Abstract CT189: Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial

Abstract

Abstract 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). Cell-free DNA (cfDNA) ESR1 mutation (ESR1mut) status prior to treatment initiation may be associated with shorter progression-free survival (PFS) under first line Pal+AI; however, the impact of the exact type of ESR1mut, of their quantitative levels and clonality are unknown. In a subsidiary analysis of the first line PADA-1 phase 3 trial, cfDNA samples previously detected as positive by ddPCR were submitted to NGS; mutations types, level and clonality were correlated with patient outcomes under first line Pal+AI. Methods: PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection in the blood of patients treated with AI-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 cfDNA from up to 4ml of plasma by a single ddPCR assay targeting E380, L536, Y537 and D538 hotspots (i.e. >90% of known ESR1 activating mutations) with 0.1% sensitivity (Jeannot et al, Oncogene 2020). We sequenced the ddPCR positive cfDNA samples using a short amplicon-based NGS panel spanning 30 genes, including the full sequence of ESR1. We assessed for the correlation between PFS and ESR1mut type (NGS), absolute level (copy/ml, ddPCR) or variant allelic frequency (VAF, NGS & ddPCR), and clonality (NGS, pending the detection of other driver mutations). Results: Among the 1,017 included patients, N=33 (3.2%) had an ESR1mut detected by ddPCR at inclusion (median VAF= 2.5%, range (0.09-46.6%). 26/33 left-over cfDNA samples were available for NGS. ESR1mut VAFs retrieved by NGS and ddPCR showed an excellent intraclass correlation coefficient (ICC= 0.98; 95% CI [0.89;0.99]). In N=3 samples with low VAF by ddPCR (<1%), NGS was not able to detect ESR1mut. ESR1 codons 380, 536, 537 and 538 were mutated in N=5, 6, 10 and 7 patients, respectively (5 patients (19.2%) having polyclonal mutations). Among evaluable patients, ESR1mut were found clonal and subclonal in 11 (47.8%) and 12 (52.2%) patients, respectively. After a median follow-up of 24.8 months (range 0-41.9 months) (485 PFS events among the 1,017 included patients), ESR1mut detection at inclusion was found to be a prognostic factor for PFS (median PFS = 11.6 months 95% CI [8.3; NR] vs 28.5 months 95% CI [23.3;30.2]; HR= 2.2 95% CI = [1.4;3.4]). ESR1mut type, clonality and baseline levels had no significant additional impact on PFS. Conclusion: Presence of ESR1mut detected in cfDNA at metastatic relapse are associated with a shorter PFS under first line AI and palbociclib. ddPCR and NGS yielded similar quantitative results, while supplementary information obtained by NGS (mutation type and clonality) did not add further prognostic information. Funding: Pfizer, French National Cancer Institute (Grant PRT-K 2020-041) Citation Format: Anne Pradines, Céline Callens, Aurélia Doussine, Ivan Bièche, Jérôme Lemonnier, Marjorie Mauduit, Thomas Bachelot, Florence Dalenc, Alain Lortholary, Barbara Pistilli, Thibault De La Motte Rouge, Renaud Sabatier, Jean-Marc Ferrero, Sylvain Ladoire, Frédérique Berger, François-Clément Bidard. Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT189.