L'attività di Everolimus è stata valutata attraverso uno studio di fase III chiamato BOLERO- 2: uno studio randomizzato, in doppio cieco e multicentrico. Attraverso questo studio viene valutata l'attività di Everolimus in associazione ad Exemestane rispetto all'attività del placebo + Exemestane.
Lo studio è stato condotto in donne in postmenopausa con carcinoma mammario con stato recettoriale ormonale positivo, HER2-negativo in stadio avanzato con recidiva o progressione dopo una precedente terapia con letrozolo o anastrozolo [81][82].
La randomizzazione è stata stratificata per la documentata sensibilità alla terapia ormonale precedente e in base alla presenza di metastasi viscerali. La sensibilità alla terapia ormonale precedente è stata definita come beneficio clinico documentato (risposta completa [RC], risposta parziale [RP], malattia stabile ≥24 settimane) ad almeno una terapia ormonale precedente nel setting avanzato oppure ad almeno 24 mesi di terapia ormonale adiuvante prima dell’insorgenza della recidiva [83][84].
L’endpoint primario dello studio è stata la sopravvivenza libera da progressione (PFS –
Progression Free Survival) valutata secondo i criteri RECIST (Response Evaluation Criteria in Solid Tumors) basata sulla valutazione dello sperimentatore (valutazione radiologica
locale). Le analisi di supporto per la PFS erano basate sulla revisione radiologica centralizzata indipendente.
tasso di risposta obiettiva, il tasso di beneficio clinico, il profilo di sicurezza, il cambiamento nella qualità di vita (QoL – Quality of Life) e il tempo al peggioramento dell’ECOG-PS (Eastern Cooperative Oncology Group Performance Status).
Un totale di 724 pazienti sono state randomizzate in rapporto di 2:1 alla combinazione Everolimus (10 mg al giorno) + Exemestane (25 mg al giorno) (n=485) o a placebo + Exemestane (25 mg al giorno) (n=239) [85].
Al momento dell’analisi finale per l’OS, la durata media del trattamento con Everolimus è stata di 24,0 settimane. La durata media del trattamento con Exemestane è stata maggiore nel gruppo Everolimus + Exemestane pari a 29,5 settimane rispetto a 14,1 settimane nel gruppo placebo + Exemestane.
I risultati di efficacia per l’endpoint primario sono stati ottenuti dall’analisi finale di PFS. Le pazienti del braccio placebo + Exemestane non effettuavano il cross over ad Everolimus al momento della progressione.
Questo studio ha mostrato un aumento della sopravvivenza libera da progressione (da 4,17 mesi a 11,7 mesi) nei pazienti che hanno ricevuto una terapia con inibitori dell'aromatasi nel trattamento adiuvante e non hanno ricevuto alcun trattamento per la
malattia avanzata. Da questi dati si deduce che i pazienti non hanno bisogno di essere pretrattati prima di eseguire la terapia con Everolimus in associazione con Exemestane. La somministrazione combinata di Everolimus con Exemestane offre un'importante alternativa alla chemioterapia nei pazienti con metastasi viscerali [80].
9- BIBLIOGRAFIA
1. Kumar, V.; Abbas, A. K.; Fausto, N. “Le Basi Patologiche delle Malattie-Patologia Generale”, 7a edizione, Elsevier.
2. Estimates of cancer burden in italy tumori 2013; 99 (3): 416-424. 3. http://www.airc.it/tumori/tumore-al-seno.asp .
4. Am J Pathol 2013, 183: 1096e1112.
5. Davies C, Pan H, Godwin J, Gray R, Peto R; ATLAS Collaborators Worldwide: ATLASe10 v 5years of adjuvant tamoxifen (TAM) in ERþ disease: effects on outcome in the first and in the second decade after diagnosis. Cancer Res 2012, 72(Suppl 3), (Abstract S1-2).
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005, 353:1659e1672.
7. Bowcock A.M.: Breast cancer genes. 1997, Breast Journal 3 : 1-6.
8. Brandt J., Garne J.P., Tengrup I., Manjer J.: Age at diagnosis in relation to survival following breast cancer : a cohort study. 2015, World Journal of Surgical Oncology 92 : 550-556.
9. Mc Pherson K., Steel C.M., Dixon J.M. : Breat Cancer – epidemiology, risk factors and genetic. 2000, British Medical Journal 321 : 624-628.
10. Kelsey J.L., Gammon M.D., John E.M.: Reproductive factors and breast cancer. 1993, Epidemiological Review 15 : 36-47.
