Albain, S. M. Nag, G. Calderillo-Ruiz et al., “Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment,” Journal of Clinical Oncology, vol. 26, no. 24, pp. 3950–3957, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Chan, G. Romieu, J. Huober et al., “Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer,” Journal of Clinical Oncology, vol. 27, no. 11, pp. 1753–1760, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. E. S. Thomas, H. L. Gomez, R. K. Li, et al., “Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment,” Journal of Clinical Oncology, vol. 25, no. 33, pp. 5210–5217, 2007.
  73. M. Martín, A. Ruiz, M. Muñoz et al., “Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial,” Lancet Oncology, vol. 8, no. 3, pp. 219–225, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. K. D. Miller, L. I. Chap, F. A. Holmes et al., “Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer,” Journal of Clinical Oncology, vol. 23, no. 4, pp. 792–799, 2005. View at Publisher · View at Google Scholar · View at Scopus
  75. D. Cameron, M. Casey, M. Press et al., “A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses,” Breast Cancer Research and Treatment, vol. 112, no. 3, pp. 533–543, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. C. E. Geyer, J. Forster, D. Lindquist, et al., “Lapatinib plus capecitabine for HER2-positive advanced breast cancer,” New England Journal of Medicine, vol. 355, no. 26, pp. 2733–2743, 2006.
  77. J. O'Shaughnessy, K. L. Blackwell, A. M. Burstein, et al., “A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy,” Journal of Clinical Oncology, vol. 26, supplement 15, abstract 1015, p. 44s, 2008.
  78. K. L. Blackwell, H. J. Burstein, G. W. Sledge, et al., “Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzumab in women with HER2-positive metastatic breast cancer progressing on trastuzumab therapy,” Cancer Research, vol. 69, no. 24, supplement, abstract 61, 2009.
  79. K. L. Blackwell, H. J. Burstein, A. M. Storniolo et al., “Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1124–1130, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Fossati, C. Confalonieri, V. Torri et al., “Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women,” Journal of Clinical Oncology, vol. 16, no. 10, pp. 3439–3460, 1998. View at Scopus
  81. F. Cardoso, P. L. Bedard, E. P. Winer et al., “International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy,” Journal of the National Cancer Institute, vol. 101, no. 17, pp. 1174–1181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  82. N. Sawada, T. Ishikawa, Y. Fukase, M. Nishida, T. Yoshikubo, and H. Ishitsuka, “Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts,” Clinical Cancer Research, vol. 4, no. 4, pp. 1013–1019, 1998. View at Scopus
  83. B. G. Somer, L. S. Schwartzberg, F. Arena, A. Epperson, D. Fu, and B. V. Fortner, “Phase II trial of nab-paclitaxel (nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC),” Journal of Clinical Oncology, vol. 25, supplement 18, abstract 1053, 2007.
  84. D. Amadori and L. Cecconetto, “Gemcitabine and taxanes in metastatic breast cancer,” Annals of Oncology, vol. 17, supplement 5, pp. v173–v176, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Mavroudis, N. Malamos, A. Alexopoulos et al., “Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: a multicenter phase II trial,” Annals of Oncology, vol. 10, no. 2, pp. 211–215, 1999. View at Publisher · View at Google Scholar · View at Scopus
  86. G. Fountzilas, C. Nicolaides, D. Bafaloukos et al., “Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a hellenic cooperative oncology group phase II study,” Cancer Investigation, vol. 18, no. 6, pp. 503–509, 2000. View at Scopus
  87. V. Roy, B. R. Laplant, G. G. Gross, C. L. Bane, and F. M. Palmieri, “Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531),” Annals of Oncology, vol. 20, no. 3, pp. 449–453, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. F. Y. Lee, R. Smykla, K. Johnston et al., “Preclinical efficacy spectrum and pharmacokinetics of ixabepilone,” Cancer Chemotherapy and Pharmacology, vol. 63, no. 2, pp. 201–212, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. F. Y. Lee, R. Borzilleri, C. R. Fairchild et al., “BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy,” Clinical Cancer Research, vol. 7, no. 5, pp. 1429–1437, 2001. View at Scopus
  90. T. C. Chou, X. G. Zhang, C. R. Harris, et al., “Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 26, pp. 15798–15802, 1998.
  91. M. A. Jordan, H. Miller, L. Ni, et al., “The Pat-21 breast cancer model derived from a patient with primary Taxol resistance recapitulates the phenotype of its origin has altered ß-tubulin expression and is sensitive to ixabepilone,” Proceedings of the American Association For Cancer Research, abstract LB-280, 2006.
