Final results of a phase II, double blind, placebo controlled, randomized trial of preoperative chemotherapy +/- gefitinib with biomarker evaluation in operable breast cancer

Purpose: To evaluate the in vivo effect of adding gefitinib to preoperative chemotherapy on the inhibition of the EGFR downstream effect on MAPKinase in patients (pts) with operable breast cancer (BC). Secondary aims: biomarker expression at baseline and at surgery, percentage of pathologic complete response (pCR), and toxicity. Patients and Methods: Enrollment has been completed as of January 2006, and 90 pts with stage IIB-IIIA BC have been randomized to receive epirubicin 90 mg/sqm and paclitaxel 175 mg/sqm on day 1 plus: gefitinib 250 mg daily from day 5 to 16 (Arm A), gefitinib 250 mg daily from day 1 to 21 (Arm B), or placebo (Arm C). Treatment plan: 4 courses every 3 weeks, followed by surgery. The following parameters were evaluated at baseline, and on the specimens of definitive surgery: pMAPKinase, EGFR/aEGFR, Ki67, apoptotic index (TUNEL test), and VEGF-R. Results: Patients characteristics were as follows: median age, 51 years (range:29-69); stage IIA: 41%, IIB 45%, and IIIA: 14% of pts ; mean T mammographic size: 3.33 cm (range 1.5-9 cm); Estrogen Receptor positivity: 69%; HER2 positivity: 20%. A total of 322 courses were administered, and 88 pts are evaluable: a grade 3/4 neutropenia was observed in of 43% of pts; three pts experienced febrile neutropenia. Non hematologic grade 2/3 toxicity: diarrhoea 4.4% , skin toxicity 11.3%, hypertransaminasemia 3.4%, and neurotoxicity 4.4% of pts; 1 episode of grade 4 hypertransaminasemia. Eight pts discontinued treatment: 1 progressive disease, 1 death for car accident, 6 adverse events (skin toxicity:1, severe mood alteration:1, grade 4 hepato-biliary toxicity: 1; grade 3 hypertransaminasemia: 3). So far, 55 pts completed treatment: 25 pts (46.3%) received breast conservative surgery; a pCR was observed in 3 pts (5%). Median expression at baseline and after therapy were respectively: pMAPK: 7.5% (range 0-60) and 0% (0-4) (p=0.0902), Ki67: 28.5% (3-90%) and 15.1% (1-90) (p=0.0013); EGFR: 0% (0-15%) and 0% (0-4%)(p=0.2682); VEGFR : 4% (0-11%) and 0% (0-11%) (p=0.0178). Conclusions: The inclusion of gefitinib in a preoperative chemotherapy program is feasible, and, despite the low number of pCRs, the rate of conservative surgery is of interest. Final, unblinded clinical-biological data will be reported at the meeting