Biomarker-driven prescribing patterns in <i>ESR1</i> <i> ^mut </i> ER+/HER2- metastatic breast cancer (mBC).

Abstract

e23373 Background: Multiple biomarker-driven therapies are approved for ER+/HER2- mBC. Oral selective estrogen degraders (SERDs) are approved for ESR1 mut ER+/HER2- mBC, but ESR1 mut may co-occur with other actionable biomarkers, including somatic PIK3CA/AKT1 / PTEN mut , germline BRCA1/2 mut , and HER2-low disease. Optimal timing of matched therapies remains uncertain in patients (pts) with multiple targetable mutations. This study evaluated institutional prescribing patterns, focusing on the first biomarker-matched therapy selected following elacestrant approval, and associated clinical characteristics in pts with ER+/HER2- ESR1 mut mBC with other actionable variants. Methods: Pts with ESR1 mut mBC were included if they had ≥1 additional targetable biomarker and received a matched agent after elacestrant approval (Jan 27, 2023). Genomic and pathology data were assessed for PIK3CA/AKT1/PTEN mut , HER2-low status (IHC 1+ or 2+/FISH negative), and g BRCA1/2 mut . Variants were considered actionable if a matched therapy was available as standard of care or through a clinical trial at treatment selection. Clinical factors annotated included age at therapy start, ECOG, hemoglobin (HgB), HgB A1c, creatinine (Cr), bilirubin, and visceral disease. Comparisons were performed across treatment groups defined by the first matched therapy received (oral SERD vs PI3K/AKTi vs Trastuzumab deruxtecan [T-Dxd]) using Kruskal–Wallis and Chi Square tests. Results: 87 pts with ESR1 mut mBC had ≥1 additional targetable variant at treatment selection (Table 1). Oral SERDs were prescribed first for most pts with concurrent PIK3CA mut , and evenly with T-Dxd for pts with HER2-low mBC. If ≥2 PI3K/AKT pathway mutations were present, a PI3K/AKTi was selected. Median age differed significantly, with older pts more likely to receive oral SERDs (SERD 73, PI3K/AKTi 64, T-Dxd 62 years; p = 0.001). Cr levels differed with lower values in T-Dxd and PI3K/AKTi groups (p = 0.034). In a subanalysis, excluding pts who received a matched agent pre-elacestrant approval (n = 55), median age was higher in oral SERD recipients (75 vs 66 vs 59 years; p &lt; 0.001). All groups had median HgB A1c &lt; 6.5 and no significant difference in Cr. Conclusions: Guidelines for initial biomarker-driven treatment selection in ER+/HER2- ESR1 mut mBC are not well defined. This work shows variability in real-world treatment practices and potential associations with toxicity-related factors. Larger analyses are planned to validate these findings and to evaluate treatment sequencing patterns in this setting. Mutation Profile SERD first (n = 43) PI3K/AKTi first (n = 21) T-Dxd first (n = 23) ESR1 + PIK3CA (n = 28) 20 (71%) 8 (29%) — ESR1 + AKT1 (n = 1) 0 1 (100%) — ESR1 + PTEN (n = 1) 0 1 (100%) — ESR1 + ≥2 PIK3CA/AKT1/PTEN (n = 5) 0 5 (100%) — ESR1 + HER2-low (n = 28) 14 (50%) — 14 (50%) ESR1 + HER2-low + ≥1 PIK3CA/AKT1/PTEN (n = 23) 8 (35%) 6 (26%) 9 (39%) ESR1 + HER2-low + BRCA1/2 + ≥1 PIK3CA/AKT1/PTEN (n = 1) 1 (100%) 0 0