Abstract P2-07-16: Rising ESR1 Mutations in Circulating Tumor DNA (ctDNA) Mediate Endocrine Therapy (ET) Resistance to Everolimus and ET but Retain Sensitivity to Fulvestrant in HR+/HER2- Metastatic Breast Cancer (MBC)

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Abstract Background: Treatment with endocrine therapy and CDK4/6 inhibitors is the first-line therapy for the management of HR+/HER2- mBC. ESR1 mutations represent a type of acquired resistance in up to 40% of patients after initial ET. Recent advancements and our previous studies (ASCO-2019 #1036, 2022 #1057, and 2023 #1038) in understanding ET resistance in ESR1-mutant HR+/ HER2- mBC have highlighted the pivotal role of circulating tumor DNA (ctDNA) in monitoring treatment response and progression. Here, we report a first-of-its-kind finding of the significance of ctDNA ESR1 mutations as a factor associated with therapeutic resistance in HR+/HER2- mBC. Methods: This study included 158 HR+/HER2- mBC patients enrolled under an IRB-approved trial (NU16B06) who received systemic treatments from 2016 to 2021 at Robert H. Lurie Cancer Center at Northwestern University. The median follow-up period was 126.3 months from the first diagnosis. 40 patients with ESR1 mutations were included for statistical analysis (Causal Inference) of the correlation between the presence of ESR1 mutations and ET resistance. Patients received various therapies including CDK 4/6 inhibitor, ET and mTOR inhibitor. None of the patients received ESR1-targeted therapy with Elacestrant. Baseline ctDNA was analyzed by Guardant 360 NGS at the time of metastatic spread and subsequent points of progression. Additional clinical, pathologic, therapy, and response data were retrospectively collected and analyzed. Results: ESR1 mutations were identified in 10 hotspots in 40 patients. The number of patients with ESR1 mutations at each hotspot, along with the mean percentage of ESR1-mutated DNA, was as follows: 13 D538G (average 11.9%), 12 Y537S (average 5.6%), 8 E380Q (average 6.3%), 1 V392I (0.1%), 1 Y537N (1.7%), 1 L536P (3.4%), 1 L536R (11.0%), 1 L536H (23.9%), 1 K520K (0.6%), and 1 K362 (15.8%). Among the 40 ESR1-mutation positive patients, 13 received Fulvestrant and 26 received Everolimus and ET. Patients treated with Everolimus and ET had a significantly higher mean percentage of ESR1-mutated DNA compared to patients who did not receive Everolimus plus ET (17.9% vs. 6.1%, p=0.01). This indicates that a higher percentage of mutated ESR1 may be associated with resistance to Everolimus and ET. Conversely, patients treated with Fulvestrant had a significantly lower mean percentage of ESR1-mutated DNA compared to patients who did not receive Fulvestrant (6.85% vs. 18.1%, p=0.04). This suggests that an increasing percentage of ESR1-mutated ctDNA correlates with an increased treatment sensitivity to Fulvestrant. Interestingly, we identified a high rate of PIK3CA co-mutations in 24 patients (60%) among the 40 patients with ESR1 mutations, with the most common co-occurring ESR1 mutation hotspots being Y537S (8 pts), E380Q (7 pts), and D538G (5 pts). Further treatment response analysis to determine the correlation between these two gene co-mutations is underway. Conclusions: Our findings indicate that the level changes of ctDNA ESR1 mutations have implications with regards to treatment sensitivity and resistance to various therapies in patients with HR+/HER2- mBC. These results suggest a potentially effective method for monitoring treatment response and guiding future therapy by providing new insights into targeting ESR1 pathways to overcome resistance. Citation Format: Janice Lu, Qiang Zhang, Natalie Heater, Lisa Flaum, Huiping Liu, Patricia Robinson, Regina Stein, Claudia Tellez, Jianhua Jiao, Andrew A. Davis, Akhil Chawla, Youbin Zhang, Massimo Cristofanilli, William Gradishar. Rising ESR1 Mutations in Circulating Tumor DNA (ctDNA) Mediate Endocrine Therapy (ET) Resistance to Everolimus and ET but Retain Sensitivity to Fulvestrant in HR+/HER2- Metastatic Breast Cancer (MBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-16.

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