11. Vogel V.G.: Breast cancer prevention: a review of current evidence . 2000, A Cancer Journal for Clinicians 50 : 156-170.
12. Sakorafas G.H., Krespis E., Pavlakis G.: Risk estimation for breast cancer development; a clinical perspective. 2002, Surgical Oncology 10 : 183-192.
13. Garber J.E., Smith B.L.: Management of the high risk and the concerned patient. In: Harris JR, Morrow M, Lippman ME, Hellman S, editors. Diseases of the breast. 1996, Philadelphia: Lippincot-Raven : 323-334.
14. Sakorafas G.H., Tsiotou A.G.: Genetic predisposition to breast cancer: a surgical perspective. 2000, British Journal of Surgery 87 : 149-162.
15. Cummings S.R., Eckert S., Krueger K.A.: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the more randomized trial. Multiple outcomes of raloxifene evaluation. 2009, Journal of American Medical Association 281 : 2189-2197.
16. Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, Meakin JW, Shelley W, Pritchard KI: An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat 1997, 44:201e210.
17. Roop RP, Ma CX: Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol 2012, 8:273e292. 18. Polyak K, Metzger Filho O. SnapShot: breast cancer. Cancer Cell 2012;22(4):562.
e1.
19. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441:424–430.
20. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8(8):627–44.
21. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296: 1655–1657. 22. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, et al.
Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 2008;453(7195):662–6.
in cell growth, metabolism and tumorigenesis. Nature 2008;454(7205):776–9. 24. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes
Dev 1999;13(22):2905–27.
25. Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM. INPP4B: the new kid on the PI3K block. Oncotarget 2011;2(4):321–8.
26. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012;486(7403):400–4.
27. Wellcome Trust Sanger Institute. Catalogue of Somatic Mutations in Can-cer (COSMIC). Available at: http://www.sanger.ac.uk/genetics/CGP/ cosmic/, accessed March 9, 2010.
28. Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resis-tance in breast cancer. Cancer Cell 2007;12:395– 402.
29. Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyper-activation results in lapatinib resistance that is reversed by the mTOR/ phosphatidylinositol 3- kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68:9221–9230.
30. Shapiro G, Kwak E, Baselga J et al. Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors. J Clin Oncol 2009;27(15 suppl):3500.
31. LoRusso P. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors. J Clin On-col 2009;27(15 suppl):3502.
32. Wen PY, Omuro AM, Batchelor TT et al. A Phase 1 safety and pharmaco-kinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 in-hibitor, in combination with temozolomide (TMZ) in patients (pts) with malignant glioma. Mol Cancer Ther 2009;8(suppl 1):B265.
33. Janne PA, Felip E, Cedres S et al. A phase 1 safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in combination with erlotinib in patients (pts) with advanced solid tumors. Mol Cancer Ther 2009;8(suppl 1):A254.
34. Porta C., Paglino C., Mosca A.: Targeting PI3K/Akt/mTOR signaling in cancer. 2014, Frontiers in Oncology 4 : 1-8.
35. Frenso-Vara J.A., Casado E., De Castro J., Cejas P., Belda-Iniesta C., Gonzales-Baron M.: PI3K/Akt signalling pathway and cancer. 2006, Cancer Treatment Reviews 30 : 193-204.
36. Kumar C.C., Madison V.: Akt crystal structure and Akt-specific inhibitors. 2005, Oncogene 24 : 493-501.
37. Zhao L., Vogt P.: Class I PI3K in oncogenic cellular transformation. 2008, Oncogene 27 : 5486-5496.
38. Engelman J.A., Luo J., Cantley L.C.: The evolution of phosphatidylinositol-3-kinases as regulators of growth and metabolism. 2006, Nature Review Genetics 7 : 606- 619.
39. Schmelzle T, Hall M. TOR, a central controller of cell growth. Cell 2000;103:253–62. 40. Mathews MB, Sonenberg N, Hershey JWB. Origins and principles of translational
control. In: Sonenberg N, Hershey JWB, Mathews MB, editors. Translational control of gene expression. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2000. p. 1–31.
41. Jacinto E, Hall M. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003;4:117–26.
42. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot 1975;28:727–32.
43. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998;31:335–40.
44. Aoki M, Blazek E, Vogt P. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci USA 2001;98:136–41. 45. Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, et al. An inhibitor of
mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc Natl Acad Sci USA 2001;98:10320–5.
46. Sekulic A, Hudson C, Homme J, Yin P, Otterness D, Karnitz L, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the
mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000;60:3504–13.
47. Sabers CJ, Martin MM, Brunn GJ, Williams J, Dumont F, Wiederrecht G, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815–22.
