BioProject

Growth factor signaling and angiogenesis may promote endocrine-resistance in breast cancer and blocking these pathways can overcome resistance in preclinical models. We conducted a phase-II study of adding the VEGFR/Ras/Raf/MAPK inhibitor sorafenib to endocrine therapy in metastatic ER-positive breast cancer, either upon progression or after maximal response with measurable residual disease. Tumor biopsies and serum were collected on days 1 and 28. Primary endpoint was response by RECIST after 3 months and secondary endpoints included safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 patients but the study closed after 11 patients because of slow accrual. 8 patients had progressive disease (PD) on entry and 3 had stable disease (SD). One patient with SD discontinued sorafenib after 2-weeks because of grade 3 rash. Of the 10 remaining patients after adding sorafenib, 7 had SD (70%), 3 had PD (30%) and median TTP was 6.1-months. Of the 8 patients who entered the study with PD on endocrine therapy, 5 converted to SD (62%) with a median TTP of 6.4-months. Notably, patients on tamoxifen had a median TTP of 8.4-months. The most common adverse events were hypophosphatemia, hypokalemia, and rash, and the majority were grade 1&2 with no grade 4 toxicities. There was a significant reduction in serum VEGFR2 and PDGFR-α on day-28 (p-values 0.0035 and 0.017, respectively). Both serum VEGF and sVEGFR-1 were increased on day-28, but the differences were not statistically significant (p-values 0.3223 and 0.084, respectively). Microarray analysis identified 32 suppressed genes with an FDR of <0.20 and at least a 2-fold change with no induced genes and 29 KEGG pathways were enriched on day-28. Our study suggests that sorafenib can restore endocrine sensitivity, particularly tamoxifen, and this strategy of adding novel agents in patients progressing on endocrine therapy should be examined in future trials. Overall design: This was a single-institution, phase II study of adding sorafenib to existing endocrine therapy. On study entry, eligible patients underwent serum sample collection and core biopsy of accessible disease (if applicable) on endocrine therapy and prior to starting sorafenib. Serum and a second biopsy were then collected on day 28. Sorafenib dose was 400mg orally twice daily along with continuing the same endocrine agent. Patients were followed monthly for clinical and toxicity evaluation. Disease response by RECIST criteria was assessed after 3 months by appropriate scans and these were obtained every 2 months thereafter until progression. Sorafenib and the endocrine agent were continued until disease progression or unacceptable toxicity