Abstract PS1-11-27: Evaluation of steroid hormone receptor expression and clinical outcomes in ER-positive breast cancer bone metastases

Abstract Background: Estrogen receptor-positive (ER+) breast cancer (BC) has a high affinity for progression in bone, which is often the initial metastatic site. ER+ BC treatment responses may depend on the expression of additional steroid hormone receptors (SHRs), such as progesterone receptors (PR) or androgen receptors (AR). However, the predictive value of these SHRs in determining ER+ BC bone metastases (BMET) outcomes remains largely unexplored. The possible functional impact of PR and AR targeting on bone-specific ER+ BC progression is also not known. To address this knowledge gap, we evaluated the predictive associations of AR and PR expression with clinical outcomes for ER+ BMET. Methods: A retrospective analysis was conducted using BC BMET samples analyzed at Caris Life Sciences, with survival outcomes inferred from insurance claims. HER2-/ER+ BMET (n=1677) specimens were identified using immunohistochemistry (IHC) (HER2-: ≤1+ intensity or ≤10% cells stained, or 2+ & >10% with CISH-null reflex test; ER+: ≥1+ & ≥1%). These samples were then stratified into four groups by IHC based on ±AR and/or PR expression (PR+: ≥1+ & ≥1%; AR+: ≥1+ & ≥10%). Associations were examined between AR ± PR expression and 1) overall survival (OS, inferred from biopsy to last contact), including CDK4/6 inhibitor time-on-therapy (CDKi TOT); 2) pathogenic gene mutations (mut) known to alter BC survival (ESR1mut or PIK3CAmut); or 3) AR-regulated gene expression. Results: SHR expression was common in ER+ BMET, with 87.1% AR+ and 59.3% PR+. “Triple positive” (AR+/PR+/ER+) BMET were the largest group (53.7%), followed by PR-null AR+/ER+ BMET (33.2%). AR-null ER+ BMET were much less common, with 5.6% or 7.3% PR+ or PR-, respectively. Only 9.4% of PR+/ER+ BMET were AR-, while 38.2% of AR+/ER+ BMET were PR-. AR positivity was associated with the longest OS for ER+ BMET. A similar trend for improved OS was observed in AR-expressing ER- BMET (n=305), though not statistically significant. When stratifying ER+ BMET by the proportion of AR+ cells stained by IHC, having a higher proportion (≥ median) was associated with longer OS only for PR+/ER+ BMET (Cox proportional hazards ratio (HR)=0.70, p=0.003 for high vs low AR % cells stained). There was no significant difference in CDKi TOT across groups. However, OS was significantly and uniquely longer for AR+ (not AR-) ER+ BMET patients (pts) who received CDKi, which was highest when PR was co-expressed (HR=0.62, p