Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in ER-positive breast cancer.

Abstract

1034 Background: Development of resistance to third-generation AIs is an important problem in ER+ve breast cancer. Several mechanisms have been identified in vitro (e.g., loss of ER expression, activation of signaling pathways independent of ER and acquisition of ER hypersensitivity), but there are no clinical data to support these. The aim of this study was to determine changes in key biomarkers expression (ER, PgR, HER2, and Ki67) in patients who had developed resistance to an AI treatment for ER+ve breast cancer. Methods: Patients with ER+ve breast cancer who had relapsed or progressed while on an AI for whom pathological material was available pre- and post- treatment were identified from the Royal Marsden Hospital database. IHC for ER, PgR, HER2, and Ki67 was performed. ER and PgR were scored by histoscore, Ki67 as % of cells positive and HER2 was scored following CAP/ASCO guidelines (HER2-positive if IHC=3+ ± FISH ratio ≥ 2.20). Results: 43 paired samples were identified. 56% patients received AI in the advanced setting; 44% relapsed on adjuvant AI. Median treatment duration was 21 months (1 to 102). There was no significant change in ER H-score, although 6 patients (14%) became ER-ve at progression on AI. PgR score decreased significantly (p=0.0016). 28 (65%) and 15 (35%) were PgR+ve pretreatment and at progression respectively. PgR+ve recurrences suggest re-establishment of estrogen signaling despite continued AI. In 6 (14%) cases PgR showed increased expression suggesting a possible acquisition of hypersensitivity. Ki67 levels were higher at progression (mean 10.4 vs. 16.7%, p<0.005) and inversely associated with ER levels (p<0.005). This association was due to high Ki67 of ER-ve lesions. Post-AI Ki67 levels were associated with time to treatment failure (p<0.05). No significant changes were observed in HER2 status. Conclusions: Most, but not all, tumors retain ER expression on acquisition of AI resistance. PgR positivity suggests persistent activation of ER pathways. Recurrent ER-ve tumors have a worse prognosis. Investigations are underway to identify potential driver mechanisms. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Novartis, Pfizer Novartis