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Systemic Therapy

  • Frederik MarméEmail author
Chapter

Abstract

Advances in systemic therapy for early as well as metastatic breast cancer, together with progress in diagnostics and surgical therapy have led to a substantial improvement in outcome. This chapter discusses the use of chemotherapy as well as targeted therapies including endocrine, anti-HER2 targeted, antiangiogenic therapies, and bone-targeted agents in the adjuvant and metastatic setting. During recent years and since the publication of this book’s first edition, new chemotherapeutic agents like eribulin have become new treatment options and there is emerging new data on the role of “old” drugs like platinum-based compounds in the treatment of breast cancer. In addition, several new agents have received approval for the treatment of breast cancer including potent HER2-directed therapies, namely pertuzumab and T-DM1 which have led to an unprecedented improvement in overall survival for patients with HER2-positive metastatic breast cancer. Furthermore, several new treatment options have been implemented for patients with hormone receptor-positive disease which can restore endocrine sensitivity, these principals include inhibition of mTOR and cdk4/6. Bone-targeted therapies to treat bone metastases are covered and new data for their use in the adjuvant setting will be covered. Furthermore, important investigational agents on the verge of entering the clinic like PI3K- and PARP inhibitors are discussed alongside with standard therapies.

Keywords

Early breast cancer Metastatic breast cancer Neoadjuvant therapy Adjuvant therapy Chemotherapy Palliative chemotherapy Anthracyclines Taxanes Tubulin inhibitors Tamoxifen Aromatase inhibitors Fulvestrant mTOR cdk4/6 PI3K Antiangiogenic therapy PARP inhibitors bisphosphonates RANKL antibodies HER2-targeted therapy Trastuzumab Pertuzumab T-DM1 

References

  1. 1.
    Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338–50.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2014;25(10):1871–88.CrossRefGoogle Scholar
  3. 3.
    Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(4):931–42.CrossRefGoogle Scholar
  4. 4.
    Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1990;8(9):1483–96.CrossRefGoogle Scholar
  5. 5.
    Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2003;21(6):976–83.CrossRefGoogle Scholar
  6. 6.
    Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1998;16(8):2651–8.CrossRefGoogle Scholar
  7. 7.
    Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(22):5166–70.CrossRefGoogle Scholar
  8. 8.
    Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006;355(18):1851–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2003;14(6):833–42.Google Scholar
  10. 10.
    FASG fasg. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(3):602–11.Google Scholar
  11. 11.
    Bonneterre J, Roche H, Kerbrat P, Bremond A, Fumoleau P, Namer M, et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(12):2686–93.CrossRefGoogle Scholar
  12. 12.
    Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, et al. Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 1997;8(2):155–62.Google Scholar
  13. 13.
    Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert P, Focan-Henrard D, et al. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1993;11(7):1253–63.CrossRefGoogle Scholar
  14. 14.
    EBCTCG EBCTC, Group, Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44.Google Scholar
  15. 15.
    von Minckwitz G, Kummel S, du Bois A, Eiermann W, Eidtmann H, Gerber B, et al. Pegfilgrastim ± ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2008;19(2):292–8.Google Scholar
  16. 16.
    Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–79.PubMedCrossRefGoogle Scholar
  17. 17.
    Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Rese (an Official Journal of the American Association for Cancer Research). 2008;14(1):14–24.CrossRefGoogle Scholar
  18. 18.
    Fumoleau P, Roche H, Kerbrat P, Bonneterre J, Romestaing P, Fargeot P, et al. Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2006;17(1):85–92.CrossRefGoogle Scholar
  19. 19.
    Ryberg M, Nielsen D, Cortese G, Nielsen G, Skovsgaard T, Andersen PK. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst. 2008;100(15):1058–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Bonneterre J, Roche H, Kerbrat P, Fumoleau P, Goudier MJ, Fargeot P, et al. Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2004;22(15):3070–9.CrossRefGoogle Scholar
  21. 21.
    Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Nardi V, Winkfield KM, Ok CY, Niemierko A, Kluk MJ, Attar EC, et al. Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to de novo disease and differ from other therapy-related myeloid neoplasms. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012.Google Scholar
  23. 23.
    Smith RE, Bryant J, DeCillis A, Anderson S. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2003;21(7):1195–204.CrossRefGoogle Scholar
  24. 24.
    Praga C, Bergh J, Bliss J, Bonneterre J, Cesana B, Coombes RC, et al. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(18):4179–91.CrossRefGoogle Scholar
  25. 25.
    Wolff AC, Blackford AL, Visvanathan K, Rugo HS, Moy B, Goldstein LJ, et al. Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(4):340–8.CrossRefGoogle Scholar
  26. 26.
    Patt DA, Duan Z, Fang S, Hortobagyi GN, Giordano SH. Acute myeloid leukemia after adjuvant breast cancer therapy in older women: understanding risk. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2007;25(25):3871–6.CrossRefGoogle Scholar
  27. 27.
    Turner N, Biganzoli L, Di Leo A. Continued value of adjuvant anthracyclines as treatment for early breast cancer. Lancet Oncol. 2015;16(7):e362–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Jones S, Holmes FA, O’Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009.Google Scholar
  29. 29.
    Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O’Regan R, et al. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2014;32(22):2311–7.CrossRefGoogle Scholar
  30. 30.
    Slamon D, Eiermann W, Robert N, Giermek J, Martin M, Jasiowka M, et al. Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC → T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 + early breast cancer. Cancer Res. 2016;76(4 Suppl):S5-04.CrossRefGoogle Scholar
  31. 31.
    Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013;14(11):1121–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134–41.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(18):2232–9.CrossRefGoogle Scholar
  34. 34.
    Li S, Blaes AH, Liu J, Hu Y, Hernandez RK, Stryker S, et al. Trends in the use of adjuvant anthracycline- and taxane-based chemotherapy regimens in early-stage breast cancer, by surgery type. ASCO Meet Abstr. 2014;32(15 suppl):e12017.Google Scholar
  35. 35.
    O’Brien MER. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX™/Doxil®) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15(3):440–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Al-Batran SE, Meerpohl HG, von Minckwitz G, Atmaca A, Kleeberg U, Harbeck N, et al. Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m2 every 4 weeks in previously treated patients with metastatic breast cancer. Oncology. 2006;70(2):141–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, et al. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2004;15(10):1527–34.CrossRefGoogle Scholar
  38. 38.
    Batist G, Harris L, Azarnia N, Lee LW, Daza-Ramirez P. Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs. 2006;17(5):587–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Henderson IC, Allegra JC, Woodcock T, Wolff S, Bryan S, Cartwright K, et al. Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1989;7(5):560–71.CrossRefGoogle Scholar
  40. 40.
    Heidemann E. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Ann Oncol. 2002;13(11):1717–29.PubMedCrossRefGoogle Scholar
  41. 41.
