Breast Cancer Research and Treatment

, Volume 125, Issue 1, pp 137–143 | Cite as

Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aromatase inhibitor resistant metastatic breast cancer

  • Claudine Isaacs
  • Pia Herbolsheimer
  • Minetta C. Liu
  • Mary Wilkinson
  • Yvonne Ottaviano
  • Gina G. Chung
  • Robert Warren
  • Jennifer Eng-Wong
  • Philip Cohen
  • Karen L. Smith
  • Karen Creswell
  • Antonella Novielli
  • Rebecca Slack
Clinical trial


We evaluated the use of sorafenib to overcome resistance to aromatase inhibitors (AIs) in patients with metastatic breast cancer who had disease recurrence or progression while on AIs. We performed a multi-institution phase I/II study of sorafenib and anastrozole 1 mg daily in 35 postmenopausal females with hormone receptor positive metastatic breast cancer resistant to AIs. Primary objectives were to determine the dose of sorafenib in conjunction with anastrozole and the clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD] ≥ 24 weeks). Secondary objectives were to determine toxicity and to evaluate if response was associated with change in number of circulating endothelial cells or circulating endothelial progenitor cells. Based on the phase I portion, sorafenib 400 mg twice daily was selected as the phase II dose. Among 35 patients, 7 had SD ≥ 24 weeks, 1 had PR ≥ 24 weeks, and 14 had progressive disease (PD) ≤ 24 weeks, corresponding to a CBR of 23%. The most common adverse events (all; Grade 3/4) were fatigue (66%; 17%), diarrhea (63%; 6%), nausea (60%; 9%), and hand-foot syndrome (57%; 34%). Dose reduction occurred in 77% of the patients and 31% came off study due to toxicity. The combination of sorafenib and anastrozole demonstrated a 23% CBR in patients with hormone receptor positive, AI-resistant metastatic breast cancer, which may be attributable to the restoration of sensitivity to AIs. Toxicities occurred frequently resulting in a high rate of discontinuation.


Breast cancer Endocrine resistance Aromatase inhibitor Anastrozole Sorafenib 



Supported by Avon-National Cancer Institute (NCI) Progress for Patients (PFP) Award 3 P30CA051008-15S3, Bayer Pharmaceutical, and the Clinical Research Management Office, the Flow Cytometry and the Biostatistics & Bioinformatics Shared Resources of Lombardi Comprehensive Cancer Center. The authors gratefully acknowledge the invaluable participation of study patients as well as the research staff Julie Castle, Alissa Mun, Jean Flack, Susie Park, Bernadette Trujillo, Carol Hatch, Mary Steimer, Lois Ravage, Jeannie Kluytenaar, Laurie Thomas, Lauren Callahan, and Jennifer O’Malley. This study was presented in part at the San Antonio Breast Cancer Symposium in 2009 and at 2008 Breast Cancer Symposium, American Society of Clinical Oncology.


