Abstract 4351
Background
In ER+ HER2- metastatic breast cancer (MBC), resistance to estrogen deprivation by Aromatase Inhibitors (AI) can stem from activating ESR1 mutations (ESR1mut) or from other less characterized, mutually exclusive mechanisms. In this study, we report on factors associated with the onset of ESR1mut during therapy (vs other mechanisms of resistance).
Methods
PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection (on cell-free DNA, every 2 months) in ER+ HER2- MBC pts treated first line with AI and palbociclib. Main inclusion criteria are pts with no overt resistance to adjuvant AI and no prior therapy for MBC. This analysis compared pts who experienced a progressive disease with no ESR1mut detected (ESR1wt-PD) with those with a rising ESR1mut detected during therapy.
Results
1017 MBC pts were included in PADA-1 from 04/2017 to 01/2019 and are being followed-up. As of 01/31/2019, 242 pts presented either with an ESR1wt-PD (n = 139, 57.4%) or a detectable ESR1mut (n = 103, 42.6% (either prior to PD or at time of PD) at any time during AI-palbociclib therapy. During the first 6 months on treatment, ESR1mut (n = 17, 18.7%) was less frequent than ESR1wt-PD (n = 74, 81.3%); after 6 months, the opposite was true (ESR1mut: n = 80, 53.0% vs ESR1wt-PD n = 71, 47.0%); this change was highly significant (Chi2 test, p < 0.001). Based to a Fine-Gray model adjusted for the number of metastases, a higher risk of ESR1mut during therapy was observed in pts with bone (HR = 2.5 [1.1; 5.6]) or skin (HR = 1.9 [1.1; 3.7]) metastases while liver metastases were associated with a lower risk of ESR1mut (HR = 0.5 [0.3; 0.8]). No other characteristic (including exposure to AI in the adjuvant setting) was associated with the onset of ESR1mut.
Conclusions
ctDNA analysis in PADA-1 suggests that ESR1mut are rarely involved in primary resistance to AI-palbociclib therapy (i.e. PD within 6 months) but may represent the most prevalent mechanism of acquired resistance. The observed association between ESR1mut and metastatic sites might underlie the reported higher efficacy of selective estrogen receptor degraders (such as fulvestrant) in pts with bone metastases.
Clinical trial identification
NCT: 03079011; EudraCT: 2016-004360-18.
Editorial acknowledgement
Legal entity responsible for the study
UNICANCER.
Funding
Pfizer.
Disclosure
F. Bidard: Advisory / Consultancy, lectures fees: Pfizer; Advisory / Consultancy, lectures fees: AstraZeneca. B. Pistilli: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Merus. T. de La Motte Rouge: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. R. Sabatier: Licensing / Royalties: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses, Licensing / Royalties: AstraZeneca; Licensing / Royalties: Tesaro; Research grant / Funding (institution): EISAI; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. F. Clatot: Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. T. Bachelot: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer. S. Delaloge: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
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