Lapatinib in Postmenopausal Women with Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer†

Abstract

Breast cancer is themost commonmalignancy in women and is the leading cause of malignancy-related death in women worldwide. Breast cancer development and tumor progression are governed by complex interactions between hormone receptors (HRs) [estrogen receptor (ER) and progesterone receptor] and the human epidermal growth factor receptor family of receptors. The human epidermal growth factor receptor family includes four subtypes: HER1 (also termed EGFR or ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Based on the expression of HR and HER2 receptors, breast cancers have been classified into various subtypes (e.g. HRpositive/HER2-positive; HR-positive/HER2-negative; HRnegative/HER2-positive; HR-negative/HER2-negative) that are increasingly being used to predict clinical outcomes and choose therapeutic options. Coexpression of HR andHER2 is common, occurring in approximately half of the breast cancers that overexpress HER2. Lapatinib (Tykerb ; Tyverb ) is an orally active, low molecular weight, reversible inhibitor of the intracellular tyrosine kinase domains of both HER1 and HER2. The features and properties of lapatinib in postmenopausal women with HR-positive, HER2-positive metastatic breast cancer are shown in table I. The efficacy of lapatinib in combination with letrozole was investigated in a phase III, randomized, double-blind, multicenter trial (EGF30008) in 1286 postmenopausal women with HR-positive, metastatic breast cancer who had not received previous treatment for advanced or metastatic disease. The women were randomized to receive oral treatment with lapatinib 1500mg/day plus letrozole 2.5mg/day, or letrozole 2.5mg/day plus placebo. Therapy was continued in both groups until disease progression or withdrawal from the trial. The patients had not previously received treatment with trastuzumab or an aromatase inhibitor. The primary endpoint of median progression-free survival in a HER2-positive population of 219 women from this trial was Table I. Features and properties of lapatinib (Tykerb , Tyverb )