  1. 1.
    Jemal A, Siegel R, Ward E et al (2009) Cancer statistics. CA Cancer J Clin 59:225–249CrossRefPubMedGoogle Scholar
  2. 2.
    Jatoi I, Tsimelzon A, Weiss H et al (2005) Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat 89:173–178CrossRefPubMedGoogle Scholar
  3. 3.
    Jatoi I, Chen BE, Anderson WF et al (2007) Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 25:1683–1690CrossRefPubMedGoogle Scholar
  4. 4.
    Dawood S, Broglio K, Gonzalez-Angulo AM et al (2008) Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol 26:4891–4898CrossRefPubMedGoogle Scholar
  5. 5.
    Chlebowski R, Cuzick J, Amakye D et al (2009) Clinical perspectives on the utility of aromatase inhibitors for the adjuvant treatment of breast cancer. Breast 18(suppl 2):S1–S11Google Scholar
  6. 6.
    Shou J, Massarweh S, Osborne CK et al (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-Her2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–935CrossRefPubMedGoogle Scholar
  7. 7.
    Kato S, Endoh H, Masuhiro Y et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494CrossRefPubMedGoogle Scholar
  8. 8.
    Adeyinka A, Nui Y, Cherlet T et al (2002) Activated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin Cancer Res 8:1747–1753PubMedGoogle Scholar
  9. 9.
    Callans LS, Naama H, Khandelwal M et al (1995) Raf-1 protein expression in human breast cancer cells. Ann Surg Oncol 2:38–42CrossRefPubMedGoogle Scholar
  10. 10.
    Von Lintig FC, Dreilinger AD, Varki NM et al (2000) Ras activation in human breast cancer. Breast Cancer Res Treat 62:51–62CrossRefGoogle Scholar
  11. 11.
    Johnston SR (2010) New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 16:1979–1987CrossRefPubMedGoogle Scholar
  12. 12.
    Wilhelm SM, Carter C, Tang L et al (2004) 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 64:7099–7109CrossRefPubMedGoogle Scholar
  13. 13.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134CrossRefPubMedGoogle Scholar
  14. 14.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390CrossRefPubMedGoogle Scholar
  15. 15.
    Bianchi G, Loibl S, Zamagni C et al (2009) Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anti Cancer Drugs 20:616–624CrossRefPubMedGoogle Scholar
  16. 16.
    Moreno-Aspitia A, Morton RF, Hillman DW et al (2009) 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 No. 336. J Clin Oncol 27:11–15CrossRefPubMedGoogle Scholar
  17. 17.
    Baselga J, Grupo Español de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos, Roché H et al (2009) SOLTI-0701: a double-blind, randomized, phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (Bc). In: Presented at the 15th European Cancer Organization (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, Berlin, Germany, September 20–24, 2009Google Scholar
  18. 18.
    Gradishar WJ, Kaklamani V, Sahoo TP et al (2009) A double-blind, randomized, placebo-controlled, phase IIb study evaluating the efficacy and safety of sorafenib in combination with paclitaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer. In: Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8–12, 2009Google Scholar
  19. 19.
    Bonelli MA, Fumarola C, Alfieri RR et al (2010) Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. doi: 10.1007/s10549-009-0714-5
  20. 20.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10CrossRefPubMedGoogle Scholar
  21. 21.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  22. 22.
    Mancuso P, Antoniotti P, Quarna J et al (2009) Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. Clin Cancer Res 15:267–273CrossRefPubMedGoogle Scholar
  23. 23.
    Steurer M, Kern J, Zitt M et al (2008) Quantification of circulating endothelial and progenitor cells: comparison of quantitative PCR and four-channel flow cytometry. BMC Res Notes 1:71CrossRefPubMedGoogle Scholar
  24. 24.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  25. 25.
    Snedecor G, Cochran W (1989) Statistical methods, 8th edn. Iowa State University Press, Ames Iowa, pp 251–252Google Scholar
  26. 26.
    Lee JM, Sarosy GA, Annunziata CM et al (2010) Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity. Br J Cancer 102:495–499CrossRefPubMedGoogle Scholar
  27. 27.
    Vroling L, Lind JS, de Haas RR et al (2009) CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients. Br J Cancer 1–8Google Scholar
  28. 28.
    Calleri A, Bono A, Bagnardi V et al (2009) Predictive potential of angiogenic growth factors and circulating endothelial cells in breast cancer patients receiving metronomic chemotherapy plus bevacizumab. Clin Cancer Res 15:7652–7657CrossRefPubMedGoogle Scholar
  29. 29.
    Schultheis AM, Lurje G, Rhodes KE et al (2008) Polymorphisms and clinical outcomes in recurrent ovarian cancer treated with cyclophoshamide and bevacizumab. Clin Cancer Res 14:7554–7563CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Claudine Isaacs
    • 1
  • Pia Herbolsheimer
    • 1
  • Minetta C. Liu
    • 1
  • Mary Wilkinson
    • 2
  • Yvonne Ottaviano
    • 3
  • Gina G. Chung
    • 4
  • Robert Warren
    • 1
  • Jennifer Eng-Wong
    • 1
  • Philip Cohen
    • 1
  • Karen L. Smith
    • 5
  • Karen Creswell
    • 1
  • Antonella Novielli
    • 1
  • Rebecca Slack
    • 1
  1. 1.Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  2. 2.Medical Oncology Associates of Northern VirginiaFairfaxUSA
  3. 3.Franklin Square Hospital CenterBaltimoreUSA
  4. 4.Yale Cancer CenterYale UniversityNew HavenUSA
  5. 5.Washington Cancer InstituteWashingtonUSA

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