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Everolimus: side effect profile and management of toxicities in breast cancer

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Abstract

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.

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References

  1. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30. doi:10.3322/caac.21166

    Article  PubMed  Google Scholar 

  2. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E (2012) Cancer treatment and survivorship statistics. CA Cancer J Clin 62(4):220–241. doi:10.3322/caac.21149

    Article  PubMed  Google Scholar 

  3. Huang S, Houghton PJ (2003) Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3(4):371–377

    Article  PubMed  CAS  Google Scholar 

  4. Baselga J (2011) Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 16(Suppl 1):12–19. doi:10.1634/theoncologist.2011-S1-12

    Article  PubMed  Google Scholar 

  5. 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 (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med 366(6):520–529. doi:10.1056/NEJMoa1109653

    Article  PubMed  CAS  Google Scholar 

  6. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E (2012) 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 30(22):2718–2724. doi:10.1200/JCO.2011.39.0708

    Article  PubMed  CAS  Google Scholar 

  7. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nunez R, Hortobagyi GN, Yu D, Esteva FJ (2011) 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 29(23):3126–3132. doi:10.1200/JCO.2010.32.2321

    Article  PubMed  CAS  Google Scholar 

  8. Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28(34):5110–5115. doi:10.1200/JCO.2009.27.8549

    Article  PubMed  CAS  Google Scholar 

  9. US Food and Drug Administration, Everolimus (2012). http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm313008.htm. Accessed in May 7 2013

  10. Hoffman R (2013) Hematology : basic principles and practice, 6th edn. Elsevier/Saunders, Philadelphia

    Google Scholar 

  11. O’Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10):1588–1595. doi:10.1200/JCO.2007.14.0988

    Article  PubMed  Google Scholar 

  12. Kirchner GI, Meier-Wiedenbach I, Manns MP (2004) Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 43(2):83–95

    Article  PubMed  CAS  Google Scholar 

  13. Barnett CM (2012) Everolimus: targeted therapy on the horizon for the treatment of breast cancer. Pharmacotherapy 32(4):383–396. doi:10.1002/j.1875-9114.2012.01084.x

    Article  PubMed  CAS  Google Scholar 

  14. Kovarik JM, Sabia HD, Figueiredo J, Zimmermann H, Reynolds C, Dilzer SC, Lasseter K, Rordorf C (2001) Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 70(5):425–430

    PubMed  CAS  Google Scholar 

  15. Awada A, Cardoso F, Fontaine C, Dirix L, De Greve J, Sotiriou C, Steinseifer J, Wouters C, Tanaka C, Zoellner U, Tang P, Piccart M (2008) The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 44(1):84–91. doi:10.1016/j.ejca.2007.10.003

    Article  PubMed  CAS  Google Scholar 

  16. Jerusalem G, Fasolo A, Dieras V, Cardoso F, Bergh J, Vittori L, Zhang Y, Massacesi C, Sahmoud T, Gianni L (2011) 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 125(2):447–455. doi:10.1007/s10549-010-1260-x

    Article  PubMed  CAS  Google Scholar 

  17. Moulder S, Gladish G, Ensor J, Gonzalez-Angulo AM, Cristofanilli M, Murray JL, Booser D, Giordano SH, Brewster A, Moore J, Rivera E, Hortobagyi GN, Tran HT (2012) A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer 118(9):2378–2384. doi:10.1002/cncr.26571

    Article  PubMed  CAS  Google Scholar 

  18. Schwarzlose-Schwarck S, Scholz CW, Regierer AC, Martus P, Neumann C, Habbel P, Liu H, Zang C, Schefe JH, Schulz CO, Possinger K, Eucker J (2012) The mTOR inhibitor everolimus in combination with carboplatin in metastatic breast cancer–a phase I trial. Anticancer Res 32(8):3435–3441

    PubMed  CAS  Google Scholar 

  19. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS (2009) 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 27(16):2630–2637. doi:10.1200/JCO.2008.18.8391

    Article  PubMed  CAS  Google Scholar 

  20. Ellard SL, Clemons M, Gelmon KA, Norris B, Kennecke H, Chia S, Pritchard K, Eisen A, Vandenberg T, Taylor M, Sauerbrei E, Mishaeli M, Huntsman D, Walsh W, Olivo M, McIntosh L, Seymour L (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 27(27):4536–4541. doi:10.1200/JCO.2008.21.3033

    Article  PubMed  CAS  Google Scholar 

  21. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, Ouwerkerk J, Logan RM, Brakenhoff JA, Lacouture ME, Gelderblom H (2012) Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17(1):135–144. doi:10.1634/theoncologist.2011-0111

    Article  PubMed  CAS  Google Scholar 

  22. Sonis S, Treister N, Chawla S, Demetri G, Haluska F (2010) Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 116(1):210–215. doi:10.1002/cncr.24696

    PubMed  CAS  Google Scholar 

  23. de Oliveira MA, Martins EMF, Wang Q, Sonis S, Demetri G, George S, Butrynski J, Treister NS (2011) Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 47(10):998–1003. doi:10.1016/j.oraloncology.2011.08.009

    Article  PubMed  Google Scholar 

  24. Martins F, de Oliveira MA, Wang Q, Sonis S, Gallottini M, George S, Treister N (2013) A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 49(4):293–298. doi:10.1016/j.oraloncology.2012.11.008

