178P - Clinical correlates and impact of ctDNA levels on detecting distinct genomic alteration in patients with metastatic colorectal cancer

Background

Liquid biopsy (LBx) based comprehensive genomic profiling (CGP) is increasingly used in clinical practice. The sensitivity of LBx is influenced by levels of circulating tumor DNA (ctDNA), but limited data is available correlating ctDNA levels with clinical parameters and their effect on detecting distinct genomic alterations in metastatic colorectal cancer (mCRC).

Methods

LBx using FoundationOne Liquid CDx was performed on plasma ctDNA at baseline in patients with RAS/BRAFV600E wild type (WT) mCRC enrolled in the CAPRI-2 GOIM trial.

Results

Among 205 patients with available baseline LBx, median ctDNA tumor fraction (TF) was 25% (range, 0.1-86%). ctDNA TF was higher among patients presenting with isolated liver involvement (n=68, ctDNA 34.5% [IQR 15.0-54.2]) or liver with other metastatic sites (n=90, ctDNA 30.0% [IQR 9.2-56.3]) as compared to those showing only lung (n=11, ctDNA 1.3% [IQR 1.0-2.3]; P<0.001) or lymph nodes involvement (n=13, ctDNA 1.7% [IQR 1.23-37.5]; P<0.001). ctDNA TF positively correlated with higher number of metastatic sites (≥3 anatomical sites: ctDNA 51% [IQR 17-66.5] vs. 1-2 sites: ctDNA 22% [IQR 2.3-49]; P<0.001), albeit only liver involvement (P<0.001) but not the number of anatomical sites (P=0.16) associated with higher ctDNA TF in the multivariable model. Samples showing copy number variants (CNV) showed higher ctDNA TF (LBx amplifications (n=64): ctDNA 45% [IQR 25-58.8] vs. 16% [IQR 1.7-48.5]; P<0.001; LBx deletions (n=12): ctDNA 56% [IQR 46.8-68.2] vs. 25% [IQR 3.3-51.0]; P<0.001), with no deletions and only 4 amplifications detected among samples showing a ctDNA TF below 10%. Patients showing a high Tumor mutational burden (TMB) (n=20) showed a numerical higher ctDNA TF (ctDNA 37.5% [IQR 16.5 vs. 56.4] vs. 28% [IQR 4.05-51.2]; P=0.08), with only one TMB-high case showing a ctDNA TF below 10%.

Conclusions

ctDNA levels depend on metastatic sites, with significantly lower levels in patients without liver involvement. Distinct alteration classes exhibit distinct analytical sensitivity, with CNV requiring higher ctDNA levels for detection.

Editorial acknowledgement

Clinical trial identification

EudraCT 2020-003008-15; NCT05312398.

Legal entity responsible for the study

The authors.

Funding

The CAPRI 2-GOIM clinical trial is partially supported by a research grant from Merck KGaA Italy.

Disclosure

All authors have declared no conflicts of interest.