Preoperative letrozole plus lapatinib/placebo for HR+/HER2 negative operable breast cancer: biomarker analyses of the randomized phase II LET-LOB study

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 previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n=43) or letrozole-placebo (Arm B, n= 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial+complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p= 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p=0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor +/HER2- disease.