Mechanisms of primary AI resistance in ER-positive HER2-negative breast cancer.

Abstract

e11519 Background: Current approaches of neoadjuvant endocrine therapy (NAET) are focusing on biomarker analysis of the diagnostic specimens however inadequate response occurs in 5-10% of patients treated. It has been reported hormone resistance may predict Ki67 level after treatment than ΔKi67. Much less is known about the difference between Ki67 increases and still high level of Ki67 after NAET. A pilot study was conducted to investigate the differences of biomarker changes in short-term NAET (letrozole vs. exemestane). Differences of resistant mechanisms between Ki67 increases and Ki67 still high expression and between two AIs were studied. Methods: Totally 116 samples from 58 postmenopausal women with ER positive HER2 negative stage 1-3 breast cancers comparing LET and EXE were analyzed with pre- and post-treatment mRNA expression of multiple biomarkers using QuantiGene Assay. Each of 29 patients took LET or EXE until the surgery (median 22 days). Compared with Ki67 expression of pre/post treatment, we classified resistance into 2 groups, Ki67 increase after treatment (INC) or Ki67 still high expression (equivalent over 14% in IHC) except those in INC (HIG). Results: Clinical characteristics were well balanced between the two treatment arms. Median % changes of Ki67 were -59% in both LET and EXE. Six cases (10%) were in INC (3/LET and 3/EXE). Among 10 cases of still high Ki67 expression, 6 (10%) were in HIG except 4 cases of Ki67 increases (3/LET and 3/EXE). All 6 cases in INC had increases of ERβ, MAPK, PIK3CA, ALDH1, NFkB, and RANKL and decrease of ERα. Five out of 6 in INC had an increase of HER2 and a decrease of PR. While changes in HIG were various, a nonsignificant trend to predict resistance was found. However all 3 cases whose HER2 increased in HIG had also increases of MAPK and PIK3CA. All 3 receiving EXE had increases of PR. Conclusions: Although both LET and EXE had significant decreases of Ki67, no significant difference was found between two. Both had 20% of primary resistance in terms of Ki67. Tumors which Ki67 increase seem to activate various signaling pathway, which mechanism is class effect of AI. What Ki67 is still high supposed to be nonclass effect.