P4-01-05: The Multikinase Inhibitor Sorafenib Can Overcome Antiestrogen Resistance in Patients with Progressive Metastatic Estrogen Receptor (ER) Positive Breast Cancer.
Authors: Moss J , Black EP , Wang C , Li L , Sloan S , Lye A , Romond E , Weiss H , Massarweh S 
Published: June 2012

Background

Resistance to antiestrogens is a major problem in metastatic breast cancer. Preclinical data suggest that growth factor signaling and angiogenesis may promote endocrine resistance and blocking such pathways may delay resistance.

Methods: We conducted a phase II clinical trial of adding sorafenib, a VEGFR and Ras/Raf/MAPK inhibitor, to antiestrogen therapy in patients with metastatic ER-positive breast cancer. Patients were required to have progressive disease on an anstiestrogen or have maximum response with residual measurable disease. A core biopsy of accessible breast disease was offered at entry and after 28 days of sorafenib. Microarray experiments were performed on frozen tissue obtained from 4 paired biopsies using Affymetrix Gene Chip HG-U133 Plus 2. Data was normalized based on the GCRMA method and Expression values of each gene were analyzed based on the significant analysis of microarray (SAM) method for paired data. Gene set analysis on KEGG pathways was performed using the gene set enrichment analysis (GSEA) method, where genes were ranked based on the absolute values of their SAM test statistics. Serum was collected on day 1 and day 28 for biomarker comparison using ELISA. Primary study endpoint was response rate by RECIST criteria after 3 months of sorafenib and secondary endpoints were safety, time to progression (TTP), and biomarker assessment.

Results: Planned sample size was 43 but the study closed after 11 patients because of slow accrual. Median age was 45 years (Range 39–72). 7 patients were on tamoxifen, 3 on an aromatase inhibitor, and 1 on fulvestrant. Of the 11 patients enrolled, 8 had progressive disease (PD) on entry and 3 had confirmed stable disease (SD) on antiestrogen alone. One patient with SD at entry discontinued sorafenib after 2 weeks because of a grade 3 rash. Of the 10 patients evaluable for response, 7 had SD (70%) and 3 had PD. Median TTP after adding sorafenib was 182 days (6 months) and in the 8 patients who entered the study with PD, 5 converted to SD (62%) with a median TTP of 192 days (6.4 months). One patient remains on treatment after 16 months of enrollment. Most common adverse events were rash in 9 patients, weight loss in 8 and hypertension in 6. Hypophosphatemia was seen in 11 patients, hypokalemia in 9, and elevated ALT/AST in 4. The majority of toxicities were grade 1. There were 6 grade 3 toxicities; rash, anorexia, hypokalemia, colitis, and 2 hypophosphatemia. No grade 4 toxicities occurred. Microarray analysis identified 29 enriched pathways with a false discovery rate of less than 25%. There was a significant reduction in mean serum Transforming growth factor beta (TGF-β) and platelet derived growth factor receptor alpha ( PDGFR-α) on day 28 (P values= &lt; 0.0001 and 0. 0.017, respectively). Tissue and serum biomarker correlates will be presented in detail at the meeting.

Conclusions: Sorafenib can overcome resistance to antiestrogens, particularly tamoxifen, and may help avoid the routine early use of chemotherapy for endocrine resistant disease. Further study of strategies to overcome endocrine resistance is warranted to help preserve patient quality of life and to investigate mechanisms of resistance.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-05.