Double-blind, placebo-controlled, multicenter randomized phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, HER2-negative, operable breast cancer.

Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole + lapatinib or placebo as neoadjuvant therapy in hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal women with stage II-IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months letrozole 2.5 mg p.o. daily plus lapatinib 1500 mg p.o. daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses. Results Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 (37%) patients had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (ORR 93% vs 63% in PIK3CA WT, p=0.040). Conclusions: The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected ER+/HER2- patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate, and similar effect on Ki67 and pAKT. Our secondary endpoint findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in hormone receptor positive/HER2-negative early breast cancer must now be independently confirmed.