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

Introduction and objective

Lapatinib (L) is a tyrosine kinase inhibitor 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 with CT and trastuzumab (T) is promising. We have therefore designed a phase II randomized trial to evaluate the activity and safety of this combination as preoperative therapy for HER2+ operable breast cancer (BC). The primary endpoint was percentage of pathologic complete response (pCR). Secondary aims were the breast objective response, breast conservative surgery, safety, molecular responses, and 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 of: paclitaxel 80 mg/m² weekly for 12 weeks, followed by four courses of FEC (5-FU 600 mg/m² + epirubicin 75 mg/m² + cyclophosphamide 600 mg/m² i.v.) every 3 weeks. T is administered at the dose of 2 mg/kg weekly in arms A and C; L is administered at 1,500 mg p.o. daily in arm B, and at 1,000 mg p.o. 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 versus CT + T or CT + L, 52 patients will be enrolled in the first stage; in case we observe 13 pCR, an additional 68 patients will be enrolled, for a total of 120 patients (Simon's design).

Results

Twelve patients have so far been randomized. Preliminary safety data will be presented at the meeting.