Abstract 369P
Background
In recent years, the exploration of circulating cfDNA has advanced significantly in the realm of cancer biomarker research, allowing a non-invasive evaluation of molecular characteristics of the tumor. More recently, TF, that reflects the proportion of tumor derived DNA on the totality of circulating DNA, has gained momentum as a noninvasive prognostic biomarker, correlating closely with tumor burden and disease aggressiveness. Albeit the cumulative evidences about the prognostic role of TF, little is known about the biology behind it.
Methods
Patients were included in prospective MATCHR study. cfDNA TF was determined using ichorCNA (V0.2.0) on shallow whole genome sequencing (LP-WGS). Total Tumor Volume (TTV) was calculated on CT scan by summing all lesions volume. Plasma proteomics was analysed on a subset of patients with Olink Explore 1536. Whole exome and RNA sequencing were performed on fresh fozen tissue. The absolute copynumber (ACN) profile and the genomic instability score (GIS) were estimated as previously described (PMID36669143). Differentially expressed genes (DEG) were identified on RNA seq data with DESeq2, using sample site and TTV for adjustment and the TF as a continuous variable of interest. The association between plasma proteins quantification, mutations status, TTV, and TF were analysed using linear regression models.
Results
Overall 253 plasma samples from 220 patients were analyzed. 203 had non-squamous histology TF prognostic role was confirmed independently from treatment received (anti pd-1/L1 m chemotherapy, targeted agents). Tumor volume was the major determinant of tumor fraction (rho 0.33, p < 0.001). After accounting for TTV, mutation in EPHA7 (p < 0.001), EP300 and FGFR4 (both p 0.005), MGA (0.02) and TP53 (0.05), as well as an higher degree of genomic instability (p 0.003) and tumor mutation burden (p 0.003) were associated to higher TF. Similarly, RNA sequencing showed suppression of pathways implicated in immune response and DNA repair. In the subset of patients with available plasma proteomics, an higher plasma levels of PARP1 was associated with increased TF after adjustement for TV (p < 0.001).
Conclusions
TF was correlated to TTV but also to higher genomic instability and immune suppression at the tumor level.
Clinical trial identification
NCT02517892
Legal entity responsible for the study
The authors
Funding
French State grant managed by the Agence Nationale de la Recherche, under the third program of investments for the future (PIA), integrated into France 2030, with reference ANR-21-RHUS-0013 (RHU REVEAL)
Disclosure
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, Summit Therapeutics; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. B. Besse: Financial Interests, Institutional, Advisory Board: AbbVie, Biontech SE, Beijing Aviston Biotechnology, Bristol Myer Squibb, CureVac AG, PharmaMar, Sanofi aventis, Regeneron; Financial Interests, Institutional, Expert Testimony: AbbVie, Bristol Myer Squibb, Eli Lilly, Ellipse pharma Ltd, CureVac AG, F.Hoffmann-La Roche Ltd, Foghorn Therapeutics Inc., Genmab, Immunocore, Owkin, Sanofi; Financial Interests, Institutional, Invited Speaker: AbbVie, AstraZeneca, Bristol Myer Squibb, MSD, Daiichi Sankyo, Eli Lilly, Ose Immunotherapeutics, Sanofi, Servier, Ose Immunotherapeutics, Sanofi, Takeda, Genmab, Taiho, AstraZeneca, Amgen, BeiGene, CureVac, Janssen, MSD, PharmaMar, Eli Lilly, Daiichi Sankyo, Enliven, Nuvalent, Ellipsis, Prelude Therapeutics; Non-Financial Interests, Personal, Leadership Role, Chair of the Scientific Chairs Council: EORTC; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Board: IFCT. All other authors have declared no conflicts of interest.