The therapeutic potential of mTOR inhibitors in breast cancer

British Journal of Clinical Pharmacology

Volumn , Issue , 2016, Pages 1189-1212

  Steelman, Linda S ^a   Martelli, Alberto M ^b   Cocco, Lucio ^b   Libra, Massimo ^c   Nicoletti, Ferdinando ^c   Abrams, Stephen L ^a   McCubrey, James A ^a  

^a EAST CAROLINA UNIVERSITY   (United States)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c UNIVERSITY OF CATANIA   (Italy)

Author keywords

drug resistance; endocrine resistance; everolimus; exemestane; metastasis; rapamycin

Indexed keywords

ANASTROZOLE; AROMATASE INHIBITOR; BEVACIZUMAB; CAPECITABINE; CISPLATIN; CIXUTUMUMAB; CYCLOPHOSPHAMIDE; DOCETAXEL; EPIRUBICIN; ERLOTINIB; EVEROLIMUS; EXEMESTANE; FULVESTRANT; GOSERELIN; LAPATINIB; LETROZOLE; LEUPRORELIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METFORMIN; NAVELBINE; PACLITAXEL; RAPAMYCIN; RAPAMYCIN DERIVATIVE; RIBOCICLIB; RIDAFOROLIMUS; TAMOXIFEN; TAMOXIFEN CITRATE; TEMSIROLIMUS; TRASTUZUMAB; UNINDEXED DRUG;

BREAST CANCER; CANCER GROWTH; CANCER HORMONE THERAPY; CANCER PATIENT; CANCER THERAPY; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; FOOD AND DRUG ADMINISTRATION; HUMAN; METASTATIC BREAST CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TRIPLE NEGATIVE BREAST CANCER;

EID: 85027931882     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12958     Document Type: Review

References (95)

