#4113 Background: Estrogen modulates angiogenesis through effects on endothelial cells and by induction of vascular endothelial growth factor (VEGF) expression. Increased VEGF promotes tumor growth and is associated with a poor response to anti-estrogen therapy. This trial evaluates the impact of bevacizumab (B) combined with anastrozole (A) or fulvestrant (F) on progression free survival (PFS) as first line endocrine therapy in metastatic breast cancer (MBC).
 Methods: Study design: Two arm nonrandomized, noncomparative trial of A or F in combination with B. Eligibility: 0 prior hormonal or chemotherapy for MBC, measureable or evaluable disease, normal LVEF, postmenopausal, normal organ function. Treatment: Arm 1: Patients (pts) who either were endocrine therapy naïve, ≥ 12 months from adjuvant endocrine therapy, or who had intolerance to or progression on tamoxifen were treated with anastrozole 1 mg po daily. Arm 2: Patients who were ≤ 12 months from adjuvant aromatase inhibitors (AIs), intolerant of or progressed on adjuvant AIs, or at physician's discretion were treated with fulvestrant 500 mg IM loading dose, 250 mg D15 and every q28 days thereafter. B 10 mg/kg q2wks beginning day 1 was administered in both arms. Concurrent trastuzumab (T) was administered in HER2+ patients. Response assessments were performed q8 wks. Pts were treated until disease progression or toxicity.
 Results: 44 pts have been enrolled with data available for 29 pts. 18 pts (62%) were treated with anastrozole and 11 pts (38%) with fulvestrant. Median age: 64 yrs (range 44-88), ECOG PS 0-17 pts (59%) and PS 1 -12 pts (41%). 7 pts (24%) presented with de novo stage IV disease. 52% had 2 or more metastatic disease sites with bone metastases predominating 16 pts (55%), 7 pts (24%) with bone only disease. There were no G3/4 heme toxicities. G3/4 non-hematologic events consisted of G3 hypertension in 3 pts (10%), arthralgias 1 pt (3%), and CHF 1 pt (3%). This symptomatic LVEF of 40% occurred in arm 1 during cycle 3 and was noted to recover to 50-55% within 1 wk. This pt did not receive T. A median of 4.5 cycles have been administered. PRs were noted in 7 pts (24%) and 14 pts (48%) demonstrated SD. PD was noted in 3 pts and 5 pts were not yet evaluable. 73% of pts are progression free at 12 months. At a median follow up of 7.5 months, median PFS and overall survival has not been reached.
 Conclusions: The combination of bevacizumab with anastrozole or fulvestrant is feasible and well tolerated with adverse events as expected, reflecting standard bevacizumab related toxicities. Bevacizumab in combination with endocrine therapy is promising with early evidence of a high rate of clinical benefit at 72%. Further follow up is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4113.

#2110 Background: Targeting angiogenesis is an effective treatment strategy in many solid tumors including breast cancer (BC). Sorafenib is a small molecule inhibitor of angiogenesis and other tumor growth signaling. We conducted a pilot phase 2 trial incorporating sorafenib into standard adjuvant BC treatment. Material and Methods: The primary endpoint of this multicenter community-based study was to assess the safety of doxorubicin and cyclophosphamide followed by paclitaxel in combination with sorafenib in patients (pts) with node positive or otherwise high-risk BC. Eligibility criteria included: either mastectomy or breast conserving surgery-with axillary node assessment for stage I, II, IIIA, and IIIC (T1-3, N3a only) BC. Pts were either lymph node positive or high-risk node negative (tumor size >2 cm; hormone receptor negative; grade 2-3; or age <35 years). Additional inclusion criteria included: HER2-negative, ECOG performance status 0-1, normal left ventricular ejection fraction by echocardiography or MUGA scan, adequate organ function, and signed informed consent. Treatment consisted of doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) both IV day 1 every 3 weeks x 4 cycles, followed by paclitaxel 175mg/m2 day 1 every 3 weeks x 4 cycles or 80mg/m2 IV weekly x 12, combined with sorafenib 400mg orally twice daily. Sorafenib was held during radiation therapy (where indicated) and resumed once completed. Sorafenib was continued for a total of 12 months and in combination with adjuvant hormonal therapy (where indicated.) LV assessments occurred after AC, paclitaxel, and every 3 months during maintenance sorafenib. Results: Forty-five pts were enrolled from 5/07 to 1/08. The median follow-up is 6 months (range 4-12 months). Baseline characteristics included: median age 54 years (35-74); ECOG 0, 93%; node positive, 80%; and hormone receptor negative 33%. Nineteen pts (42%) discontinued sorafenib before completing paclitaxel (mean time on sorafenib 3.7 weeks; <1 week in 18% of all pts). 9 of these 19 pts (47%) stopped sorafenib due to symptoms. Grade (G) 3/4 non-hematologic toxicity during sorafenib therapy in >5%: arthralgias/myalgias, neuropathy, pain, and pulmonary symptoms (8% each), and rash (11%). G3/4 hematologic toxicity during sorafenib treatment was limited to neutropenia in 11%. There were no sorafenib-related deaths. Discussion: In this pilot study, sorafenib was generally associated with limited severe toxicity when combined with paclitaxel following AC. However, many pts discontinued sorafenib early suggesting sequential scheduling may be more feasible than concurrent administration with chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2110.

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