Abstract 2163: Circulating H3K27 nucleosomes to monitor lung cancer patients during treatment, a universal biomarker quantifying the molecular residual disease (MRD) in plasma samples

Abstract Introduction: Treatment options of lung cancer (LC) comprise radiotherapy, and/or combined treatment approaches, including chemotherapy, immunotherapy and targeted therapies based on the tumoral molecular profile. Following curative-intent first-line therapies, clinical surveillance involves serial CT imaging. However, such surveillance can detect only macroscopic disease recurrence and is frequently inconclusive. NGS has been utilized to help identify and monitor treatment plans. Nucleosomes, complexes of DNA and histones proteins, are released during cell death into blood circulation. Trimethylation of lysine 27 on histone H3 (H3K27Me3), catalyzed by enhancer of zeste homolog 2 (EZH2), is a crucial epigenetic process in tumorigenesis. We investigated if H3K27Me3-nucleosome concentration could be a biomarker for molecular residual disease (MRD). Patients and Methods: Plasmas were retrospectively collected from patients with advanced LC during treatment (CIRCAN’s cohort, n= 200) and from healthy donors (n=100). We carried out standard targeted NGS on paired plasmas. Samples were divided in two sub-groups based on genetical results: ctDNA negative (n=120) or positive (n=80) for presence of somatic alterations. Concentration of circulating H3K27Me3-nucleosome was measured using chemiluminescent Nu.Q® immunoassay (Belgian Volition SRL, Belgium). Results: Significantly elevated concentrations of H3K27Me3-nucleosomes were found in LC plasmas during the follow-up of patients compared to healthy donors (median 14.9 ng/ml vs 6.15 ng/ml, respectively, p<0.001). In addition, H3K27Me3 levels is lower in the ctDNA-negative group compared to ctDNA-positive group (median 12.1 vs 24.8 ng/ml, respectively, p<0.001). At a clinical cut-off of 14 ng/ml, 62% of samples were positive for either H3K27Me3 or ctDNA, or for both, suggesting an active disease progression compared to only 40% detection using the NGS assay alone. 38% of the patients have low levels of H3K27Me3 and were ctDNA-negative strongly suggesting a therapeutic response under treatment. Conclusions: High levels of Nu.Q® H3K27Me3 could allow physicians to detect MRD in LC patients following treatment with curative intent. This could be achieved by monitoring testing of patients at defined intervals of treatment and recovery, alongside imaging, to incorporate analyses of evolving molecular landscapes during treatment. In this setting, the H3K27Me3-nucleosome quantification, to complete the molecular exploration of cfDNA is highly encouraging, especially in advanced NSCLC, where re-tissue biopsies are impractical, expensive, and may cause undue harm. H3K27Me3-nucleosome quantification may also be useful in patient identification for specific treatments such as EZH2 inhibitor, but this requires investigation. Citation Format: Emmanuel Grolleau, Julie Candiracci, Arnaud Gauthier, Gaelle Lescuyer, David Barthelemy, Christine Haon, Florence Geiguer, Margaux Raffin, Nathalie Hardat, Julie Balandier, Rémi Rabeuf, Anne-Sophie Wozny, Guillaume Rommelaere, Claire Rodriguez-Lafrasse, Fabien Subtil, Sébastien Couraud, Marielle Herzog, Lea Payen-Gay. Circulating H3K27 nucleosomes to monitor lung cancer patients during treatment, a universal biomarker quantifying the molecular residual disease (MRD) in plasma samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2163.