1. American Cancer Society, http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-046381.pdf (last accessed 15 December 2015).
2. Bostner J, Karlsson E, Eding CB, Perez-Tenorio G, Franzén H, Konstantinell A, et al. S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts. Endocr Relat Cancer 2015; 22: 331–43.
3. Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005; 23: 5314–22.
4. Dancey JE, Curiel R, Purvis J. Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. Semin Oncol 2009; 36 (Suppl 3): S46–58.
5. Buckner JC, Forouzesh B, Erlichman C, Hidalgo M, Boni JP, Dukart G, et al. Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. Invest New Drugs 2010; 28: 334–42.
6. Fleming GF, Ma CX, Huo D, Sattar H, Tretiakova M, Lin L, et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 2012; 136: 355–63.
7. Arena F. Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast cancer. Cancer Manag Res 2014; 6: 389–95.
8. Royce ME, Osman D. Everolimus in the treatment of metastatic breast cancer. Breast Cancer (Auckl) 2015; 9: 73–9.
9. Lumachi F, Santeufemia DA, Basso SM. Current medical treatment of estrogen receptor-positive breast cancer. World J Biol Chem 2015; 6: 231–9.
10. Zucchini G, Geuna E, Milani A, Aversa C, Martinello R, Montemurro F. Clinical utility of exemestane in the treatment of breast cancer. Int J Womens Health 2015; 7: 551–63.
11. Bostner J, Karlsson E, Eding CB, Perez-Tenorio G, Franzén H, Konstantinell A, et al. S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts. Endocr Relat Cancer 2015; 22: 331–43.
12. Alayev A, Salamon RS, Berger SM, Schwartz NS, Cuesta R, Snyder RB, et al. mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation. Oncogene 2015. doi:10.1038/onc.2015.414.
13. 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 2012; 30: 2718–24.
14. Choi JH, Jung SH. Appropriate design of prospective studies. J Clin Oncol 2013; 31: 510–1.
15. Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol 2015; 26: 120–5.
16. Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, et al. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure. Breast Cancer Res Treat 2014; 143: 325–32.
17. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27: 2630–7.
18. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013; 31: 195–202.
19. Hortobagyi GN. Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. Neoplasia 2015; 17: 279–88.
20. 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-2. Ann Oncol 2014; 25: 2357–62.
21. Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 2013; 105: 654–63.
22. Divers J, O'Shaughnessy J. Stomatitis associated with use of mTOR inhibitors: implications for patients with invasive breast cancer. Clin J Oncol Nurs 2015; 19: 468–74.
23. Qiao L, Liang Y, Mira RR, Lu Y, Gu J, Zheng Q. Mammalian target of rapamycin (mTOR) inhibitors and combined chemotherapy in breast cancer: a meta-analysis of randomized controlled trials. Int J Clin Exp Med 2014; 7: 3333–43.
24. Southwest Oncology Group. S1207 hormone therapy with or without everolimus in treating patients with breast cancer (e3). Bethesda, MD: National Library of Medicine (US), 2000. Available at: https://clinicaltrials.gov/ct2/show/NCT01674140?term=S1207+Hormone+Therapy+With+or+Without+Everolimus+in+Treating+Patients+With+Breast+Cancer&rank=1 (last accessed 15 December 2015).
25. Novartis Pharmaceuticals. Open-label, phase II, study of everolimus plus letrozole in postmenopausal women with ER+, HER2- metastatic or locally advanced breast cancer (Bolero-4). Bethesda, MD: National Library of Medicine (US), 2000.Available at: https://clinicaltrials.gov/ct2/show/ NCT01698918 (last accessed 15 December 2015).
26. Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 2011; 10: 1093–101.
27. McCubrey JA, Davis NM, Abrams SL, Montalto G, Cervello M, Libra M, et al. Targeting breast cancer initiating cells: advances in breast cancer research and therapy. Adv Biol Regul 2014; 56: 81–107.
28. Fitzgerald TL, Lertpiriyapong K, Cocco L, Martelli AM, Libra M, Candido S, et al. Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells. Adv Biol Reg 2015; 59: 65–81.
29. Baer R, Cintas C, Therville N, Guillermet-Guibert J. Implication of PI3K/Akt pathway in pancreatic cancer: when PI3K isoforms matter? Adv Biol Regul 2015; 59: 19–35.
30. Bertrand FE, McCubrey JA, Angus CW, Nutter JM, Sigounas G. NOTCH and PTEN in prostate cancer. Adv Biol Regul 2014; 56: 51–65.
31. Bradshaw RA, Pundavela J, Biarc J, Chalkley RJ, Burlingame AL, Hondermarck H. NGF and ProNGF: regulation of neuronal and neoplastic responses through receptor signaling. Adv Biol Regul 2015; 58: 16–27.
32. Jhanwar-Uniyal M, Gillick JL, Neil J, Tobias M, Thwing ZE, Murali R. Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: a tale of two complexes. Adv Biol Regul 2015; 57: 64–74.
