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