    Rowinsky EK. Clinical pharmacology of Taxol. J Natl Cancer Inst Monogr. 1993;15:25–37.Google Scholar
  42. 42.
    Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2006;24(36):5664–71.CrossRefGoogle Scholar
  43. 43.
    Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005;352(22):2302–13.PubMedCrossRefGoogle Scholar
  44. 44.
    Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, et al. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013;14(1):72–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Martin M, Segui MA, Anton A, Ruiz A, Ramos M, Adrover E, et al. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010;363(23):2200–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, et al. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expressiondagger. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2014;25(8):1551–7.CrossRefGoogle Scholar
  47. 47.
    Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, et al. Long-term follow-up of the E1199 Phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(21):2353–60.CrossRefGoogle Scholar
  48. 48.
    Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(24):5542–51.CrossRefGoogle Scholar
  49. 49.
    Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(10):1642–9.CrossRefGoogle Scholar
  50. 50.
    Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, Cowan D, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357(15):1496–506.PubMedCrossRefGoogle Scholar
  51. 51.
    Andre F, Broglio K, Roche H, Martin M, Mackey JR, Penault-Llorca F, et al. Estrogen receptor expression and efficacy of docetaxel-containing adjuvant chemotherapy in patients with node-positive breast cancer: results from a pooled analysis. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(16):2636–43.CrossRefGoogle Scholar
  52. 52.
    De Laurentiis M, Cancello G, D’Agostino D, Giuliano M, Giordano A, Montagna E, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(1):44–53.CrossRefGoogle Scholar
  53. 53.
    Jacquin JP, Jones S, Magne N, Chapelle C, Ellis P, Janni W, et al. Docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer. Consistency of effect independent of nodal and biomarker status: a meta-analysis of 14 randomized clinical trials. Breast Cancer Res Treat. 2012;134(3):903–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2015;26(8):1533–46.CrossRefGoogle Scholar
  55. 55.
    Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358(16):1663–71.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(29):3877–84.CrossRefGoogle Scholar
  57. 57.
    O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2002;20(12):2812–23.CrossRefGoogle Scholar
  58. 58.
    Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, et al. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004;5(4):273–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(24):3950–7.CrossRefGoogle Scholar
  60. 60.
    Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2006;12(4):1317–24.CrossRefGoogle Scholar
  61. 61.
    Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(31):7794–803.CrossRefGoogle Scholar
  62. 62.
    Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(22):3611–9.CrossRefGoogle Scholar
  63. 63.
    Gebhart G, Gamez C, Holmes E, Robles J, Garcia C, Cortes M, et al. 18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO. J Nucl Med (Official Publication, Society of Nuclear Medicine). 2013;54(11):1862–8.Google Scholar
  64. 64.
    Untch M, Jackisch C, Schneeweiß A, Conrad B, Aktas B, Denkert C, et al. Abstract S2-07: a randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. Cancer Res. 2015;75(9 Suppl):S2-07.CrossRefGoogle Scholar
  65. 65.
    von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, et al. Abstract P1–14-11: nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). Cancer Res. 2016;76(4 Suppl):P1-14-1.Google Scholar
  66. 66.
    Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2010;28(20):3256–63.CrossRefGoogle Scholar
  67. 67.
    Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2007;25(33):5210–7.CrossRefGoogle Scholar
  68. 68.
    Baselga J, Zambetti M, Llombart-Cussac A, Manikhas G, Kubista E, Steger GG, et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(4):526–34.CrossRefGoogle Scholar
  69. 69.
    Thomas ES. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(13):2223.CrossRefGoogle Scholar
  70. 70.
    Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2007;25(23):3407–14.CrossRefGoogle Scholar
  71. 71.
    EMEA. Questions and answers on the withdrawal of the marketing authorisation for Ixempra 2009. Available from http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2010/01/WC500062428.pdf.
  72. 72.
    Vogel C, O’Rourke M, Winer E, Hochster H, Chang A, Adamkiewicz B, et al. Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 1999;10(4):397–402.CrossRefGoogle Scholar
  73. 73.
    Weber BL, Vogel C, Jones S, Harvey H, Hutchins L, Bigley J, et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1995;13(11):2722–30.CrossRefGoogle Scholar
  74. 74.
    Romero A, Rabinovich MG, Vallejo CT, Perez JE, Rodriguez R, Cuevas MA, et al. Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1994;12(2):336–41.CrossRefGoogle Scholar
  75. 75.
    Garcia-Conde J, Lluch A, Martin M, Casado A, Gervasio H, De Oliveira C, et al. Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 1994;5(9):854–7.CrossRefGoogle Scholar
  76. 76.
    Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, et al. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1993;11(7):1245–52.CrossRefGoogle Scholar
  77. 77.
    Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, et al. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1994;12(10):2094–101.CrossRefGoogle Scholar
  78. 78.
    Degardin M, Bonneterre J, Hecquet B, Pion JM, Adenis A, Horner D, et al. Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 1994;5(5):423–6.CrossRefGoogle Scholar
  79. 79.
    Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O’Rourke M, et al. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1995;13(10):2567–74.CrossRefGoogle Scholar
  80. 80.
    Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, 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 Oncol. 2007;8(3):219–25.PubMedCrossRefGoogle Scholar
  81. 81.
    Pajk B, Cufer T, Canney P, Ellis P, Cameron D, Blot E, et al. Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial. Breast. 2008;17(2):180–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Baweja M, Suman VJ, Fitch TR, Mailliard JA, Bernath A, Rowland KM, et al. Phase II trial of oral vinorelbine for the treatment of metastatic breast cancer in patients > or = 65 years of age: an NCCTG study. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2006;17(4):623–9.CrossRefGoogle Scholar
  83. 83.
    Freyer G, Delozier T, Lichinister M, Gedouin D, Bougnoux P, His P, et al. Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2003;21(1):35–40.CrossRefGoogle Scholar
  84. 84.
    Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, 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 (Official Journal of the American Society of Clinical Oncology). 2011;29(3):264–71.CrossRefGoogle Scholar
  85. 85.
    Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther. 2008;7(7):2003–11.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.PubMedCrossRefGoogle Scholar
  87. 87.
    Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(6):594–601.CrossRefGoogle Scholar
  88. 88.
    Twelves C, Cortes J, Vahdat L, Olivo M, He Y, Kaufman PA, et al. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014;148(3):553–61.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Madondo MT, Quinn M, Plebanski M. Low dose cyclophosphamide: mechanisms of T cell modulation. Cancer Treat Rev. 2016;42:3–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992;6(3):163–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award Lecture. Cancer Res. 1989;49(1):1–7.PubMedGoogle Scholar
  92. 92.
    Bonadonna G, Moliterni A, Zambetti M, Daidone MG, Pilotti S, Gianni L, et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ. 2005;330(7485):217.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332(14):901–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(12):3103–10.CrossRefGoogle Scholar
  95. 95.
    Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1990;8(6):1005–18.CrossRefGoogle Scholar
  96. 96.
