Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer

Purpose
This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical
and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone
receptor (HR) –positive/human epidermal growth factor receptor 2 (HER2) –negative operable
breast cancer.
Methods
Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly
assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus
lapatinib 1,500 mg orally 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 Ki-67 and pAKT expression from baseline to surgery was observed in both
arms. Overall, 34 patients (37%) 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 (objective response rate, 93% v 63% in PIK3CA wild type; P .040).
Conclusion
The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and
manageable toxicities. In unselected estrogen receptor–positive/HER2-negative patients, letrozolelapatinib
and letrozole-placebo resulted in a similar overall clinical response rate and similar effect
on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA
mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer
must now be independently confirmed.