Background: ESR1 mutations (ESR1m) are acquired resistance mutations that evolve during treatment with aromatase inhibitor (AI) therapy in approximately 40% of ER+ HER2- metastatic breast cancer (mBC) patients and are indicative of poor outcomes. Patients with ESR1m acquired on AI may retain treatment response if switched to selective estrogen receptor degraders (SERDs) like fulvestrant. Circulating tumor DNA (ctDNA) analysis can detect the emergence of ESR1 mutations and simultaneously determine molecular response to therapy through changes in quantitative ctDNA tumor fraction (ctDNA TF). We used real-world data (RWD) to study the combined effect of acquired ESR1 mutation status and ctDNA TF dynamics on overall survival in ER+ HER2- mBC.

Methods: Tempus xF Monitor is a ctDNA assay that measures quantitative molecular changes in ctDNA TF by utilizing diverse genomic events, dynamically weighting somatic variant allele frequencies and copy number variants, while using germline information to inform these estimates and providing single nucleotide variant (SNV) results on 105 genes including ESR1. Non-responders (NR) were characterized as < 50% reduction in ctDNA TF while responders (MR) experienced ≥ 50% reduction in ctDNA TF. We selected a cohort from the deidentified Tempus multimodal database of 101 HR+ HER- mBC patients with a baseline xF test up to one year prior to or 3 months post AI therapy start. Real-world overall survival (rwOS) was defined as the interval from AI start to death, censored on the last known physician follow-up. Kaplan Meier analysis and Cox proportional hazards models were fitted to evaluate the relationship between ESR1m and MR/NR status with rwOS.

Results: In our evaluable cohort, (n=101), median age 59, ESR1m was detected in 29.7% (n=30) patients. ESR1m patients had shorter rwOS compared to ESR1 WT patients (median ESR1m rwOS 63.8 months, median rwOS not reached for ESR1 WT; p=0.013, HR=3.45 [1.9-9.2]). Across the cohort, regardless of ESR1 status, 23.8% (24/101) of patients were characterized as ΔctDNA TF MR, 60.4% (61/101) as NR and 15.8% (16/101) of patients with ctDNA TF values below the limit of blank (b-LOB). Within the NR group, 35.5% (22/61) were also ESR1m, while only 20.8% (5/24) and 18.8% (3/16) ESR1m patients were in the MR and b-LOB group, respectively. Patients with combined ESR1m + NR ΔctDNA TF (n=22) experienced shorter rwOS (p=0.015) compared to MR ΔctDNA TF patients with WT ESR1 (p=0.024, HR=6.61 [1.3-34.2]).

Conclusions: xF Monitor is a ctDNA assay that tracks changes in quantitative ctDNA TF and simultaneously monitors for the emergence of ESR1m, providing a diagnostic that identifies resistance to AI therapy and enables early switch to therapies that could improve outcomes in a patient population with poor prognosis. A larger prospective clinical study is needed to validate these findings.

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