36P Megestrol acetate resistance in estrogen receptor-positive advanced breast cancer in the MEGA trial

Abstract

Megestrol-Acetate (MA) has activity after progressive disease (PD) on aromatase inhibitors, providing a disease control rate of 40% and a duration of clinical benefit of 10 months. Ligand-bound progesterone receptor modulates estrogen receptor (ER) activity and reprograms ER-regulated transcription in breast cancer (BC), leading to regression of tumour xenografts. MEGA trial [NCT03024580] aimed to evaluate modulation of steroid receptor activity in advanced BC. Here we present the clinical and preliminary translational data. Eligible patients (pts) had metastatic ER+ HER2- BC, and were randomized to receive MA or another HT agent (AHT), Tamoxifen or Exemestane, with 10 pts planned for each arm. The primary endpoint was PFS, secondary were clinical benefit rate and OS. Tumour biopsies and blood for translational analysis (TA) were collected before day 1 of treatment and at PD. Paired samples were analysed by RNA-seq and by chromatin immunoprecipitation and sequencing (ChIPseq) for histone acetylation (H3K27-Ac). From Aug/17 to Jan/20, a total of 20 pts were recruited and evaluable for efficacy. 16 pts evaluable for TA. No difference was observed between both arms in mPFS, MA = 121 vs AHT = 137 days (p=0.66), or mOS, MA=26 vs AHT=30 months, (p=0.35). The best clinical response at 12 weeks (w) was stable disease for MA was (50%) and AHT (58%) and the duration of response >24w for both was 25%. 10 pts in the MA arm had samples evaluable for TA. RNA-seq (n=7) analysis revealed enrichment for estrogen early and late response pathways in MA resistant samples. There was a global increase in H3K27 acetylation (n=10) at ESR1 motifs in MA resistant samples at PD, although a subgroup of pts (n=3 of 10) showed decreased H3K27Ac at these loci globally. Numerically higher median PFS and OS was observed among pts with decreased (N=3) vs increased (N=7) H3K27Ac at ESR1 motif at PD, respectively mPFS 223 (84-337) vs 137 days (46-291), (p=0.25) and mOS 30 (26-35) vs 14 (7-63) months (p=0.42). Translational analysis find evidence of increased transcriptional activity at ER regulated genes in most resistant samples. This could indicate that MA resistant tumours will retain sensitivity to further HT, requiring future research to proof this hypothesis.