  92. F. Lee, M. N. Jure-Kunkel, and M. E. Salvati, “Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence,” Therapeutic Advances in Medical Oncology, vol. 3, no. 1, pp. 11–25, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. G. N. Hortobagyi, E. A. Perez, E. Vrdoljak E, et al., “Analysis of overall survival (OS) among patients (pts) with metastatic breast cancer (MBC) receiving either ixabepilone (I) plus capecitabine (C) or C alone: results from two randomized phase III trials,” Breast Cancer Symposium Proceedings, vol. 178, abstract 186, 2008.
  94. S. Moulder, H. Li, M. Wang et al., “A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial,” Breast Cancer Research and Treatment, vol. 119, no. 3, pp. 663–671, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. H. S. Rugo, M. Campone, D. Amadori, et al., “Randomized phase II study of weekly versus every 3 week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC): final results,” Journal of Clinical Oncology, vol. 28, supplement 15, abstract 1040, 2010.
  96. M. Andersson, E. Lidbrink, K. Bjerre 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,” Journal of Clinical Oncology, vol. 29, no. 3, pp. 264–271, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. E. A. Perez, “Gemcitabine and platinum combinations in patients with breast cancer previously treated with anthracyclines and/or taxanes,” Clinical Breast Cancer, vol. 4, supplement 3, pp. S113–S116, 2004. View at Scopus
  98. D. Loesch, L. Asmar, K. McIntyre et al., “Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer,” Clinical Breast Cancer, vol. 8, no. 2, pp. 178–186, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. D. Yardley, H. Burris III, L. Simons et al., “A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer,” Clinical Breast Cancer, vol. 8, no. 5, pp. 425–431, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. J. O'Shaughnessy, C. Osborne, J. E. Pippen, et al., “Iniparib plus chemotherapy in metastatic triple-negative breast cancer,” New England Journal of Medicine, vol. 364, no. 3, pp. 205–214, 2011.
  101. J. O. O'Shaughnessy, L. S. Schwartzberg, M. A. Danso, et al., “A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC),” Journal of Clinical Oncology, vol. 29, supplement 15, abstract 1007, 2011.
  102. R. Bai, K. D. Paull, C. L. Herald, L. Malspeis, G. R. Pettit, and E. Hamel, “Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin: discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data,” Journal of Biological Chemistry, vol. 266, no. 24, pp. 15882–15889, 1991. View at Scopus
  103. M. J. Towle, K. A. Salvato, J. Budrow et al., “In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B,” Cancer Research, vol. 61, no. 3, pp. 1013–1021, 2001. View at Scopus
  104. G. Kuznetsov, K. TenDyke, M. Yu, and B. Littlefield, “Antiproliferative effects of halichondrin B analog eribulin mesylate (E7389) against paclitaxelresistant human cancer cells in vitro,” AACR Meeting Abstracts, abstract C58, 2007.
  105. L. T. Vahdat, B. Pruitt, C. J. Fabian et al., “Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane,” Journal of Clinical Oncology, vol. 27, no. 18, pp. 2954–2961, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. J. Cortes, L. Vahdat, J. L. Blum et al., “Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine,” Journal of Clinical Oncology, vol. 28, no. 25, pp. 3922–3928, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. H. Iwata, K. Aogi, N. Masuda, et al., “Efficacy and safety of eribulin in Japanese patients (pts) with advanced breast cancer,” Journal of Clinical Oncology, vol. 28, supplement 15, abstract 1081, 2010.
  108. J. Cortes, J. O'Shaughnessy, D. Loesch et al., “Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study,” The Lancet, vol. 377, no. 9769, pp. 914–923, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. E. H. Romond, E. A. Perez, J. Bryant, et al., “Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer,” New England Journal of Medicine, vol. 353, no. 16, pp. 1673–1684, 2005.