    Colleoni M. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13(1):73–80.PubMedCrossRefGoogle Scholar
  97. 97.
    Colleoni M, Gray KP, Gelber SI, Lang I, Thurlimann BJK, Gianni L, et al. Low-dose oral cyclophosphamide-methotrexate maintenance (CMM) for receptor-negative early breast cancer (BC). ASCO Meet Abstr. 2015;33(15 suppl):1002.Google Scholar
  98. 98.
    Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011;33(4):369–83.PubMedCrossRefGoogle Scholar
  99. 99.
    Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638–47.PubMedCrossRefGoogle Scholar
  100. 100.
    Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(9):1492–501.CrossRefGoogle Scholar
  101. 101.
    Pirvulescu C, von Minckwitz G, Loibl S. Bendamustine in metastatic breast cancer: an old drug in new design. Breast care. 2008;3(5):333–9.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    von Minckwitz G, Chernozemsky I, Sirakova L, Chilingirov P, Souchon R, Marschner N, et al. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs. 2005;16(8):871–7.CrossRefGoogle Scholar
  103. 103.
    Reichmann U, Bokemeyer C, Wallwiener D, Bamberg M, Huober J. Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2007;18(12):1981–4.CrossRefGoogle Scholar
  104. 104.
    Decatris MP, Sundar S, O’Byrne KJ. Platinum-based chemotherapy in metastatic breast cancer: current status. Cancer Treat Rev. 2004;30(1):53–81.PubMedCrossRefGoogle Scholar
  105. 105.
    Kolaric K, Roth A. Phase II clinical trial of cis-dichlorodiammine platinum (cis-DDP) for antitumorigenic activity in previously untreated patients with metastatic breast cancer. Cancer Chemother Pharmacol. 1983;11(2):108–12.PubMedCrossRefGoogle Scholar
  106. 106.
    Sledge GW Jr, Loehrer PJ Sr, Roth BJ, Einhorn LH. Cisplatin as first-line therapy for metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1988;6(12):1811–4.CrossRefGoogle Scholar
  107. 107.
    Yap HY, Salem P, Hortobagyi GN, Bodey GP Sr, Buzdar AU, Tashima CK, et al. Phase II study of cis-dichlorodiammineplatinum(II) in advanced breast cancer. Cancer Treat Rep. 1978;62(3):405–8.PubMedGoogle Scholar
  108. 108.
    Forastiere AA, Hakes TB, Wittes JT, Wittes RE. Cisplatin in the treatment of metastatic breast carcinoma: a prospective randomized trial of two dosage schedules. Am J Clin Oncol. 1982;5(3):243–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Martino S, Samal BA, Singhakowinta A, Yoshida S, Mackenzie M, Jain J, et al. A phase II study of cis-diamminedichloroplatinum II for advanced breast cancer. Two dose schedules. J Cancer Res Clin Oncol. 1984;108(3):354–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Marme F, Schneeweiss A. Targeted therapies in triple-negative breast cancer. Breast care. 2015;10(3):159–66.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Baselga J, Gomez P, Greil R, Braga S, Climent MA, Wardley AM, et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013;31(20):2586–92.CrossRefGoogle Scholar
  112. 112.
    Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(21):2615–23.CrossRefGoogle Scholar
  113. 113.
    Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, et al. TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(17):1902–9.CrossRefGoogle Scholar
  114. 114.
    Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, et al. Abstract S3-01: the TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Res. 2015;75(9 Suppl):S3–4.Google Scholar
  115. 115.
    von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.CrossRefGoogle Scholar
  116. 116.
    Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(1):13–21.CrossRefGoogle Scholar
  117. 117.
    Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke E, et al. Abstract S6-07: comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. Cancer Res. 2016;76(4 Suppl):S6-07.Google Scholar
  118. 118.
    von Minckwitz G, Loibl S, Schneeweiss A, Salat C, Rezai M, Zahm D-M, et al. Abstract S2-04: early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Cancer Res. 2016;76(4 Suppl):S2-04.CrossRefGoogle Scholar
  119. 119.
    Sikov W, Berry D, Perou C, Singh B, Cirrincione C, Tolaney S, et al. Abstract S2-05: event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC ± carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). Cancer Res. 2016;76(4 Suppl):S2-05.CrossRefGoogle Scholar
  120. 120.
    Goodsell DS. The molecular perspective: methotrexate. Oncologist. 1999;4(4):340–1.PubMedGoogle Scholar
  121. 121.
    Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, et al. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015;385(9980):1863–72.PubMedCrossRefGoogle Scholar
  122. 122.
    O’Shaughnessy JA, Kaufmann M, Siedentopf F, Dalivoust P, Debled M, Robert NJ, et al. Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer. Oncologist. 2012;17(4):476–84.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, 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. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(10):1252–60.CrossRefGoogle Scholar
  124. 124.
    Chan A, Verrill M. Capecitabine and vinorelbine in metastatic breast cancer. Eur J Cancer. 2009;45(13):2253–65.PubMedCrossRefGoogle Scholar
  125. 125.
    Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, et al. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009;10(12):1145–51.PubMedCrossRefGoogle Scholar
  126. 126.
    Joensuu H, Gligorov J. Adjuvant treatments for triple-negative breast cancers. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2012;23 Suppl 6:vi40–vi5.Google Scholar
  127. 127.
    J O’Shaughnessy. First efficacy results of a randomized, open-label, phase III study of adjuvant doxorubicin plus cyclophosphamide, followed by docetaxel with or without capecitabine, in high-risk early breast cancer. Cancer Res. 2010;72(24 suppl):S2-4.Google Scholar
  128. 128.
    Jiang Y, Yin W, Zhou L, Yan T, Zhou Q, Du Y, et al. First efficacy results of capecitabine with anthracycline- and taxane-based adjuvant therapy in high-risk early breast cancer: a meta-analysis. PLoS ONE. 2012;7(3):e32474.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013;31(29):3623–30.CrossRefGoogle Scholar
  130. 130.
    Toi M, Lee S-J, Lee E, Ohtani S, Im Y-H, Im S-A, et al. Abstract S1-07: a phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Cancer Res. 2016;76(4 Suppl):S1-07.CrossRefGoogle Scholar
  131. 131.
    Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2004;22(14):2918–26.CrossRefGoogle Scholar
  132. 132.
    Seidman AD. The evolving role of gemcitabine in the management of breast cancer. Oncology. 2001;60(3):189–98.PubMedCrossRefGoogle Scholar
  133. 133.
    Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology. 2001;15(2 Suppl 3):11–4.PubMedGoogle Scholar
  134. 134.
    Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res. 1990;50(14):4417–22.PubMedGoogle Scholar
  135. 135.
    Ferrazzi E, Stievano L. Gemcitabine: monochemotherapy of breast cancer. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2006;17(Suppl 5):v169–72.CrossRefGoogle Scholar
  136. 136.
