Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion: ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [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 PD2-06.

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