Operable Breast Cancer: preliminary results of a phase II, double blind, placebo controlled, randomized trial of preoperative chemotherapy +/- gefitinib with biomarkers evaluation

Introduction: EGFR is expressed in 14-80% of breast tumors. The activity and safety of TKIs in earlier stages and in combination with chemotherapy has yet to be characterized. To evaluate the in vivo interaction between gefitinib and its target in patients (pts) with operable breast cancer (BC), we designed this phase II randomized trial of preoperative chemotherapy +/- gefitinib. Secondary aims: evaluation of biomarker modulation at baseline and at surgery, percentage of pathologic complete response (pCR), and toxicity. Patients and Methods: After core biopsy, pts with stage IIB-IIIA BC were randomized to receive: epirubicin (E) 90 mg/sqm as iv bolus on day 1 and paclitaxel (T) 175 mg/sqm as a 3-hour infusion on day 1 plus: gefitinib 250 mg daily from day 5 to16 (Arm A), gefitinib 250 mg daily from day 1 to 21 (Arm B), or placebo (Arm C). Four courses were administered every 3 weeks, and then pts underwent surgery. The following parameters were evaluated at baseline, and on the specimens of definitive surgery: pMAPKinase, EGFR/aEGFR expression, Ki67, apoptotic index (TUNEL test), and VEGF-R (Flk1) expression. Results: So far 40/90 planned pts have been entered; thirty-three pts have received at least one course of treatment and are evaluable for toxicity. Median age was 50 years (range:34-66); 85% of pts had stage IIA-IIB disease; 63% had Estrogen Receptor positive tumors. A total of 104 courses were administered; treatment was generally well tolerated. Two pts experienced febrile neutropenia. Six pts discontinued treatment: 1 pt due to progressive disease, 1 died for a car accident, and 4 pts due to toxicity (cutaneous toxicity:1, severe mood alteration:1, grade4 hepato-biliary toxicity: 1; grade3 hypertransaminasemia:1). Twenty-one pts completed treatment plan and underwent surgery; 7 pts (33%) received breast conservative surgery. A pCR was observed in 2 pts (9,5%). Median expression at baseline and after therapy were respectively: Ki67: 33,3% (range 3-90%) and 17,5% (range 1-80) (p=0.039); EGFr: 8,2% (range 0-80%) and 0,5% (range 0-4%); pMAPK: 13,8% (range 0-65) and 8,3% (range 0-70), VEGFR positivity 54% and 23,5%. Conclusions: Despite the low number of pts, the inclusion of gefitinib in a preoperative chemotherapy program is feasible, and the toxicity profile of this combination is not dissimilar to that reported for gefitinib or for the ET combination alone. By preliminary assessment, the expression of all the evaluated biomarkers tended to be lower after treatment, despite this reduction is significant for Ki67 only