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

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

NCT04932525.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

STING trial was supported by Prism-National Precision Medicine Center in Oncology funded by the France 2030 program and the French National Research Agency (ANR) under grant No. ANR-18-IBHU-0002.

Disclosure

M. Tagliamento: Non-Financial Interests, Member, International Lung Cancer Foundation Fellow: IASLC; Non-Financial Interests, Member, Lung Cancer Group: EORTC; Other, Travel and accommodation expenses: Eli Lilly. M.R. Ghigna: Financial Interests, Institutional, Advisory Board: MSD. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, prIME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre; Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. L. Pasquina, R. Madison, G. Oxnard: Financial Interests, Personal, Full or part-time Employment: Foundation medicine; Financial Interests, Personal, Stocks or ownership: Roche Holding AG. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.