    Gudena V, Montero AJ, Gluck S. Gemcitabine and taxanes in metastatic breast cancer: a systematic review. Ther Clin Risk Manag. 2008;4(6):1157–64.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, et al. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(11):1753–60.CrossRefGoogle Scholar
  138. 138.
    Schechter AL, Hung MC, Vaidyanathan L, Weinberg RA, Yang-Feng TL, Francke U, et al. The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science. 1985;229(4717):976–8.PubMedCrossRefGoogle Scholar
  139. 139.
    Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230(4730):1132–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Shih C, Padhy LC, Murray M, Weinberg RA. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature. 1981;290(5803):261–4.PubMedCrossRefGoogle Scholar
  142. 142.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12.PubMedCrossRefGoogle Scholar
  143. 143.
    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(4785):177–82.PubMedCrossRefGoogle Scholar
  144. 144.
    Harries M, Smith I. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer. 2002;9(2):75–85.PubMedCrossRefGoogle Scholar
  145. 145.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, 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 (Official Journal of the American Society of Clinical Oncology). 1999;17(9):2639–48.CrossRefGoogle Scholar
  146. 146.
    Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2002;20(3):719–26.CrossRefGoogle Scholar
  147. 147.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.PubMedCrossRefGoogle Scholar
  148. 148.
    Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(19):4265–74.CrossRefGoogle Scholar
  149. 149.
    Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan 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 (Official Journal of the American Society of Clinical Oncology). 2012;30(21):2585–92.CrossRefGoogle Scholar
  150. 150.
    Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(33):5529–37.CrossRefGoogle Scholar
  151. 151.
    von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, 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 (Official Journal of the American Society of Clinical Oncology). 2009;27(12):1999–2006.CrossRefGoogle Scholar
  152. 152.
    Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, 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 (Official Journal of the American Society of Clinical Oncology). 2010;28(7):1124–30.CrossRefGoogle Scholar
  153. 153.
    Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15(6):640–7.PubMedCrossRefGoogle Scholar
  154. 154.
    Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(16):3676–85.CrossRefGoogle Scholar
  155. 155.
    Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2007;13(1):228–33.CrossRefGoogle Scholar
  156. 156.
    Untch M, Fasching PA, Konecny GE, Hasmuller S, Lebeau A, Kreienberg R, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(25):3351–7.CrossRefGoogle Scholar
  157. 157.
    Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2010;28(12):2024–31.CrossRefGoogle Scholar
  158. 158.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.PubMedCrossRefGoogle Scholar
  159. 159.
    Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021–8.PubMedCrossRefGoogle Scholar
  160. 160.
    Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, 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 (Official Journal of the American Society of Clinical Oncology). 2014;32(33):3744–52.CrossRefGoogle Scholar
  161. 161.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84.PubMedCrossRefGoogle Scholar
  162. 162.
    Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(34):4491–7.CrossRefGoogle Scholar
  163. 163.
    Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354(8):809–20.PubMedCrossRefGoogle Scholar
  164. 164.
    Pivot X, Romieu G, Debled M, Pierga J-Y, Kerbrat P, Bachelot T, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14(8):741–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013.Google Scholar
  166. 166.
    Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim S-B, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012;13(9):869–78.PubMedCrossRefGoogle Scholar
  167. 167.
    de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2014;32(20):2159–65.CrossRefGoogle Scholar
  168. 168.
    Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(31):3792–9.CrossRefGoogle Scholar
  169. 169.
    Advani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA. Long-term cardiac safety analysis of NCCTG N9831 (Alliance) adjuvant trastuzumab trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015.Google Scholar
  170. 170.
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–43.PubMedCrossRefGoogle Scholar
  171. 171.
    Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924–34.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, 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 Res Treat. 2008;112(3):533–43.PubMedCrossRefGoogle Scholar
  173. 173.
    Pivot X, Manikhas A, Zurawski B, Chmielowska E, Karaszewska B, Allerton R, et al. CEREBEL (EGF111438): a phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(14):1564–73.CrossRefGoogle Scholar
  174. 174.
    Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(34):5544–52.CrossRefGoogle Scholar
  175. 175.
    Schwartzberg LS, Franco SX, Florance A, O’Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122–9.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(33):5538–46.CrossRefGoogle Scholar
  177. 177.
    Mukherjee A, Dhadda AS, Shehata M, Chan S. Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer. Expert Opin Pharmacother. 2007;8(13):2189–204.PubMedCrossRefGoogle Scholar
  178. 178.
    Montemurro F, Valabrega G, Aglietta M. Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert Opin Biol Ther. 2007;7(2):257–68.PubMedCrossRefGoogle Scholar
  179. 179.
    Dhillon S, Wagstaff AJ. Lapatinib. Drugs. 2007;67(14):2101–8; discussion 9–10.Google Scholar
  180. 180.
    Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(23):5305–13.CrossRefGoogle Scholar
  181. 181.
    de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, 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(10):1137–46.PubMedCrossRefGoogle Scholar
  182. 182.
    Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83(6):679–86.PubMedCrossRefGoogle Scholar
  183. 183.
    Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816):633–40.PubMedCrossRefGoogle Scholar
  184. 184.
    Piccart-Gebhart MJ, Holmes AP, Baselga J, De Azambuja E, Dueck AC, Viale G, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L), or their combination (T + L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). ASCO Meet Abstr. 2014;32(18 suppl):LBA4.Google Scholar
  185. 185.
    Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, 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(2):135–44.PubMedCrossRefGoogle Scholar
  186. 186.
    Guarneri V, Frassoldati A, Piacentini F, Jovic G, Giovannelli S, Oliva C, et al. Preoperative chemotherapy plus lapatinib or trastuzumab or both in HER2-positive operable breast cancer (CHERLOB Trial). Clin Breast Cancer. 2008;8(2):192–4.PubMedCrossRefGoogle Scholar
  187. 187.
    Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, 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(12):1183–92.PubMedCrossRefGoogle Scholar
  188. 188.
    Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother (CII). 2006;55(6):717–27.CrossRefGoogle Scholar
  189. 189.
    Attard G, Kitzen J, Blagden SP, Fong PC, Pronk LC, Zhi J, et al. A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours. Br J Cancer. 2007;97(10):1338–43.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, 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 (Official Journal of the American Society of Clinical Oncology). 2010;28(7):1138–44.CrossRefGoogle Scholar
  191. 191.
    Cortes J, Fumoleau P, Bianchi GV, Petrella TM, Gelmon K, Pivot X, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(14):1594–600.CrossRefGoogle Scholar
  192. 192.
    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34.PubMedCrossRefGoogle Scholar
  193. 193.
    Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461–71.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–19.PubMedCrossRefGoogle Scholar
  195. 195.
    Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32.PubMedCrossRefGoogle Scholar
  196. 196.
    Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2013;24(9):2278–84.CrossRefGoogle Scholar
  197. 197.
