The SChISM study: Circulating cell-free DNA size profiles as predictors of progression in advanced carcinoma treated with immune-checkpoint inhibitors
Résumé
Background
Circulating cell-free DNA (cfDNA) offers a promising noninvasive way to predict resistance to immune-checkpoint inhibitors (ICI), for which robust biomarkers are still lacking.
Methods
The SChISM (Size CfDNA Immunotherapy Signature Monitoring) proof-of-concept study (NCT05083494) collected baseline plasmatic cfDNA size profiles from 126 ICI-treated advanced carcinomas, quantified using the innovative, patented and standardized BIABooster device (Adelis). Fragmentome-derived variables and standard clinical variables (including neutrophils-to-lymphocyte ratio, NLR) were analyzed for univariable associations with early progression (EP, progression at first imaging) and progression-free survival (PFS). Multivariable analysis was carried through both unsupervised and supervised learning. Twenty-six variable selection methods combined with 11 models were benchmarked to derive a multivariable predictive model relying on a minimal subset of variables.
Results
Higher cfDNA concentration and high quantities of short fragments (111-240 base pairs (bp)) were associated with poor response and reduced PFS, unlike long fragments (> 300 bp). The proportion of fragments longer than 1650 bp exhibited the strongest association, with non-EP odds ratio = 0.39 [95% CI: 0.25-0.62] and PFS hazard ratio = 0.54 [95% CI: 0.42-0.68]. Unsupervised learning identified four patient clusters significantly associated with EP (p=0.004, Pearson’s Chi-squared test) and PFS (p=0.001, log-rank test). The multivariable machine learning analysis identified a subset of nine variables that shown greater performances in a logistic regression model:$$AUC_{signature}=88.5±3.3\%$$ EP positive predictive value $$PPV_{signature}=69.4±7.49\%$$ compared to single marker $$AUC_{R_{[>1650]}}=73.6±3.70\%$$ $$PPV_{R_{[>1650]}}=55.8±7.46\%$$ $$AUC_{NLR}=68.9±5.02\%$$ $$PPV_{NLR}=52.6±8.75\%$$.
Conclusion
cfDNA size profiles significantly associated with progression and PFS during ICI, outperforming the routinely used markers.
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