27 juni 2012: voor het effect van toevoegen van sorafenib aan andere medicijnen bij borstkanker lees het overzichtsartikel in medscape: Clinical Overview of Sorafenib in Breast Cancer. Onderaan dit artikel hebben we een referentielijst gerelateerd aan dit odnerwerp toegevoegd.

10 september 2008: Bron: persbericht van universiteit van Georgetown.

Wanneer borstkankerpatienten naast hun hormoontherapie (o.a. Arimidex en Femara ) ook sorafenib nemen dan blijkt dat bij 26% de resistentie voor hormoontherapie wordt opgegeven en de hormoonkuur weer werkzaam wordt. Dit blijkt uit een kleinschalige studie bij 22 vrouwen met resistente borstkanker. Sorafenib heeft onder de naam Nexavar bewezen effectief te kunnen zijn bij uitgezaaide nierkanker. Ook zijn er trials bij melanomen gedaan die positieve effecten laten zien van Sorafenib.  Wel bijna altijd in combinatie met andere medicijnen.

Phase II study finds sorafenib helps reverse disease resistance to anti-hormonal therapy

FRIDAY, Sept. 5 (HealthDay News) -- The drug sorafenib may help "re-sensitize" certain breast cancer tumors to anti-hormonal drugs, Georgetown University Medical Center researchers say.

Women with estrogen-receptor or progesterone-receptor positive (ER or PR positive) metastatic breast cancers often take anti-hormonal medicines, such as aromatase inhibitors, to keep the cancer under control. Aromatase inhibitors lower the amount of estrogen in the body.

However, the tumor eventually becomes resistant to anti-hormonal drugs, and the cancer begins to grow.

"At first, the tumor's growth is halted, because the aromatase inhibitor is depriving the cancer of the estrogen it needs to grow. Eventually, though, the cancer will figure out another way to thrive in the absence of the estrogen," Dr. Claudine Isaacs, clinical director of the breast cancer program at Georgetown University Medical Center's Lombardi Comprehensive Cancer Center, said in a university news release.

Isaacs and her colleagues wanted to find out if a new approach can restore the effectiveness of anti-hormonal drugs against these tumors.

The phase II study included 27 postmenopausal women with metastatic breast cancer that had recurred or progressed while the women were taking the aromatase inhibitor anastrozole. Preliminary analysis of study data showed that 26 percent of the women showed a clinical benefit response while taking both sorafenib and anastrozole.

"Given what we know about the ineffectiveness of sorafenib alone in metastatic breast cancer, we believe the benefit that we're seeing may be attributable to the restoration of sensitivity to aromatase inhibitors," Isaacs said. "To manage breast cancer long-term, it's apparent that we may need to continually switch drugs to keep up with how a cancer evolves and evades each approach. In a sense, for each step back, we hope to take two steps forward."


The study was to be presented Sept. 5 at the 2008 ASCO breast Cancer Symposium in Washington, D.C. Isaacs is part of the speaker's bureau for Pfizer Inc., which makes the aromatase inhibitor Exemestane.