    Moya-Horno I, Cortes J. The expanding role of pertuzumab in the treatment of HER2-positive breast cancer. Breast Cancer (Dove Med Press). 2015;7:125–32.PubMedPubMedCentralGoogle Scholar
  198. 198.
    Swain SM, Ewer MS, Cortes J, Amadori D, Miles D, Knott A, et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study. Oncologist. 2013;18(3):257–64.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Jiang H, Rugo HS. Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options. Ther Adv Med Oncol. 2015;7(6):321–39.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Krop IE, Kim S-B, González-Martín A, LoRusso PM, Ferrero J-M, Smitt M, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014.Google Scholar
  202. 202.
    Wildiers H, Kim S-B, Gonzalez-Martin A, LoRusso P, Ferrero J-M, Yu R, et al. Abstract S5-05: trastuzumab emtansine improves overall survival versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. Cancer Res. 2016;76(4 Suppl):S5–6.Google Scholar
  203. 203.
    Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013;31(9):1157–63.CrossRefGoogle Scholar
  204. 204.
    Krop IE, Lin NU, Blackwell K, Guardino E, Huober J, Lu M, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2015;26(1):113–9.CrossRefGoogle Scholar
  205. 205.
    Bartsch R, Berghoff AS, Preusser M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol. 2014;116(1):205–6.PubMedCrossRefGoogle Scholar
  206. 206.
    de Vries CL, Linn SC, Brandsma D. Response of symptomatic brain metastases from HER-2 overexpressing breast cancer with T-DM1. J Neurooncol. 2016.Google Scholar
  207. 207.
    Ellis PA, Barrios CH, Eiermann W, Toi M, Im Y-H, Conte PF, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) {±} pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. ASCO Meet Abstr. 2015;33(15 suppl):507.Google Scholar
  208. 208.
    Harbeck N, Gluz O, Christgen M, Braun M, Kuemmel S, Schumacher C, et al. Abstract S5-03: final analysis of WSG-ADAPT HER2+/HR+ phase II trial: efficacy, safety, and predictive markers for 12-weeks of neoadjuvant TDM1 with or without endocrine therapy versus trastuzumab + endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer. Cancer Res. 2016;76(4 Suppl):S5–03.Google Scholar
  209. 209.
    Cortés J, Dieras V, Ro J, Barriere J, Bachelot T, Hurvitz S, et al. Abstract P5-19-07: randomized phase II trial of afatinib alone or with vinorelbine versus investigator’s choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-Breast 3. Cancer Res. 2015;75(9 Suppl):P5-19-07.Google Scholar
  210. 210.
    Harbeck N, Huang C-S, Hurvitz S, Yeh D-C, Shao Z, Im S-A, et al. Abstract P5-19-01: randomized phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1. Cancer Res. 2015;75(9 Suppl):P5-19-01.Google Scholar
  211. 211.
    Chan A, Delaloge S, Holmes F, Moy B, Iwata H, Harker G, et al. Abstract S5-02: neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). Cancer Res. 2016;76(4 Suppl):S5–6.Google Scholar
  212. 212.
    Lu CH, Wyszomierski SL, Tseng LM, Sun MH, Lan KH, Neal CL, et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2007;13(19):5883–8.CrossRefGoogle Scholar
  213. 213.
    Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015;16(7):816–29.PubMedCrossRefGoogle Scholar
  214. 214.
    Andre F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580–91.PubMedCrossRefGoogle Scholar
  215. 215.
    Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593–9.PubMedGoogle Scholar
  216. 216.
    Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol. 2006;3(1):24–40.PubMedCrossRefGoogle Scholar
  217. 217.
    Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2(10):727–39.PubMedCrossRefGoogle Scholar
  218. 218.
    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7(9):987–9.PubMedCrossRefGoogle Scholar
  219. 219.
    Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(5 Suppl 16):117–24.PubMedCrossRefGoogle Scholar
  220. 220.
    Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(30):4966–72.CrossRefGoogle Scholar
  221. 221.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76.PubMedCrossRefGoogle Scholar
  222. 222.
    Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2010;28(20):3239–47.CrossRefGoogle Scholar
  223. 223.
    Brufsky A, Valero V, Tiangco B, Dakhil S, Brize A, Rugo HS, et al. Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial. Breast Cancer Res Treat. 2012;133(3):1067–75.PubMedCrossRefGoogle Scholar
  224. 224.
    Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, 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. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(32):4286–93.CrossRefGoogle Scholar
  225. 225.
    Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, et al. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013;14(2):125–33.PubMedCrossRefGoogle Scholar
  226. 226.
    Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(21):2361–9.CrossRefGoogle Scholar
  227. 227.
    Miles DW, Dieras V, Cortes J, Duenne AA, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2013;24(11):2773–80.CrossRefGoogle Scholar
  228. 228.
    Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2009;15(2):441–51.CrossRefGoogle Scholar
  229. 229.
    Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtio J, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2009;20(10):1639–46.CrossRefGoogle Scholar
  230. 230.
    Linderholm BK, Gruvbreger-Saal S, Ferno M, Bendahl PO, Malmstrom P. Vascular endothelial growth factor is a strong predictor of early distant recurrences in a prospective study of premenopausal women with lymph-node negative breast cancer. Breast. 2008;17(5):484–91.PubMedCrossRefGoogle Scholar
  231. 231.
    von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366(4):299–309.CrossRefGoogle Scholar
  232. 232.
    von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)dagger. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2014;25(12):2363–72.CrossRefGoogle Scholar
  233. 233.
    Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366(4):310–20.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Bear HD, Tang G, Rastogi P, Geyer CE, Liu Q, Robidoux A, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):1037–48.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14(10):933–42.PubMedCrossRefGoogle Scholar
  236. 236.
    Miller K, O’Neill AM, Dang CT, Northfelt DW, Gradishar WJ, Goldstein LJ, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: final results from Eastern Cooperative Oncology Group E5103. ASCO Meet Abstr. 2014;32(15 suppl):500.Google Scholar
  237. 237.
    David Miles LF, Yan V. Wang, Joyce O’Shaughnessy. MERiDiAN: a phase III, randomized, double-blind study of the efficacy, safety, and associated biomarkers of bevacizumab plus paclitaxel compared with paclitaxel plus placebo, as first-line treatment of patients with HER2-negative metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013;31(suppl; abstr TPS1142).Google Scholar
  238. 238.
    Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010;121(1):121–31.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Moreno-Aspitia A, Morton RF, Hillman DW, Lingle WL, Rowland KM Jr, Wiesenfeld M, et al. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2009;27(1):11–5.CrossRefGoogle Scholar
  240. 240.
    Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, Siena S, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009;20(7):616–24.PubMedCrossRefGoogle Scholar
  241. 241.
    Taylor SK, Chia S, Dent S, Clemons M, Agulnik M, Grenci P, et al. A phase II study of pazopanib in patients with recurrent or metastatic invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II consortium. Oncologist. 2010;15(8):810–8.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(11):1810–6.CrossRefGoogle Scholar
  243. 243.
