4351 - Emergence of ESR1 mutation in cell-free DNA during first line aromatase inhibitor and palbociclib: an exploratory analysis of the PADA-1 trial

Background

In ER+ HER2- metastatic breast cancer (MBC), resistance to estrogen deprivation by Aromatase Inhibitors (AI) can stem from activating ESR1 mutations (ESR1_mut) or from other less characterized, mutually exclusive mechanisms. In this study, we report on factors associated with the onset of ESR1_mut during therapy (vs other mechanisms of resistance).

Methods

PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1_mut 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 ESR1_mut detected (ESR1_wt-PD) with those with a rising ESR1_mut 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 ESR1_wt-PD (n = 139, 57.4%) or a detectable ESR1_mut (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, ESR1_mut (n = 17, 18.7%) was less frequent than ESR1_wt-PD (n = 74, 81.3%); after 6 months, the opposite was true (ESR1mut: n = 80, 53.0% vs ESR1_wt-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 ESR1_mut 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 ESR1_mut (HR = 0.5 [0.3; 0.8]). No other characteristic (including exposure to AI in the adjuvant setting) was associated with the onset of ESR1_mut.

Conclusions

ctDNA analysis in PADA-1 suggests that ESR1_mut 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 ESR1_mut 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.