Clinical overview of sorafenib in breast cancer


  1. Althuis MD, Dozier JD, Anderson WF et al.: Global trends in breast cancer incidence and mortality 1973–1997. Int. J. Epidemiol. 34, 405–412 (2005).
  2. Marshall CJ: Raf gets it together. Nature 383, 127–128 (1996).
  3. Davies H, Bignell GR, Cox C et al.: Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
  4. Sivaraman VS, Wang H, Nuovo GJ, Malbon CC: Hyperexpression of mitogen-activated protein kinase in human breast cancer. J. Clin. Invest. 99, 1478–1483 (1997).
  5. Kolch W. Meaningful relationships the regulation of the Ras/Raf/Mek-ERK pathway by protein interactions. Biochem. J. 351, 289–305 (2000).
  6. Takahashi T, Ueno H, Shibuya M: VEGF activates protein kinase C-dependent, but Ras independent Raf–MEK–MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221–2230 (1999).
  7. Adjei AA: Signal transduction pathway targets for anticancer drug discovery. Curr. Pharm. Des. 6, 361–378 (2000).
  8. Lee JT Jr, McCubrey JA: The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention. Leukemia 16, 486–507 (2002).
  9. Franklin RA, McCubrey JA: Kinases positive and negative regulators of apoptosis. Leukemia 14, 2019–2034 (2000).
  10. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).
  11. Weinstein-Oppenheimer CR, Blalock WL, Steelman LS, Chang F, McCubrey JA: Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-dependent tumors. Pharm. Ther. 88, 229–279 (2000).
  12. Samuels ML, Weber MJ, Bishop JM, McMahon M: Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human Raf-1 protein kinase. Mol. Cell. Biol. 13, 6241–6252 (1993).
  13. Folkman J: Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
  14. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).
  15. Ferrara N: Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9(Suppl. 1), 2–10 (2004).
  16. Dvorak HF: Angiogenesis: update 2005. J. Thromb. Haemost. 3, 1835–1842 (2005).
  17. Underiner TL, Ruggeri B, Gingrich DE: Development of vascular endothelial growth factor receptor (VEGFR) kinase inhibitors as antiangiogenic agents in cancer therapy. Curr. Med. Chem. 11, 731–745 (2004).
  18. Avastin®, package insert. Genentech, CA, USA (2009).
  19. Miller K, Wang M, Gralow J et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for MBC. N. Engl. J. Med.357(26),2666–2667 (2007).
  20. Robert NJ, Dieras V, Glaspy J et al.: RIBBON-1: randomized, double-blind, placebo controlled, Phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or MBC. Presented at: 2009 ASCO Annual Meeting. Chicago, IL, USA, 30 May–2 June (2009) (Abstract 1005).
  21. Ro J, Bresser J, Ro JY et al.: SIS/PDGF-B expression in benign and malignant human breast lesions. Oncogene 4(3), 351–354 (1989).
  22. Ginsburg E, Vonderhaar BK: Stimulation of growth of human breast cancer cells (T47D) by platelet derived growth factor. Cancer Lett. 58(1–2), 137–144 (1991). Erratum in: Cancer Lett.59(3),267 (1991).
  23. Ariad S, Seymour L, Bezwoda WR: Platelet-derived growth factor (PDGF) in plasma of breast cancer patients: correlation with stage and rate of progression. Breast Cancer Res. Treat. 20(1), 11–17 (1991).
  24. Coltrera MD, Wang J, Porter PL, Gown AM: Expression of platelet-derived growth factor B-chain and the platelet-derived growth factor receptor β subunit in human breast tissue and breast carcinoma. Cancer Res. 55(12), 2703–2708 (1995).
  25. Bhardwaj B, Klassen J, Cossette N et al.: Localization of platelet-derived growth factor β receptor expression in the periepithelial stroma of human breast carcinoma. Clin. Cancer Res. 2(4), 773–782 (1996).
  26. English JM, Cobb MH: Pharmacological inhibitors of MAPK pathways. Trends Pharmacol. Sci. 23, 40–45 (2002).
  27. Lee JT, McCubrey JA: Targeting the Raf kinase cascade in cancer therapy – novel molecular targets and therapeutic strategies. Exp. Opin. 6, 1–20 (2002).
  28. Gasparini G, Longo R, Torino F, Morabito A: Therapy of breast cancer with molecular targeting agents. Ann. Oncol. 16(Suppl. 4), IV28–IV36 (2005).
  29. Lin NU, Winer EP: New targets for therapy in breast cancer: small molecule tyrosine kinase inhibitors. Breast Cancer Res. 6(5), 204–210 (2004).
  30. Kaklamani V, O'Regan RM: New targeted therapies in breast cancer. Semin. Oncol. 31(2 Suppl. 4), 20–25 (2004).
  31. Rexer BN, Ghosh R, Arteaga CL: Inhibition of PI3K and MEK: it is all about combinations and biomarkers. Clin. Cancer Res. 15(14), 4518–4520 (2009).
  32. Fischgräbe J, Wülfing P: Targeted therapies in breast cancer: established drugs and recent developments. Curr. Clin. Pharmacol. 3(2), 85–98 (2008).
  33. Johnston SRD: Targeting downstream effectors of epidermal growth factor receptor/HER2 in breast cancer with either farnesyltransferase inhibitors or mTOR antagonists. Int. J. Gynecol. Cancer 16(Suppl. 2), 543–548 (2006).
  34. Nexavar®, package insert. Onyx Pharmaceutical, CA, USA (2005).
  35. Strumberg D, Richly H, Hilger RA et al.: Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J. Clin. Oncol. 23, 965–972 (2005).
  36. Cobleigh MA, Langmuir VK, Sledge GW et al.: A Phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin. Oncol. 30(Suppl. 16), 117–124 (2003).
  37. Wilhelm S, Carter C, Lynch M et al.: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 5, 835–844 (2006).
  38. Wilhelm SM, Carter C, Tang L 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. 64, 7099–7109 (2004).
  39. Wilhelm S, Chien DS: BAY 43–9006: preclinical data. Curr. Pharm. Des. 8, 2255–2257 (2002).
  40. Lierman E, Lahortiga I, Van Miegroet H et al.: The ability of sorafenib to inhibit oncogenic PDGFRβ and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica 92, 27–34 (2007).
  41. Moore M, Hirte HW, Siu L et al.: Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43–9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann. Oncol. 16, 1688–1694 (2005).
  42. Hotte SJ, Hirte HW: BAY 43–9006: early clinical data in patients with advanced solid malignancies. Curr. Pharm. Des. 8, 99–110 (2002).
  43. Carlomagno F, Anaganti S, Guida T et al.: BAY 43–9006 inhibition of oncogenic RET mutants. J. Natl Cancer Inst. 98, 326–334 (2006).