48. Keith CT, Schreiber SL. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 1995;270:50–1.
49. Bosotti R, Isacchi A, Sonnhammer EL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 2000;25:225–7.
50. Vogt PK. PI 3-kinase, mTOR, protein synthesis and cancer. Trends Mol Med 2001;11:482–4.
51. Gingras A, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001;15:807–26.
52. Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 1999;96:14866–70.
53. Powers T, Walter P. Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 1999;10:987– 1000.
54. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin
associated protein. Proc Natl Acad Sci USA 1999;96:4438–42.
55. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B:identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999;344:427–31.
56. Yokogami K, Wakisaka S, Avruch J, Reeves SA. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 2000;10:47–50.
57. Luo Y, Marx SO, Kiyokawa H, Koff A, Massagué J, Marks AR. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol 1996;16:6744–51.
58. Vicier C., Dieci M.V., Arnedos M., Delaloge S., Viens P., Andre F.: Clinical
development of mTOR inhibitors in breast cancer. 2014, Breast Cncer Research 16 : 203-212.
59. Peterson T.R., Laplante M., Thoreen C.C., Sancak Y., Kang S.A., Kuehl W.N., Gray N.S., Sabatini D.M.: DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. 2009, Cell 137 : 873-886. 60. Wander S.A., Hennessy B.T., Slingerland J.M.: Next-generation mTOR inhibitors in
clinical oncology: how pathway complexity informs therapeutic strategy. 2011, Journal Clinical Investigation 121 : 1231-1241.
61. Zhou H., Huang S.: The complexes of mammalian target of rapamycin. 2010, Current Protein and Peptide Science 11 : 409-424.
62. Xiaoju M.M, Blenis J.: Molecular mechanisms of mTOR-mediated translational control. 2009, Nature Reviews Molecular Cell Biology 10 : 307-318.
63. Hay N., Soneberg N.: Upsteam and downstream of mTOR. 2004, Genes & Development 18 : 1926-1945.
64. Engelman J.A., Luo J., Cantley L.C.: The evolution of phosphatidylinositol-3-kinases as regulators of growth and metabolism. 2006, Nature Review Genetics 7 : 606- 619.
65. Pearce L.R., Komander D., Alessi D.R.: The nuts and bolts of AGC protein kinases. 2010, Nature Reviews Moleculars Cell Biology 11 : 9-22.
66. Roop RP, Ma CX: Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol 2012, 8:273e292. 67. Schwartzberg LS, Franco SX, Florance A, O’Rourke L, Maltzman J, Johnston S:
Lapatinib plus letrozole as first-line therapy for HER-2þ hormone receptor-positive metastatic breast cancer. Oncologist 2010, 15:122e129.
68. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012, 366:520e529.
69. Acconcia F, Kumar R: Signaling regulation of genomic and non-genomic functions of estrogen receptors. Cancer Lett 2006, 238:1e14.
70. Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R; Combined Hormone Agents Trialists’ Group and the European Organization for Research and Treatment of Cancer: 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 2001, 19:343e353.
71. Ellis MJ, Tao Y, Young O, White S, Proia AD, Murray J, Renshaw L, Faratian D, Thomas J, Dowsett M, Krause A, Evans DB, Miller WR, Dixon JM: Estrogen-
independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 2006, 24:3019e3025.
72. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive
Clin Oncol 2009, 27:5529e5537.
73. Ghayad SE, Cohen PA. Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov. 2010;5:29–57. 74. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol.
2010;7:209–219.
75.http://www.ema.europa.eu/docs/it_IT/document_library/EPAR__Product_Informa
tion/human/000273/WC500046437.pdf .
76. Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an international randomized Phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarco-mas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31:2485–2492.
77. US National Institutes of Health. Available from: Clinicaltrials gov. Accessed December 12, 2013.
78.http://www.ema.europa.eu/docs/it_IT/document_library/EPAR__Product_Informa
tion/human/000799/WC500039912.pdf .
79. Chan S, Scheulen ME, Johnston S, 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;23:5314–5322.
80.http://www.ema.europa.eu/docs/it_IT/document_library/EPAR__Product_Informa
tion/human/001038/WC500022814.pdf
81. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012, 366:520e529.
82. Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemes-tane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression- free survival analysis. Adv Ther. 2013;30: 870–884.
83. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo
controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor- positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664– 1670.
84. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, Phase 3 randomised trial. Lancet Oncol. 2013;14:989–998.
85. Campone M, Bachelot T, Gnant M, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer. 2013;49:2621– 2632.