33. Fragoso R, Barata JT. PTEN and leukemia stem cells. Adv Biol Regul 2014; 56: 22–9.
34. Follo MY, Manzoli L, Poli A, McCubrey JA, Cocco L. PLC and PI3K/Akt/mTOR signalling in disease and cancer. Adv Biol Regul 2015; 57: 10–6.
35. Laurent PA, Severin S, Gratacap MP, Payrastre B. Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1. Adv Biol Regul 2014; 54: 162–74.
36. Maertens O, Cichowski K. An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer. Adv Biol Regul 2014; 55: 1–14.
37. McCubrey JA, Davis NM, Abrams SL, Montalto G, Cervello M, Basecke J, et al. Diverse roles of GSK-3: Tumor promoter-tumor suppressor, target in cancer therapy. Adv Biol Regul 2014; 54: 176–96.
38. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, et al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget 2014; 5: 2881–911.
39. McCubrey JA, Abrams SL, Fitzgerald TL, Cocco L, Martelli AM, Montalto G, et al. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. Adv Biol Regul 2015; 57: 75–101.
40. Davis NM, Sokolosky M, Stadelman K, Abrams SL, Libra M, Candido S, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget 2014; 5: 4603–50.
41. Chappell WH, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Martelli AM, Cocco L, et al. Novel roles of androgen receptor, epidermal growth factor receptor, TP53, regulatory RNAs, NF-kappa-B, chromosomal translocations, neutrophil associated gelatinase, and matrix metalloproteinase-9 in prostate cancer and prostate cancer stem cells. Adv Biol Regul 2016; 60: 64–87.
42. Yamamoto-Ibusuki M, Arnedos M, André F. Targeted therapies for ER+/HER2- metastatic breast cancer. BMC Med 2015; 13: 137.
43. Ma CX. PI3K pathway as a therapeutic target in breast cancer. Am J Hematol Oncol 2015; 11: 23–9.
44. Martelli AM, Lonetti A, Buontempo F, Ricci F, Tazzari PL, Evangelisti C, et al. Targeting signaling pathways in T-cell acute lymphoblastic leukemia initiating cells. Adv Biol Regul 2014; 56: 6–21.
45. Ciuffreda L, Falcone I, Incani UC, Del Curatolo A, Conciatori F, Matteoni S, et al. PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting. Adv Biol Regul 2014; 56: 66–80.
46. Spinelli L, Lindsay YE, Leslie NR. PTEN inhibitors: an evaluation of current compounds. Adv Biol Regul 2015; 57: 102–11.
47. Toker A, Marmiroli S. Signaling specificity in the Akt pathway in biology and disease. Adv Biol Regul 2014; 55: 28–38.
48. Ukaji T, Umezawa K. Novel approaches to target NF-κB and other signaling pathways in cancer stem cells. Adv Biol Regul 2014; 56: 108–15.
49. Karthik GM, Ma R, Lövrot J, Kis LL, Lindh C, Blomquist L, et al. mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells. Cancer Lett 2015; 367: 76–87.
50. Acevedo-Gadea C, Hatzis C, Chung G, Fishbach N, Lezon-Geyda K, Zelterman D, et al. Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy. Breast Cancer Res Treat 2015; 150: 157–67.
51. 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: 816–29.
52. André 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: 580–91.
53. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6: 117–27.
54. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395–402.
55. Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, et al. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 2009; 15: 7266–76.
56. Singh J, Novik Y, Stein S, Volm M, Meyers M, Smith J, et al. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res 2014; 16: R32.
57. Gonzalez-Angulo AM, Akcakanat A, Liu S, Green MC, Murray JL, Chen H, et al. Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer. Ann Oncol 2014; 25: 1122–7.
58. Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, 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 2016; 34: 419–26.
59. Deluche E, Onesti E, Andre F. Precision medicine for metastatic breast cancer. Am Soc Clin Oncol Educ Book 2015; 35: e2–7.
60. Wang Y, Wei J, Li L, Fan C, Sun Y. Combined use of metformin and everolimus is synergistic in the treatment of breast cancer cells. Oncol Res 2015; 22: 193–201.
61. Leung EY, Askarian-Amiri M, Finlay GJ, Rewcastle GW, Baguley BC. Potentiation of growth inhibitory responses of the mTOR inhibitor everolimus by dual mTORC1/2 inhibitors in cultured breast cancer cell lines. PLoS One 2015; 10: e0131400.
62. Mi W, Ye Q, Liu S, She QB. AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis. Oncotarget 2015; 6: 13962–77.
63. Holder AM, Akcakanat A, Adkins F, Evans K, Chen H, Wei C, et al. Epithelial to mesenchymal transition is associated with rapamycin resistance. Oncotarget 2015; 6: 19500–13.
64. Alayev A, Berger SM, Kramer MY, Schwartz NS, Holz MK. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J Cell Biochem 2015; 116: 450–7.
65. Brohée L, Demine S, Willems J, Arnould T, Colige AC, Deroanne CF. Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment. Oncotarget 2015; 6: 11264–80.
