2339P Clinical and genomic correlates of plasma circulating tumor DNA (ctDNA) tumor fraction (TF) in patients with advanced NSCLC

Circulating tumor DNA (ctDNA) tumor fraction (TF) is a promising biomarker for cancer diagnosis, follow-up and prognosis. TF depends on tumor burden (TB) but the correlation is moderate and other biological characteristics may play a role. In this study, we investigate the underlying genomic features affecting the relationship between TF and TB, assessed by PET scan. Patients with NSCLC from the prospective STING trial (NCT04932525) who had both profiling with FoundationOne®LiquidCDx (F1LCDx™) and a PET scan performed within 42 days from either baseline (BL) or at treatment progression (PD) were included in this study. Foundation Medicine’s ctDNA TF on F1LCDx is a composite algorithm prioritizing aneuploidy at higher levels to avoid germline signal and prioritizing variant allele frequency of canonical alterations at lower levels to maximize dynamic range. Tumor burden was calculated with PET scan-derived total metabolic tumor volume (tMTV) with a semi-automated analysis based on a 42% fixed-relative threshold of standardized uptake value (SUV) SUVmax. Genes altered in at least 2.5% of the cohort were evaluated by a multivariate linear regression using gene mutations and rearrangements as covariates and the logarithm of the TF/tMTV ratio as the dependent variable. Of 242 liquid biopsies, 38 lacked clinically relevant variants; tissue molecular characterization was used for 17 of these patients. Overall, tMTV was correlated with TF (rho 0.402, p < 0.0001). No difference was seen between BL or PD (p = 0.997). In the multivariate model, alterations associated with higher TF/tMTV ratio were MLL2 (ß coefficient = 1.45, p = 0.03), PTEN (ß = 1.28, p = 0.045), RBM10 (ß = 1.06, p = 0.046), RB1 (ß = 0.91, p = 0.028), and TP53 (ß = 0.87, p = 0.004). ALK rearrangements (ß = -1.04, p = 0.049) and ATM alterations (ß = -1.46, p = 0.002) were associated with lower shedding. Higher tMTV was seen in patients with STK11 mutation (117 vs 56 cm3, p = 0.001). Alterations in genes implicated in cell cycle regulation, proliferation and apoptosis are associated with the ratio of TF to tMTV assessed by PET scan. ctDNA TF may therefore provide additional clinical utility beyond tumor burden surrogacy to design precise treatment strategy.