    Crown JP, Dieras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, et al. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013;31(23):2870–8.CrossRefGoogle Scholar
  244. 244.
    Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(9):921–9.CrossRefGoogle Scholar
  245. 245.
    Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011;11(2):82–92.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.PubMedCrossRefGoogle Scholar
  247. 247.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109.PubMedCrossRefGoogle Scholar
  248. 248.
    Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, et al. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2013;19(10):2745–54.CrossRefGoogle Scholar
  249. 249.
    Baselga J, Segalla JG, Roche H, Del Giglio A, Pinczowski H, Ciruelos EM, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(13):1484–91.CrossRefGoogle Scholar
  250. 250.
    Baselga J, Zamagni C, Gomez P, Bermejo B, Nagai S, Melichar B, et al. LBA8A PHASE III RANDOMIZED, DOUBLE-BLIND, TRIAL COMPARING SORAFENIB PLUS CAPECITABINE VERSUS PLACEBO PLUS CAPECITABINE IN THE TREATMENT OF LOCALLY ADVANCED OR METASTATIC HER2-NEGATIVE BREAST CANCER (RESILIENCE). Ann Oncol. 2014;25(suppl 4).Google Scholar
  251. 251.
    Marme F, Gerber B, Schmidt M, Moebus VJ, Foerster FG, Grischke E-M, et al. Sorafenib (SOR) plus docetaxel (DOC) as first-line therapy in patients with HER2-negative metastatic breast cancer (MBC): a randomized, placebo-controlled phase II trial. ASCO Meet Abstr. 2014;32(15 suppl):1072.Google Scholar
  252. 252.
    Mariani G, Burdaeva O, Roman L, Staroslawska E, Udovitsa D, Driol P, et al. A double-blind, randomized phase lib study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (pl) when administered in combination with docetaxel and/or letrozole in patients with metastatic breast cancer (MBC): FM-B07-01 trial. Eur J Cancer. 47:10.Google Scholar
  253. 253.
    Tan AR, Johannes H, Rastogi P, Jacobs SA, Robidoux A, Flynn PJ, et al. Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study. Breast Cancer Res Treat. 2015;149(1):163–9.PubMedCrossRefGoogle Scholar
  254. 254.
    Hyams DM, Chan A, de Oliveira C, Snyder R, Vinholes J, Audeh MW, et al. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. Invest New Drugs. 2013;31(5):1345–54.PubMedCrossRefGoogle Scholar
  255. 255.
    Amiri-Kordestani L, Tan AR, Swain SM. Pazopanib for the treatment of breast cancer. Expert Opin Investig Drugs. 2012;21(2):217–25.PubMedCrossRefGoogle Scholar
  256. 256.
    Taylor SK, Chia S, Dent S, Clemons M, Agulnik M, Grenci P, et al. A phase II study of pazopanib in patients with recurrent or metastatic invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II consortium. Oncologist. 2010;15(8):810–8.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014;50(2):320–31.PubMedCrossRefGoogle Scholar
  258. 258.
    Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(28):3499–506.CrossRefGoogle Scholar
  259. 259.
    Sideras K, Dueck AC, Hobday TJ, Rowland KM Jr, Allred JB, Northfelt DW, et al. North central cancer treatment group (NCCTG) N0537: phase II trial of VEGF-trap in patients with metastatic breast cancer previously treated with an anthracycline and/or a taxane. Clin Breast Cancer. 2012;12(6):387–91.PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.PubMedCrossRefGoogle Scholar
  261. 261.
    Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665–73.PubMedCrossRefGoogle Scholar
  262. 262.
    Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(2):141–8.CrossRefGoogle Scholar
  263. 263.
    Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165–77.PubMedCrossRefGoogle Scholar
  264. 264.
    Falcon BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A, et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol. 2009;175(5):2159–70.PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Reiss Y, Knedla A, Tal AO, Schmidt MH, Jugold M, Kiessling F, et al. Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2. J Pathol. 2009;217(4):571–80.PubMedCrossRefGoogle Scholar
  266. 266.
    Thomas M, Augustin HG. The role of the Angiopoietins in vascular morphogenesis. Angiogenesis. 2009;12(2):125–37.PubMedCrossRefGoogle Scholar
  267. 267.
    Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae D-S, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(8):799–808.PubMedCrossRefGoogle Scholar
  268. 268.
    Dieras V, Wildiers H, Jassem J, Dirix LY, Guastalla JP, Bono P, et al. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast. 2015;24(3):182–90.PubMedCrossRefGoogle Scholar
  269. 269.
    Mirkin S, Pickar JH. Selective estrogen receptor modulators (SERMs): a review of clinical data. Maturitas. 2015;80(1):52–7.PubMedCrossRefGoogle Scholar
  270. 270.
    Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology) 2007;25(25):3837–45.Google Scholar
  271. 271.
    Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97(1):30–9.PubMedCrossRefGoogle Scholar
  272. 272.
    Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95(23):1758–64.PubMedCrossRefGoogle Scholar
  273. 273.
    Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(36):9312–8.CrossRefGoogle Scholar
  274. 274.
    Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2007;25(33):5187–93.CrossRefGoogle Scholar
  275. 275.
    Higgins MJ, Stearns V. Pharmacogenetics of endocrine therapy for breast cancer. Annu Rev Med. 2011;62:281–93.PubMedCrossRefGoogle Scholar
  276. 276.
    Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012;104(6):441–51.PubMedPubMedCentralCrossRefGoogle Scholar
  277. 277.
    Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012;104(6):452–60.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25(2):270–5.Google Scholar
  279. 279.
    Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1998;16(10):3439–60.CrossRefGoogle Scholar
  280. 280.
    Litherland S, Jackson IM. Antioestrogens in the management of hormone-dependent cancer. Cancer Treat Rev. 1988;15(3):183–94.PubMedCrossRefGoogle Scholar
  281. 281.
    Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers EM, Wheeler TK, et al. A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer. 1984;50(2):199–205.PubMedPubMedCentralCrossRefGoogle Scholar
  282. 282.
    Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339(22):1609–18.PubMedCrossRefGoogle Scholar
  283. 283.
    EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.Google Scholar
  284. 284.
    Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84.PubMedCrossRefGoogle Scholar
  285. 285.
    Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2012.Google Scholar
  286. 286.
    Gray RG, Rea D, Handley K, Bowden SJ, Perry P, Earl HM, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. ASCO Meet Abstr. 2013;31(15 suppl):5.Google Scholar
  287. 287.
    Cuzick J, Sestak I, Pinder SE, Ellis IO, Forsyth S, Bundred NJ, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol. 2011;12(1):21–9.PubMedCrossRefGoogle Scholar
  288. 288.
    Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97(22):1652–62.PubMedCrossRefGoogle Scholar
  289. 289.
    Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353(9169):1993–2000.PubMedCrossRefGoogle Scholar
  290. 290.
    Altundag K, Ibrahim NK. Aromatase inhibitors in breast cancer: an overview. Oncologist. 2006;11(6):553–62.PubMedCrossRefGoogle Scholar
  291. 291.
    Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001;92(9):2247–58.PubMedCrossRefGoogle Scholar
  292. 292.
    Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(10):2596–606.CrossRefGoogle Scholar
  293. 293.
    Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(30):4883–90.CrossRefGoogle Scholar
  294. 294.
    Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003;98(2):229–38.PubMedCrossRefGoogle Scholar
  295. 295.
    Miller WR, Bartlett J, Brodie AM, Brueggemeier RW, di Salle E, Lonning PE, et al. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist. 2008;13(8):829–37.PubMedCrossRefGoogle Scholar
  296. 296.
    Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304–20.PubMedPubMedCentralCrossRefGoogle Scholar
  297. 297.
    Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135–41.PubMedCrossRefGoogle Scholar
  298. 298.
    Breast International Group 1-98 Collaborative G, Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353(26):2747–57.Google Scholar
  299. 299.
    Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncology. 2011;12(12):1101–8.PubMedCrossRefGoogle Scholar
  300. 300.
    Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, et al. Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(7):709–17.CrossRefGoogle Scholar
  301. 301.
    Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005;366(9484):455–62.PubMedCrossRefGoogle Scholar
  302. 302.
    Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2007;25(19):2664–70.CrossRefGoogle Scholar
  303. 303.
    EBCTCG. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–52.Google Scholar
  304. 304.
    Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2014;32(21):2255–69.CrossRefGoogle Scholar
  305. 305.
    National Comprehensive Cancer Network N. breast cancer 2016. Available from http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  306. 306.
    Arbeitsgemeinschaft Gynaekologische Onkologie OM. Guidelines Breast Version 2016.1 2016. Available from http://www.ago-online.de/de/infothek-fuer-aerzte/leitlinienempfehlungen/mamma/.
  307. 307.
    Chumsri S. Clinical utilities of aromatase inhibitors in breast cancer. Int J Womens Health. 2015;7:493–9.PubMedPubMedCentralCrossRefGoogle Scholar
  308. 308.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Livingston RB, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2013;24(2):355–61.CrossRefGoogle Scholar
  309. 309.
    Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(7):718–21.CrossRefGoogle Scholar
  310. 310.
    Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(12):1965–71.CrossRefGoogle Scholar
  311. 311.
    Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007;99(24):1845–53.PubMedCrossRefGoogle Scholar
  312. 312.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97(17):1262–71.PubMedCrossRefGoogle Scholar
  313. 313.
    Niravath P. Aromatase inhibitor-induced arthralgia: a review. Ann Oncol (Official Journal of the European Society for Medical Oncology/ ESMO). 2013;24(6):1443–9.CrossRefGoogle Scholar
  314. 314.
    Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51(15):3867–73.PubMedGoogle Scholar
  315. 315.
    Kuter I, Gee JM, Hegg R, Singer CF, Badwe RA, Lowe ES, et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat. 2012;133(1):237–46.PubMedCrossRefGoogle Scholar
  316. 316.
    Ellis MJ, Llombart-Cussac A, Feltl D, Dewar JA, Jasiowka M, Hewson N, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2015;33(32):3781–7.CrossRefGoogle Scholar
  317. 317.
    Robertson JF, Lindemann JP, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat. 2012;136(2):503–11.PubMedCrossRefGoogle Scholar
  318. 318.
    Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337.Google Scholar
  319. 319.
    Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2010;28(30):4594–600.CrossRefGoogle Scholar
  320. 320.
    Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435–44.PubMedPubMedCentralCrossRefGoogle Scholar
  321. 321.
    Bergh J, Jonsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattstrom D, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(16):1919–25.CrossRefGoogle Scholar
  322. 322.
    Migliaccio I, Malorni L, Hart CD, Guarducci C, Di Leo A. Endocrine therapy considerations in postmenopausal patients with hormone receptor positive, human epidermal growth factor receptor type 2 negative advanced breast cancers. BMC Med. 2015;13:46.PubMedPubMedCentralCrossRefGoogle Scholar
  323. 323.
    Rody A, Loibl S, von Minckwitz G, Kaufmann M. Use of goserelin in the treatment of breast cancer. Expert Rev Anticancer Ther. 2005;5(4):591–604.PubMedCrossRefGoogle Scholar
  324. 324.
    Beatson. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;148(3802).Google Scholar
  325. 325.
    Boccardo F, Rubagotti A, Perrotta A, Amoroso D, Balestrero M, De Matteis A, et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 1994;5(4):337–42.CrossRefGoogle Scholar
  326. 326.
    Buchanan RB, Blamey RW, Durrant KR, Howell A, Paterson AG, Preece PE, et al. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1986;4(9):1326–30.CrossRefGoogle Scholar
  327. 327.
    Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(2):343–53.CrossRefGoogle Scholar
  328. 328.
    Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, et al. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst. 2000;92(11):903–11.PubMedCrossRefGoogle Scholar
  329. 329.
    Davidson NE, O’Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(25):5973–82.CrossRefGoogle Scholar
  330. 330.
    Cuzick J, Ambroisine L, Davidson N, Jakesz R, Kaufmann M, Regan M, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007;369(9574):1711–23.PubMedCrossRefGoogle Scholar
  331. 331.
    Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014.Google Scholar
  332. 332.
    Hershman DL. Perfecting breast-cancer treatment–incremental gains and musculoskeletal pains. N Engl J Med. 2015;372(5):477–8.PubMedCrossRefGoogle Scholar
  333. 333.
    Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(33):4452–61.CrossRefGoogle Scholar
  334. 334.
    Lauring J, Park BH, Wolff AC. The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Canc Netw. 2013;11(6):670–8.PubMedPubMedCentralGoogle Scholar
  335. 335.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.PubMedCrossRefGoogle Scholar
  336. 336.
    Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2014;25(12):2357–62.CrossRefGoogle Scholar
  337. 337.
    Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, 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. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2012;30(22):2718–24.CrossRefGoogle Scholar
  338. 338.
    Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2015.Google Scholar
  339. 339.
    Sabine VS, Crozier C, Brookes CL, Drake C, Piper T, van de Velde CJ, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2014;32(27):2951–8.CrossRefGoogle Scholar
  340. 340.
    Mayer IA, Arteaga CL. PIK3CA activating mutations: a discordant role in early versus advanced hormone-dependent estrogen receptor-positive breast cancer? J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2014;32(27):2932–4.CrossRefGoogle Scholar
  341. 341.
    Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955–62.PubMedPubMedCentralCrossRefGoogle Scholar
  342. 342.
    Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.PubMedCrossRefGoogle Scholar
  343. 343.