66. Ding XF, Yin DQ, Chen Q, Zhang HY, Zhou J, Chen G. Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts. Tumour Biol 2015; 36: 1463–9.
67. Kabos P, Finlay-Schultz J, Li C, Kline E, Finlayson C, Wisell J, et al. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. Breast Cancer Res Treat 2012; 135: 415–32.
68. Landis MD, Lehmann BD, Pietenpol JA, Chang JC. Patient-derived breast tumor xenografts facilitating personalized cancer therapy. Breast Cancer Res 2013; 15: 201.
69. Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME, et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 2013; 24: 120–9.
70. Whittle JR, Lewis MT, Lindeman GJ, Visvader JE. Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res 2015; 17: 17.
71. Chatterjee A, Mukhopadhyay S, Tung K, Patel D, Foster DA. Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways. Cancer Lett 2015; 360: 134–40.
72. Leontieva OV, Blagosklonny MV. Tumor promoter-induced cellular senescence: cell cycle arrest followed by geroconversion. Oncotarget 2014; 5: 12715–27.
73. Chi KH, Ko HL, Yang KL, Lee CY, Chi MS, Kao SJ. Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort. Oncotarget 2015; 6: 16735–45.
74. Guichard SM, Curwen J, Bihani T, D'Cruz CM, Yates JW, Grondine M, et al. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther 2015; 14: 2508–18.
75. Bendell JC, Kelley RK, Shih KC, Grabowsky JA, Bergsland E, Jones S, et al. A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma. Cancer 2015; 121: 3481–90.
76. Jiang Z, Wu S, Wu X, Zhong J, Lv A, Jiao J, et al. Blocking mammalian target of rapamycin alleviates bone cancer pain and morphine tolerance via μ-opioid receptor. Int J Cancer 2016; 138: 2013–20.
77. Blackwell K, Burris H, Gomez P, Lynn Henry N, Isakoff S, Campana F, et al. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. Breast Cancer Res Treat 2015; 154: 287–97.
78. Ji Y, Di W, Yang Q, Lu Z, Cai W, Wu J. Inhibition of autophagy increases proliferation inhibition and apoptosis induced by the PI3K/mTOR inhibitor NVP-BEZ235 in breast cancer cells. Clin Lab 2015; 61: 1043–51.
79. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Improved clinical and cell cycle response with an mTOR inhibitor, daily oral RAD001 (everolimus) plus letrozole versus placebo plus letrozole in a randomized phase II neoadjuvant trial in ER+ breast cancer. J Clin Oncol 2008; 26 (suppl) abstr 530.
80. Jerusalem GH, Dieras V, Cardoso F, Bergh J, Fasolo A, Rorive A, et al. Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol 2008; 26 (suppl) abstr 1057.
81. Tanaka C, O'Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26: 1596–602.
82. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011; 29: 3126–32.
83. Jerusalem G, Fasolo A, Dieras V, Cardoso F, Bergh J, Vittori L, et al. Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2011; 125: 447–55.
84. Andre F, O'Regan R, Ozgurogulu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER-2-positive, advanced breast cancer (BOLERO-3): a randomized, double-blind, placebo-combined phase 3 trial. Lancet Oncol 2014; 15: 580–91.
85. Seller M, Ray-Coguard I, Melichar B, Yardley DA, Wang RX, Dodion PF, et al. Oral ridaforolimus plus trastuzumab for patients with HER2+ trastuzumab-refractory metastatic breast cancer. Clin Breast Cancer 2015; 15: 60–5.
86. von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. GBG/AGO-B study groups.Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG44-GeparQuinto). Ann Oncol 2014; 25: 2363–72.
87. von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012; 366: 299–309.
88. Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al. German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Group.Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 2012; 13: 135–44.
89. Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi G, et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol 2014; 25: 808–15.
90. Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 2013; 30: 370–84.
91. Campone M, Beck JT, Gnant M, Neven P, Pritchard KI, Bachelot T, et al. Health-related quality of life and disease symptoms in postmenopausal women with HR(+), HER(-) advanced breast cancer treated with everolimus plus exemestane versus exemestane monotherapy. Curr Med Res Opin 2013; 29: 1463–73.
92. Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer 2014; 21: 703–14.
93. 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: 520–9.
94. Piha-Paul SA, Munster PN, Hollebecque A, Argiles G, Dajani O, Cheng JD, et al. Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumors. Eur J Cancer 2015; 51: 1865–73.
95. Gupta S, Argilies G, Munster PN, Hollebecque A, Dajani O, Cheng JD, et al. A Phase I trial combined ridaforolimus and MK-2206 in patients with advanced malignancies. Clin Cancer Res 2015; 21: 5235–44.