  44. Yu C, Bruzek LM, Kaufmann SH et al.: The raf kinase inhibitor BAY 43– 9006 accelerates Mcl-1 degradation and regulates pro-apoptotic function. Clin. Cancer Res. 46, 6155 (2005).
  45. Richly H, Kupsch P, Passage K et al.: Results of a Phase I trial of BAY 43–9006 in combination with doxorubicin in patients with refractory solid tumors. J. Clin. Oncol. 23, 207 (2004) (Abstract).
  46. Azad NS, Annunziata C, Barrett T et al.: Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: clinical and translational results. J. Clin. Oncol. 25, 3542 (2007) (Abstract).
  47. Escudier B, Eisen T, Stadler WM et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134, (2007).
    ▪▪ Demonstrates that sorafenib as a single agent has significant activity in metastatic renal cell carcinoma.
  48. Llovet J, Ricci S, Mazzaferro V et al.: Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359(4), 378–390 (2008).
    ▪▪ Demonstrates that sorafenib as a single agent has significant activity in metastatic hepatocellular carcinoma.
  49. Moreno-Aspitia A, Morton RF, Hillman DW et al.: Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracycline or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J. Clinic. Oncol. 27(1), 11–15 (2009).
    ▪▪ Demonstrates that sorafenib as a single agent has low activity in metastatic breast cancer.
  50. Bianchi G, Loibl S, Zamagni C et al.: Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs 20(7), 616–624 (2009).
    ▪▪ Corroborates that sorafenib as single agent has low activity in metastatic breast cancer.
  51. Kober F, Hermann M, Handler A et al.: Effect of sorafenib in symptomatic metastatic medullary thyroid cancer. J. Clin. Oncol. 25, 617. Presented at: 2007 ASCO Annual Meeting. Chicago, IL, USA, 1–5 June (2007) (Abstract 14065).
  52. Adjei AA, Molina JR, Hillman SL et al.: A front-line window of opportunity Phase II study of sorafenib in patients with advanced non-small cell lung cancer: A North Central Cancer Treatment Group study. J. Clin. Oncol. 25, 396. Presented at: 2007 ASCO Annual Meeting. Chicago, IL, USA, 1–5 June (2007) (Abstract 7547).
  53. Keohan M, D'Adamo D, Qin L et al.: Analysis of toxicity in a Phase II study of sorafenib in soft tissue sarcoma (STS). J. Clin. Oncol. 25, 560. Presented at: 2007 ASCO Annual Meeting. Chicago, IL, USA, 1–5 June (2007) (Abstract 10061).
  54. Agarwala SS, Keilholz U, Hogg D et al.: Randomized Phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma. J. Clin. Oncol. 25, 474. Presented at: 2007 ASCO Annual Meeting. Chicago, IL, USA, 1–5 June (2007) (Abstract 8510).
  55. Elser C, Siu LL, Winquist E et al.: Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J. Clin. Oncol. 25, 3766–3773 (2007).
  56. Baselga J, Gianni L, Gradishar WJ et al.: Phase IIb double-blind, randomized, placebo-controlled trials for the efficacy and safety of sorafenib in patients (pts) with metastatic or locally advanced breast cancer (BC): review of the Trials to Investigate the Effects of Sorafenib in BC (TIES) program. Presented at: 2009 ASCO Annual Meeting. Chicago, IL, USA, 4–8 June (2009).
  57. Gradishar WJ, Kaklamani V, Prasad Sahoo T et al.: A double-blind, randomized, placebo-controlled, Phase IIb study evaluating the efficacy and safety of sorafenib (SOR) in combination with paclitaxel (PAC) as a first-line therapy in patients (pts) with locally recurrent or metastatic breast cancer (BC). Presented at: 32nd Annual San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December (2009) (Abstract 44).
    ▪ Demonstrates that sorafenib in combination with paclitaxel is active but associated with significant toxicity and why some of these toxicities may apply only to some regions of the world.
  58. Baselga J; Grupo Español de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos, Roché H et al.: SOLTI-0701: A multinational double-blind, randomized Phase IIB study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC). Presented at: ECCO 15 and 34th ESMO Multidisciplinary Congress. Berlin, Germany, 20–24 September (2009) (Abstract 3LBA). Updated at: 32nd Annual San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December (2009) (Abstract 45).
    ▪ Demonstrates significant activity of sorafenib in combination with capecitabine.
  59. Bonelli MA, Fumarola C, Alfieri RR et al.: Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res. Treat. (2010) (Epub ahead of print).
  60. Tan A, Reiss M, Wong S et al.: Letrozole and sorafenib as first-line therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (MBC): preliminary results. Presented at: 2009 ASCO Breast Cancer Symposium. San Francisco, CA, USA, 8–10 October (2009) (Abstract 256).
  61. Isaacs C, Wilkinson M, Liu MC et al.: Phase I/II study of sorafenib with anastrozole to overcome resistance to aromatase inhibitors (AIs) in patients with hormone receptor positive (ER/PR+) AI resistant metastatic breast cancer (MBC). Presented at: 32nd Annual San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December (2009) (Abstract 3090).
  62. Azad NS, Posadas EM, Kwitkowski VE et al.: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J. Clin. Oncol. 26, 3709–3714 (2008).
  63. Spigel DR, Molthrop D, Peacock N et al.: A pilot study of adjuvant doxorubicin and cyclophosphamide followed by paclitaxel plus sorafenib in women with node positive or high-risk breast cancer. Presented at: 32nd Annual San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December (2009) (Abstract 2110).
  64. Miller KD, Chap LI, Holmes FA et al.: Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).
  65. Brufski A, Bondarenko IN, Smirnov S 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 HER2-negative metastatic breast cancer. Presented at: 32nd Annual San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 9–13 December (2009) (Abstract 42).
  66. Traina TA, Theodoulou M, Feigin K et al.: Phase I study of a novel capecitabine schedule based on the Norton–Simon mathematical model in patients with metastatic breast cancer. J. Clin. Oncol.26(11),1797–1802 (2008).

