Abstract 395P
Background
Molecular profiling of circulating tumor DNA (ctDNA) is critical for personalizing lung cancer treatment. In patients with negative molecular profiling, abnormal levels of methylated nucleosomes (H3K27Me3) can offer additional insight.
Methods
We analyzed 883 plasma samples from treatment-naive NSCLC patients for H3K27Me3-nucleosome levels using the Nu.Q® immunoassay. ctDNA analysis on the same samples by NGS was performed: a comprehensive custom NGS assay (n=363; 77 genes, 1% sensitivity), a targeted ultra-deep technique (n=172; 33 genes, 0.2% sensitivity) and Plasma SeqSensei™ (n=348; 4 genes, 0.2% sensitivity). The contribution of H3K27Me3 to molecular profiling and its prognostic value for overall survival (OS - based on INSEE public database) were assessed. This study is based on an interim analysis, as the full dataset of 1050 samples has not yet been fully processed.
Results
Mutation rates on ctDNA (ctDNA+) were 34% positive with a comprehensive custom-validated NGS assay, 66% with targeted ultra-deep technique, and 29% with Plasma SeqSensei™. H3K27Me3 levels were higher in ctDNA+ samples compared to those with no alteration detected (ctDNA-) (median 28.5 ng/ml vs 16.2 ng/ml, P < 0.0001). Interestingly, 27%, 8%, and 30% of ctDNA- samples tested with the comprehensive custom NGS assay, the targeted ultra-deep technique and plasma SeqSensei™, respectively, were still found positive for H3K27Me3 (cutoff of 22.5 ng/mL (Grolleau et al. 2023)). H3K27Me3 levels were higher in patients who died compared to survivors (median 39.3 ng/ml vs 20.5 ng/ml, P < 0.0001). Survival analysis showed that ctDNA+ patients with high H3K27Me3 levels had the worst OS (cutoff 65.5 ng/ml, HR=1.9, 95% CI 0.9–3.7). Moreover, ctDNA- patients with high H3K27Me3 levels had a worse OS; with a high hazard ratio compared to those with low H3K27Me3 levels (cutoff=51 ng/ml, HR=4.3, 95% CI 2.5–7.5).
Conclusions
This study highlights the importance of H3K27Me3 as a non-invasive marker for detecting tumor burden to complement the current ctDNA gold standard. Moreover, when combined with ctDNA, H3K27Me3 levels improve the prognostic value for overall survival and could help inform treatment decisions.
Legal entity responsible for the study
Hospices Civils de Lyon
Funding
Belgian Volition
Disclosure
S. Couraud: Financial Interests, Institutional, Funding: Adene, BD Bioscience, Cellgene, Chugai, Janssen, Lilly, Takeda, Transdiag, Volition; Financial Interests, Personal and Institutional, Funding: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, Sanofi; Financial Interests, Personal, Funding: Health Event, Maat Pharma, Pierre Fabre; Non-Financial Interests, Personal, Leadership Role: National guidelines in thoracic oncology (ARISTOT); Non-Financial Interests, Personal, Member of Board of Directors: Sociétéde Pneumologie de Langue Francaise, Adene. A. Kotronoulas, J. Candiracci: Other, Personal, Full or part-time Employment: Belgian Volition. M. Herzog: Other, Personal, Full or part-time Employment: Belgian Volition; Financial Interests, Personal, Stocks/Shares: VolitionRx. All other authors have declared no conflicts of interest.