    Krop I, Johnston S, Mayer IA, Dickler M, Ganju V, Forero-Torres A, et al. Abstract S2-02: The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer—Part I results. Cancer Res. 2015;75(9 Suppl):S2-02.CrossRefGoogle Scholar
  344. 344.
    Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, et al. Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2− advanced breast cancer (BC): first results from the randomized, Phase III BELLE-2 trial. Cancer Res. 2016(Supplement):S6-01.Google Scholar
  345. 345.
    Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press). 2014;6:123–33.PubMedCentralGoogle Scholar
  346. 346.
    Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology. 2013;27(12):1263–9, 74–9.Google Scholar
  347. 347.
    Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18(3):333–45.PubMedPubMedCentralCrossRefGoogle Scholar
  348. 348.
    Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res (BCR). 2009;11(5):R77.CrossRefGoogle Scholar
  349. 349.
    Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.PubMedCrossRefGoogle Scholar
  350. 350.
    Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in Hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015.Google Scholar
  351. 351.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedCrossRefGoogle Scholar
  352. 352.
    Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, 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(9737):235–44.PubMedCrossRefGoogle Scholar
  353. 353.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.PubMedCrossRefGoogle Scholar
  354. 354.
    Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, 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;12(9):852–61.PubMedCrossRefGoogle Scholar
  355. 355.
    Rugo H, Olopade O, DeMichele A, van ‘t Veer L, Buxton M, Hylton N, et al. Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Cancer Res. 2013;73(24 Suppl):S5-02.Google Scholar
  356. 356.
    Gampenrieder SP, Rinnerthaler G, Greil R. Bone-targeted therapy in metastatic breast cancer—all well-established knowledge? Breast Care. 2014;9(5):323–30.PubMedPubMedCentralCrossRefGoogle Scholar
  357. 357.
    Van Acker HH, Anguille S, Willemen Y, Smits EL, Van Tendeloo VF. Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2016;158:24–40.PubMedCrossRefGoogle Scholar
  358. 358.
    Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76.PubMedCrossRefGoogle Scholar
  359. 359.
    Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2005;23(15):3314–21.CrossRefGoogle Scholar
  360. 360.
    Rosen LS, Gordon DH, Dugan W Jr, Major P, Eisenberg PD, Provencher L, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100(1):36–43.PubMedCrossRefGoogle Scholar
  361. 361.
    Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004;100(12):2613–21.PubMedCrossRefGoogle Scholar
  362. 362.
    Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane database of systematic reviews. 2012;2:CD003474.Google Scholar
  363. 363.
    Tripathy D, Lichinitzer M, Lazarev A, MacLachlan SA, Apffelstaedt J, Budde M, et al. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2004;15(5):743–50.CrossRefGoogle Scholar
  364. 364.
    Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. 2004;90(6):1133–7.PubMedPubMedCentralCrossRefGoogle Scholar
  365. 365.
    Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88(5):1082–90.PubMedCrossRefGoogle Scholar
  366. 366.
    Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 1999;17(3):846–54.CrossRefGoogle Scholar
  367. 367.
    Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial–the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2003;21(16):3150–7.CrossRefGoogle Scholar
  368. 368.
    Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98(8):1735–44.PubMedCrossRefGoogle Scholar
  369. 369.
    Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncology. 2014;15(1):114–22.PubMedCrossRefGoogle Scholar
  370. 370.
    Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2001;19(2):558–67.CrossRefGoogle Scholar
  371. 371.
    Ibrahim MF, Mazzarello S, Shorr R, Vandermeer L, Jacobs C, Hilton J, et al. Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2015;26(11):2205–13.CrossRefGoogle Scholar
  372. 372.
    Mortimer JE, Pal SK. Safety considerations for use of bone-targeted agents in patients with cancer. Semin Oncol. 2010;37(Suppl 1):S66–72.PubMedCrossRefGoogle Scholar
  373. 373.
    Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2012;23(5):1341–7.CrossRefGoogle Scholar
  374. 374.
    Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2010;28(35):5132–9.CrossRefGoogle Scholar
  375. 375.
    Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2011;29(9):1125–32.CrossRefGoogle Scholar
  376. 376.
    Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.PubMedPubMedCentralCrossRefGoogle Scholar
  377. 377.
    Henry D, Vadhan-Raj S, Hirsh V, von Moos R, Hungria V, Costa L, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer (Official Journal of the Multinational Association of Supportive Care in Cancer). 2014;22(3):679–87.CrossRefGoogle Scholar
  378. 378.
    von Moos R, Body JJ, Egerdie B, Stopeck A, Brown JE, Damyanov D, et al. Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid. Support Care Cancer Official Journal of the Multinational Association of Supportive Care in Cancer). 2013;21(12):3497–507.CrossRefGoogle Scholar
  379. 379.
    Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2008;26(30):4875–82.CrossRefGoogle Scholar
  380. 380.
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65.PubMedCrossRefGoogle Scholar
  381. 381.
    Hall DG, Stoica G. Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system. J Bone Miner Res. 1994;9(2):221–30.PubMedCrossRefGoogle Scholar
  382. 382.
    Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol (Official Journal of the European Society for Medical Oncology/ESMO). 2014.Google Scholar
  383. 383.
    Gnant M, Eidtmann H. The anti-tumor effect of bisphosphonates ABCSG-12, ZO-FAST and more. Crit Rev Oncol/Hematol. 2010;74(Suppl 1):S2-6.Google Scholar
  384. 384.
    Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, et al. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012.Google Scholar
  385. 385.
    von Minckwitz G, Mobus V, Schneeweiss A, Huober J, Thomssen C, Untch M, et al. German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer. J Clin Oncol (Official Journal of the American Society of Clinical Oncology). 2013.Google Scholar
  386. 386.
    Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol. 2014;15(9):997–1006.PubMedCrossRefGoogle Scholar
  387. 387.
    Knauer M, Thurlimann B. Adjuvant bisphosphonates in breast cancer treatment. Breast Care. 2014;9(5):319–22.PubMedPubMedCentralCrossRefGoogle Scholar
  388. 388.
    Coleman R. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001):1353–61.PubMedCrossRefGoogle Scholar
  389. 389.
    Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res (An Official Journal of the American Association for Cancer Research). 2014;20(11):2922–32.CrossRefGoogle Scholar
  390. 390.
    Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–43.PubMedCrossRefGoogle Scholar
  391. 391.
    Gnant M, Pfeiler G, Dubsky P, Hubalek M, Greil R, Jakesz R, et al. Abstract S2-02: the impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Cancer Res. 2016;76(4 Suppl):S2-02.CrossRefGoogle Scholar
  392. 392.
    Marmé F, Schneeweiss A. Targeted therapies in triple-negative breast cancer. Breast Care (Basel). 2015;10(3):159–66. doi: 10.1159/000433622.

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Gynecologic Oncology, National Center of Tumor DiseasesUniversity Hospital, University of HeidelbergHeidelbergGermany

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