Exploring genomic analysis and methylome profiling in longitudinal series of p.G12C KRAS mutated NSCLC patients treated with sotorasib

Aims: in the genomic era, the advent of next generation sequencing (NGS) technologies has rapidly transformed the clinical paradigm of NSCLC patients who could benefit from a wide series of clinically approved biomarker driven therapies. Among them, KRAS p. G12C hotspot mutation became part of the mandatory testing gene panel by electing NSCLC patients to sotorasib. Epigenomic signatures, including hypermethylation of CpGs islands, may be relevant in tailoring therapeutic algorithms in oncogene addicted NSCLC patients. Here we aimed to dynamically track KRAS p. G12C genomic variations by integrating methylation profile in a longitudinal series of n = 91 liquid biopsy samples from n = 22 p. G12C positive NSCLC patients treated with sotorasib. A combined NGS panel (Avida Duo Methyl Reagent Kit, Avida Biomed) simultaneously evaluating n = 105 cancer-related genes and calculating methylation index (MI) score among 3400 differentially methylated regions (DMRs) was adopted, correlating molecular data with clinical outcomes. Overall, exon 2 p. G12C KRAS mutation was detected in 40.9%, 15.8% and 70.6% baseline, T1 and TP samples, respectively. MI was successfully measured in all instances. Of note, exon 2 p. G12C KRAS mutation and MI score highlighted a trend simultaneously moving forward T1 point (r = 0.68, p = 0.06) and TP (r = 0.87, p = 0.000103). Methylation signature may be combined with genomic analysis to personalize therapeutic strategies for KRAS p. G12C mutated NSCLC patients. “Multiomic” analysis of tumor-informative molecular targets (genomic profile, methylation status) lay the basis for dynamic fingerprints of NSCLC patients preventing early relapses and augmenting clinical benefits of targeted therapies.