Abstract 1949: <i>ESR1</i> mutations in circulating tumor DNA (ctDNA) are significant predictors of chemotherapy resistance to paclitaxel and carboplatin in metastatic breast cancer (MBC)

Background: ESR1 (estrogen receptor 1) mutations play a significant role on resistance to endocrine therapy in estrogen receptor-positive (ER+) MBC. Our previous work demonstrated that monitoring ctDNA ESR1 mutations serves as a predictive tool for poor prognosis in MBC (ASCO 2022 #1057, SABCS 2024 #1421). Here, we report new findings indicating that increasing ctDNA ESR1 mutations are associated with chemotherapy resistance, an area that has been scarcely explored. Methods: The study included 158 ER+ MBC patients enrolled under IRB-approved trial (NU16B06) who received treatments in 2016-2022 at Robert H. Lurie Cancer Center, Northwestern University. The median follow-up period was 126.3 months. Baseline ctDNA was analyzed by Guardant 360 NGS panel. Only patients with ESR1 mutations were included for statistical analysis (Causal Inference) of correlation between the ESR1 mutations with the chemotherapy resistance. Results: ESR1 mutations were identified in 10 hotspots among 40 out of 158 patients. The ctDNA ESR1 mutations including 8 E380Q (mean 6.3%), 12 Y537S (mean 5.6%), 13 D538G (mean 11.9%), 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%). The criterion for chemotherapy resistance is defined as a change in the drug following treatment or disease progression observed by the last visit after this treatment. The numbers of cases sensitive vs resistant to chemotherapy along with the corresponding drugs are as follows: Doxorubicin (22 vs 18), Epirubicin (33 vs 7), Pegylated Liposomal doxorubicin (37 vs 3), Carboplatin (25 vs 15), Paclitaxel (21 vs 19), Docetaxel (23 vs 17), Vinorelbine (29 vs 11), Ixabepilone (34 vs 6), Eribulin (32 vs 8), Capecitabine (17 vs 23), Cyclophosphamide (16 vs 24), Gemcitabine (36 vs 4), and Nab paclitaxel (35 vs 5). Significant differences were observed in rising ctDNA ESR1 mutation levels with a cut-off above 2.9% between the Paclitaxel-resistant group (19 patients) and the Paclitaxel-sensitive group (21 patients), with a chi-square statistic of 6.352 (P=0.011). Similarly, significant differences were found in ESR1 mutation levels with a cut-off above 2.1% between the Carboplatin-resistant group (15 patients) and the Carboplatin-sensitive group (25 patients), with a chi-square statistic of 4.177 (P=0.041). No significant associations were identified between ESR1 mutations and resistance to other drugs. Conclusions: These findings demonstrate for the first time that ctDNA ESR1 mutations are associated with chemotherapy resistance to both Carboplatin and Paclitaxel. Such mutations contribute to tumor heterogeneity, enabling mutated receptors to support tumor survival despite cytotoxic treatment. Detecting ESR1 mutations in MBC may serve as a consideration for guiding chemotherapy decisions and exploring alternative therapeutics. Citation Format: Qiang Zhang, Justin W. Zhang, Andrew Davis, Jianhua Jiao, Paolo D'Amico, Lorenzo Gerratana, Weijun Qin, Xinkun Wang, Akhil Chawla, Lisa Flaum, Leonidas C. Platanias, William Gradishar. ESR1 mutations in circulating tumor DNA (ctDNA) are significant predictors of chemotherapy resistance to paclitaxel and carboplatin in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1949.