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• W3013013722 abstract "Abstract Background: ER+ metastatic breast cancer (mBC) remains a clinical challenge as most patients (pts) eventually have disease progression on treatment (tx). Multiple molecular mechanisms of resistance to standard-of-care drugs have been reported including mutations in ESR1 (mESR1) or PIK3CA (mPIK3CA); understanding how these affect response to subsequent tx is important. Elacestrant (RAD1901), an investigational oral selective estrogen receptor degrader (SERD), has demonstrated preclinical efficacy in pt-derived xenograft models of ER+ BC, including models harboring mESR1 and mPIK3CA. Elacestrant was evaluated in 2 phase 1 clinical trials (NCT02650817, NCT02338349) in postmenopausal women with ER+/HER2- mBC, including pts that had received multiple prior endocrine tx (median=3) and targeted tx, including CDK4/6 inhibitors (38%). Circulating tumor DNA (ctDNA) collected in these 2 trials was used to characterize the molecular features of this heavily pretreated population and correlate them with elacestrant response. Methods: ctDNA samples were collected at baseline (BL), on-tx (OT) and end-of-tx (EOT). BL samples were analyzed using the Guardant360® assay (Guardant Health) to detect genomic alterations in 73 relevant genes. Changes in BL mESR1 allele frequency of 12 single nucleotide variants (SNVs) in the ligand binding domain of ESR1 were assessed in paired OT and EOT ctDNA samples using the OncoBEAM™ platform (Sysmex Inostics). Response was assessed using RECIST v1.1. Results: Among 73 pts enrolled in these 2 trials, 57 had BL samples. At least 1 alteration was detected in 93% (n=53) of pt samples, with alterations detected in 52 of the 73 genes in the Guardant360® panel. The most frequently detected BL alterations were in ESR1 (47%) and PIK3CA (44%), with alterations in both genes observed in 21% of pts. At BL, 25% (14/57) of pt samples had &gt;1 mESR1; the most commonly detected mESR1 were Y537S (56%), D538G (56%), and Y537N (26%). Following elacestrant tx, there was a decrease in mESR1 allele frequency in 100% of samples (11/11 mESR1 SNVs decreased OT in 9/9 pts). In paired EOT samples from pts lacking mESR1 at BL analyzed to date (N=23), 1 new mESR1 was detected in 1 pt. Among response-evaluable (RE) pts with mESR1 at BL (n=16), there were 4 partial responses (PR; 25%); clinical benefit rate (CBR) at 24 weeks (ie, stable disease + PR) in clinical benefit evaluable (CBE) pts was 52% (11/21); and median progression-free survival (mPFS) in intention-to-treat (ITT) pts was 8.6 mo. Among RE pts with mPIK3CA at BL (n=16), there were 2 PRs (13%); CBR at 24 weeks in CBE pts was 24% (5/21); and mPFS (ITT pts) was 1.9 mo. Conclusions: Relevant genomic alterations, especially in ESR1 and PI3KCA, were detected at BL in a significant proportion of heavily pretreated postmenopausal women with ER+/HER2- mBC enrolled in elacestrant phase 1 trials. Clinical benefit, including PR, was observed in pts with genomic alterations, including mESR1 and PIK3CA. Elacestrant monotherapy vs. standard of care endocrine tx is currently being studied in the phase 3 “EMERALD” study in ER+/HER2- mBC pts, including pts with mESR1, who have received 1 or 2 prior lines of endocrine tx and prior CDK4/6i (NCT03778931). Citation Format: Teeru Bihani, JungAh Jung, Hitisha K Patel, Aditya Bardia, Peter Kabos, Virginia Kaklamani, Agnes Jager, Philippe Aftimos, Sharon Wilks, Elisabeth de Vries, Wael Harb, Donald Richards, Amy Weise, Robert Wesolowski, Catharina CW Menke-van der Houven van Oordt, Paul Conkling, Patrick Neven, Maureen G Conlan. Genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-05." @default.
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• W3013013722 date "2020-02-15" @default.
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• W3013013722 title "Abstract P5-01-05: Genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer" @default.
• W3013013722 doi "https://doi.org/10.1158/1538-7445.sabcs19-p5-01-05" @default.
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