Background: Endocrine therapy for metastatic estrogen receptor (ER) positive breast cancer is effective and relatively nontoxic, but resistance eventually develops in all patients. Preclinical data suggest that growth factor signaling and angiogenesis may promote endocrine resistance and blocking such pathways may restore endocrine sensitivity and delay resistance.

Methods: We conducted a phase II trial of administering sorafenib, which inhibits VEGFR and Ras/Raf/MAPK, to patients with metastatic ER-positive breast cancer after at least 3 months of antiestrogen use. Patients were required to have either stable disease or progressive non-visceral metastasis. Measurable disease was required. Sorafenib 400 mg BID was administered along with the same antiestrogen patients were already taking. A core biopsy of accessible disease was offered at entry and after 28 days of sorafenib. Serum was collected on day 1 and day 28 for VEGF, VEGFR, and VEGFR2 analysis. Primary endpoint was response rate by RECIST criteria after 3 months of sorafenib. Secondary endpoints were safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 but the study closed after 11 patients because of slow accrual.

Results: Median age at entry 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). 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. Two of the SD patients had minor responses, but no partial responses were seen. Median TTP after adding sorafenib was 182 days (6 months). Of the 8 patients who entered the study with progressive disease, 5 converted to stable disease (62%) with a median TTP of 136 days (4.5 months). There was a significant reduction in mean serum VEGFR2 on day 28 (P 0.0035) with borderline significant reduction of VEGFR (P 0.08). In the 7 patients with SD as best response, mean VEGFR and VEGFR2 levels were significantly reduced (P 0.016 and 0.038, respectively). There was no significant change in serum VEGF in any of the groups tested. Most common adverse events were rash in 9 patients, weight loss in 8, and hypertension in 6. Most common laboratory abnormalities were hypophosphatemia in 11 patients, hypokalemia in 9, and elevated ALT/AST in 4. The majority of toxicities were grade 1. There were 5 grade 3 toxicities; rash, anorexia, hypokalemia, and 2 hypophosphatemia. No grade 4 toxicities occurred. Overall, treatment was well tolerated and all toxicities were reversible upon sorafenib discontinuation. Tissue biomarkers including 4 paired biopsies will be examined.

Conclusions: Sorafenib may prolong antiestrogen benefit in patients with metastatic ERpositive breast cancer and in particular can restore endocrine sensitivity in patients with disease progression on such therapy. Clinical trials that target endocrine resistance remain critical for understanding mechanisms of resistance and can help preserve patient quality of life by avoiding the early use of more toxic treatments.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-19.