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• W2944373454 abstract "Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER positive breast cancer. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. Based on preclinical and clinical data, SERDs are expected be effective in patients harboring ESR1 mutations. Biomarker analysis was performed on plasma and tumor samples from the Phase I study of GDC-0927 in metastatic breast cancer (Dickler et al, SABCS 2017) with the goal of evaluating activity in both ESR1 mutant and wildtype tumors, and to assess ER pathway modulation. Methods: Hotspot mutations in ESR1, PIK3CA, and AKT1 were analyzed in baseline, on-treatment and end of treatment plasma derived circulating tumor DNA (ctDNA) using the BEAMing assay in patients treated at multiple dose levels of GDC-0927. A subset of samples was analyzed with Foundation Medicine's next generation sequencing ctDNA assay (FACT), which covers genomic alterations in 62 commonly altered genes. Paired pre- and on-treatment biopsies were collected to assess ER pathway modulation. ER, PR, and Ki67 protein levels were analyzed by immunohistochemistry. Gene expression analysis was performed using Illumina's RNA Access library preparation kit followed by paired-end (2x50b, 50M reads) sequencing on the HiSeq. Results: Baseline and on-treatment plasma samples were available for 40 patients. ESR1 and PIK3CA mutations were observed in 52% and 33% of patient baseline samples, respectively (BEAMing method). Mutant allele frequencies (MAF) generally declined in the first on-treatment samples collected for both ESR1 (16 out of 21 samples) and PIK3CA (7 out of 12 samples). The majority of the reductions were greater than 95% relative to baseline. Increases in ESR1 MAFs were observed in later time-points and were not associated with any particular ESR1 mutation. There were six instances for which an ESR1 mutation was detected in an on-treatment sample that was not detected in the baseline sample, three at L536P and one each at D538G, L536H, and S463P, and four out of six with MAFs close to the limit of detection. The FACT assay also detected alterations in CDH1, NF1, PTEN, and TP53 in baseline samples. The relationship between MAF changes and clinical benefit to GDC-0927 will be presented. A predefined, experimentally-derived set of ER target genes were evaluated in pre- and on-treatment tumor biopsy pairs from six patients. Four of the six patients showed evidence of suppression in ER pathway activity, one patient treated at the 1000 mg dose level and three at the 1400 mg dose. The degree of pathway suppression was associated with pre-treatment pathway levels and decreases of ER and Ki67 protein levels. Conclusions: We report here evidence of consistent reduction of ESR1 and PIK3CA ctDNA in patients treated with GDC-0927. ER pathway suppression was observed at both the transcript and protein level confirming pharmacodynamic activity of the SERD. Citation Format: Spoerke JM, Daemen A, Chang C-W, Giltnane J, Metcalfe C, Dickler MN, Bardia A, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez Martin A, Cortes J, Martin M, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Liu L, Li R, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Lackner MR. Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-01." @default.
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• W2944373454 date "2019-02-15" @default.
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• W2944373454 title "Abstract P5-11-01: Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD)" @default.
• W2944373454 doi "https://doi.org/10.1158/1538-7445.sabcs18-p5-11-01" @default.
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