  110. I. Smith, M. Procter, R. D. Gelber et al., “2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial,” The Lancet, vol. 369, no. 9555, pp. 29–36, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. M. D. Pegram, T. Pienkowski, D. W. Northfelt et al., “Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer,” Journal of the National Cancer Institute, vol. 96, no. 10, pp. 759–769, 2004. View at Scopus
  112. H. Burris, D. Yardley, S. Jones et al., “Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer,” Journal of Clinical Oncology, vol. 22, no. 9, pp. 1621–1629, 2004. View at Publisher · View at Google Scholar · View at Scopus
  113. N. Robert, B. Leyland-Jones, L. Asmar et al., “Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2—overexpressing metastatic breast cancer,” Journal of Clinical Oncology, vol. 24, no. 18, pp. 2786–2792, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. G. Schaller, I. Fuchs, T. Gonsch et al., “Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes,” Journal of Clinical Oncology, vol. 25, no. 22, pp. 3246–3250, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. T. Ishida, T. Kiba, M. Takeda et al., “Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes,” Cancer Chemotherapy and Pharmacology, vol. 64, no. 2, pp. 361–369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  116. R. Bartsch, C. Wenzel, S. P. Gampenreider, et al., “Trastuzumab and gemcitabine as salvage therapy in heavily pretreated patients with metastatic breast cancer,” Cancer Chemotherapy and Pharmacology, vol. 62, no. 5, pp. 903–910, 2008.
  117. D. A. Yardley, M. Seiler, I. Ray-Coquard, et al., “Ridaforolimus (AP23573; MK-8669) in combination with trastuzumab for patients with HER2-positive trastuzumab-refractory metastatic breast cancer: a multicenter phase 2 clinical trial,” Cancer Research, vol. 69, supplement 3, abstract 3091, 2009.
  118. J. Infante, D. A. Yardley, H. Burris III et al., “Phase II trial of weekly docetaxel, vinorelbine, and trastuzumab in the first-line treatment of patients with her2-positive metastatic breast cancer,” Clinical Breast Cancer, vol. 9, no. 1, pp. 23–28, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. D. A. Yardley, L. Hart, L. D. Bosserman, et al., “Phase II study evaluating lapatinib (L) in combination with albumin bound paclitaxel (ab-Pac) in women who have received 0-1 chemotherapy regimen for HER2 overexpressing (HER2+) metastatic breast cancer (MBC),” Cancer Research, vol. 71, no. 24, supplement, abstract P1-12-10, 2011.
  120. J. O'Shaughnessy, D. Miles, R. J. Gray, et al., “A meta-analysis of overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC),” Journal of Clinical Oncology, vol. 28, supplement 15, abstract 1005, 2010.
  121. S. Hegewisch-Becker, C. A. Lerchenmuller, A. Welt, et al., “Capecitabine (Cap) combined with bevacizumab (Bev) with or without vinorelbine (Vin) in first-line metastatic breast cancer (MBC): first safety results from the randomized CARIN trial,” Journal of Clinical Oncology, vol. 29, supplement 15, abstract 1044, 2011.
  122. A. M. Brufsky, S. Hurvitz, E. Perez, et al., “RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer,” Journal of Clinical Oncology, vol. 29, no. 32, pp. 4286–4293, 2011.
  123. A. M. Brufsky, S. A. Hurvitz, E. A. Perez, et al., “Final overall survival (OS) and safety analyses of RIBBON-2, a randomized phase III trial of bevacizumab (BEV) versus placebo (PL) combined with second-line chemotherapy (CT) for HER2-negative BEV-naive metastatic breast cancer (MBC),” Journal of Clinical Oncology, vol. 30, supplement 27, abstract 100, 2012.
  124. G. W. Sledge, K. Miller, C. Moisa, and W. Gradishar, “Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-line in metatastic breast cancer,” Journal of Clinical Oncology, vol. 25, supplement 18, abstract 1013, p. 35s, 2007.
  125. FDA Public Hearing, “Proposal to withdraw approval for the breast cancer indication for bevacizumab (Avastin),” June 2011, http://www.fda.gov/downloads/NewsEvents/MeetingsConferencesWorkshops/UCM261699.pdf.
  126. S. A. Hurvitz, M. D. Pegram, L. -S Lin, et al., “Final results of a phase II trial evaluating trastuzumab and bevacizumab as first line treatment of HER2-amplified advanced breast cancer,” Cancer Research, vol. 69, no. 24, supplement 3, abstract 6094, 2009.
  127. H. S. Rugo, S. Franco, P. Munster, et al., “A phase II evaluation of lapatinib and bevacizumab in HER-2+ metatastic breast cancer,” Journal of Clinical Oncology, vol. 26, supplement 15, abstract 1042, p. 51s, 2008.
  128. J. Baselga, K. A. Gelmon, S. Verma 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,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1138–1144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. J. Baselga, J. Cortés, S. B. Kim, et al., “Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer,” New England Journal of Medicine, vol. 366, no. 2, pp. 109–119, 2012.
  130. Roche Media Release, “New data from Phase III study showed that people with HER2-positive metastatic breast cancer lived longer with Roche’s Perjeta,” June 2012, http://www.roche.com/media/media_releases/med-cor-2012-06-22.htm.