    101. US NIH: Clinicaltrials.gov http://clinicaltrials.gov
    102. NCT00632541: Hoosier Oncology Group BRE06–109. A Phase II of Sorafenib and bevacizumab in Metastatic Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00632541 (Accessed January 2010)
    103. NCT00825734: Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00825734 (Accessed December 2009)
    104. NCT00828074: Phase I/II Trial of Sorafenib Tosylate and Vinorelbine Ditartrate in Women with Stage IV Adenocarcinoma of the Breast http://clinicaltrials.gov/ct2/results?term_NCT00828074 (Accessed December 2009)
    105. NCT00764972: Phase IB/II Trial of Sorafenib and Vinorelbine as First Line Treatment in Metastatic Breast Cancer. http://clinicaltrials.gov/ct2/results?term_NCT00764972 (Accessed December 2009)
    106. NCT00493636: A Double-Blind, Randomized Phase IIb Study of Sorafenib Compared to Placebo When Administered in Combination With Chemotherapy for Patients With Locally Advanced or MBC That Has Progressed During or After Bevacizumab Therapy http://clinicaltrials.gov/ct2/results?term_NCT00493636 (Accessed December 2009)
    107. NCT00622466: Phase II Study of Sorafenib Tosylate and Paclitaxel in Patients with Metastatic HER2-Negative Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00622466 (Accessed December 2009)
    108. NCT00499525: Phase II Study of Paclitaxel With Versus Without Sorafenib Tosylate in Patients with Locally Recurrent or Metastatic Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00499525 (Accessed December 2009)
    109. NCT00722072: Sorafenib and Fulvestrant in Treating Patients with Locally Advanced or Metastatic Breast Cancer That Did Not Respond to Aromatase Inhibitor Therapy http://clinicaltrials.gov/ct2/results?term_NCT00722072 (Accessed December 2009)
    110. NCT00525161: Study Adding Multikinase Inhibitor Sorafenib to Existing Endocrine Therapy in Patients with Advanced Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00525161 (Accessed December 2009)
    111. NCT00217399: Phase I/II Trial of Sorafenib in Combination with Anastrozole in Post-Menopausal Women with Estrogen Receptor and/or Progesterone Receptor Positive Metastatic Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00217399 (Accessed December 2009)
    112. NCT00634634: Phase I/II Trial of Letrozole and Sorafenib in Post-Menopausal Hormone Receptor Positive Breast Cancer. http://clinicaltrials.gov/ct2/results?term_NCT00634634 (Accessed December 2009)
    113. NCT00433511: Doxorubicin, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer http://clinicaltrials.gov/ct2/results?term_NCT00433511 (Accessed December 2009)

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