    Article  PubMed  CAS  Google Scholar 

  25. Nicolatou-Galitis O, Nikolaidi A, Athanassiadis I, Papadopoulou E, Sonis S (2013) Oral ulcers in patients with advanced breast cancer receiving everolimus: a case series report on clinical presentation and management. Oral Surg Oral Med Oral Pathol Oral Radiol. doi:10.1016/j.oooo.2013.02.022

    PubMed  Google Scholar 

  26. Peterson ME (2013) Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. Support Care Cancer 21(8):2341–2349. doi:10.1007/s00520-013-1826-3

    Article  PubMed  Google Scholar 

  27. Ferte C, Paci A, Zizi M, Gonzales DB, Goubar A, Gomez-Roca C, Massard C, Sahmoud T, Andre F, Soria JC (2011) Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur J Cancer 47(15):2249–2255. doi:10.1016/j.ejca.2011.03.017

    Article  PubMed  CAS  Google Scholar 

  28. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22(12):2336–2347. doi:10.1200/JCO.2004.08.116

    Article  PubMed  CAS  Google Scholar 

  29. AFINITOR [prescribing information] (2012) Novartis Pharmaceuticals Corporation, East Hanover, NJ

  30. Ramirez-Fort MK, Case EC, Rosen AC, Cerci FB, Wu S, Lacouture ME (2012) Rash to the mTOR Inhibitor everolimus: systematic review and meta-analysis. Am J Clin Oncol. doi:10.1097/COC.0b013e318277d62f

  31. Soefje SA, Karnad A, Brenner AJ (2011) Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol 6(2):125–129. doi:10.1007/s11523-011-0174-9

    Article  PubMed  Google Scholar 

  32. Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E, Stockfleth E (2010) mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transplant 24(2):149–156. doi:10.1111/j.1399-0012.2010.01232.x

    Article  PubMed  CAS  Google Scholar 

  33. Huffman TA, Mothe-Satney I, Lawrence JC Jr (2002) Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci USA 99(2):1047–1052. doi:10.1073/pnas.022634399

    Article  PubMed  CAS  Google Scholar 

  34. Alasker A, Meskawi M, Sun M, Ismail S, Hanna N, Hansen J, Tian Z, Bianchi M, Perrotte P, Karakiewicz PI (2013) A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. Cancer Treat Rev 39(4):388–401. doi:10.1016/j.ctrv.2012.12.006

    Article  PubMed  CAS  Google Scholar 

  35. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A, R-S Group (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456. doi:10.1016/S0140-6736(08)61039-9

    Article  PubMed  CAS  Google Scholar 

  36. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A, R-S Group (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116(18):4256–4265. doi:10.1002/cncr.25219

    Article  PubMed  CAS  Google Scholar 

  37. Appleby L, Morrissey S, Bellmunt J, Rosenberg J (2011) Management of treatment-related toxicity with targeted therapies for renal cell carcinoma: evidence-based practice and best practices. Hematol Oncol Clin North Am 25(4):893–915. doi:10.1016/j.hoc.2011.05.004

    Article  PubMed  Google Scholar 

  38. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes A, European Association for Study of D (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32(1):193–203. doi:10.2337/dc08-9025

    Article  PubMed  CAS  Google Scholar 

  39. Hutson TE, Figlin RA, Kuhn JG, Motzer RJ (2008) Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 13(10):1084–1096. doi:10.1634/theoncologist.2008-0120

    Article  PubMed  CAS  Google Scholar 

  40. Seruga B, Gan HK, Knox JJ (2009) Managing toxicities and optimal dosing of targeted drugs in advanced kidney cancer. Curr Oncol 16(Suppl 1):S52–S59

    PubMed  Google Scholar 

  41. Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, Pond GR, Seymour L, Niroumand M (2006) Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 42(12):1875–1880. doi:10.1016/j.ejca.2006.03.015

    Article  PubMed  CAS  Google Scholar 

  42. Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, Cincotta M, Shapiro M, Duran I, Berkenblit A (2011) Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol 29(13):1750–1756. doi:10.1200/JCO.2010.29.2235

    Article  PubMed  CAS  Google Scholar 

  43. White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ (2010) Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 182(3):396–403. doi:10.1164/rccm.200911-1720OC

    Article  PubMed  Google Scholar 

  44. Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E (2012) Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials. Acta Oncol 51(7):873–879. doi:10.3109/0284186X.2012.705019

    Article  PubMed  CAS  Google Scholar 

  45. Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH (2004) Sirolimus-associated pulmonary toxicity. Transplantation 77(8):1215–1220

    Article  PubMed  CAS  Google Scholar 

  46. Dabydeen DA, Jagannathan JP, Ramaiya N, Krajewski K, Schutz FA, Cho DC, Pedrosa I, Choueiri TK (2012) Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 48(10):1519–1524. doi:10.1016/j.ejca.2012.03.012

    Article  PubMed  CAS  Google Scholar 

  47. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, Creel P, Dickow B, Fischer P, Gornell SS, Meloni F, Motzer RJ (2011) Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 47(9):1287–1298. doi:10.1016/j.ejca.2011.02.014

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

Dr. Paplomata and Dr. Zelnak have nothing to disclose. Dr. O’Regan acts as consultant/advisory role for Novartis.

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  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Road, Atlanta, GA, 30322, USA

    Elisavet Paplomata, Amelia Zelnak & Ruth O’Regan

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  1. Elisavet Paplomata
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Correspondence to Ruth O’Regan.

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Paplomata, E., Zelnak, A. & O’Regan, R. Everolimus: side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat 140, 453–462 (2013). https://doi.org/10.1007/s10549-013-2630-y

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