Preliminary safety data of preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2-positive operable breast cancer

Introduction and aims: Lapatinib (L) is a TKI of EGFR and HER2. The inhibition of these two pathways can affect tumor growth by reducing the EGFR-dependent proliferative stimulus, by restoring apoptosis, and possibly by enhancing sensitivity to chemotherapy (CT). On these premises, the combination of L with CT or CT and trastuzumab (T) is promising. We have therefore designed a phase II randomized trial to evaluate activity and safety of this combination as preoperative therapy for HER2+ operable breast cancer (BC). Primary endpoint: %of pCR. Secondary aims: breast objective response, breast conservative surgery, safety, molecular responses, gene expression related to pCR. Patients and methods: After a core biopsy for diagnosis, biomarker evaluation and storage of fresh tissue for molecular analyses, patients with HER2+ stage II-IIIA BC are randomized to: Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists in: paclitaxel 80 mg/sqm wkly for 12 wks, followed by 4 courses of FEC (5FU 600 mg/smq + Epirubicin 75 mg/sqm + Cyclophosphamide 600 mg/sqm iv) q3wks. T is administered at the dose of 2 mg/kg wkly in arms A and C; L is administered at 1500 mg po daily in arm B, and at 1000 mg po daily in arm C. Both T and L are administered throughout the duration of CT. The following biomarkers are evaluated at baseline, and at surgery: EGFR, HER2, pTEN, pAKT, pMAPK, Apoptosis (TUNEL Test), Ki67. Sample size: assuming a 50% increase in the pCR rate for the CT+T+L arm vs CT+T or CT+L, in the first stage 52 patients will be enrolled; in case we observe 16 pCR, additional 68 patients will be enrolled, for a total of 120 patients (Simon’s design). Results 12 patients have been randomized so far. Preliminary safety data will be presented at the meeting