Gastric Cancer. 2025;28(4):620-630.

Pairwise analysis of plasma cell-free DNA before and after palliative second-line paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer.

, , , , , , , , , , , , , , ,

제1저자 김지원, 경동수 · 교신저자 이근욱

PMID 40148708 PMC12174237 DOI 10.1007/s10120-025-01604-y IF 6.1 소화기내과

소속 (5)

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-Ro-173-Beon-Gil, Bundang-Gu, Seongnam, 13620, Republic of Korea.
IMBdx, Inc., 131 Gasandigital-1-Ro, Geumcheon-Gu, Seoul, 08506, Republic of Korea.
Biomedical Research Institute, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-Ro-173-Beon-Gil, Bundang-Gu, Seongnam, 13620, Republic of Korea.
Department of Statistics, Hankuk University of Foreign Studies, 81 Oedae-Ro, Cheoin-Gu, Yongin, 17035, Republic of Korea.
Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-Ro-173-Beon-Gil, Bundang-Gu, Seongnam, 13620, Republic of Korea. hmodoctor@snubh.org.

Abstract

BACKGROUND This study compared plasma cell-free DNA (cfDNA) and tumor tissue DNA (ttDNA) to explore the clinical applicability of cfDNA in patients with metastatic gastric cancer (mGC) receiving palliative second-line paclitaxel + ramucirumab treatment.

METHODS Targeted sequencing of 106 genes was conducted using germline DNA and cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA). The results were compared with those of ttDNA-based cancer panel data.

RESULTS Of 76 consecutive patients, 46 (27 males; median age 57.5 [range, 32-73] years) who had all three samples were included. Combined analysis of ttDNA and baseline-cfDNA revealed that TP53 (58.7%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.0%). For these genes, the sensitivity and positive predictive value of baseline-cfDNA over ttDNA were 71.8% and 51.9%, respectively. When baseline-cfDNA and PD-cfDNA results were combined, 34 patients (73.9%) were found to have additional mutations compared with ttDNA results alone. PD-cfDNA analysis revealed 14 novel pathogenic mutations in ten patients (21.7%). At baseline, patients with a high circulating tumor DNA fraction concentration showed a significantly shorter progression-free survival (PFS) (P = 0.016) in univariable and multivariable analyses. High maximal variant allele frequency (VAF) (P = 0.022), high sum of VAF (P = 0.028), and high TP53 VAF (P = 0.022) were associated with worse PFS in univariable analysis.

CONCLUSIONS Although cfDNA alone cannot replace ttDNA entirely, cfDNA analysis revealed additional mutations. Notably, PD-cfDNA analysis revealed novel pathogenic mutations that emerged during treatment. Moreover, the baseline circulating tumor DNA fraction concentration and VAF values were associated with longer PFS.

Keywords

Anti-cancer therapyCell-free DNACirculating tumor DNAClonal evolutionGastric cancer

Figures

**Fig. 1** Oncoplot of 46 patients with gastric cancer. For each gene, each patient had two boxes denoting different sample types: ttDNA (upper box) and cfDNA at baseline and PD (lower box). Vertical bar plots at the top and right show the number of mutations with different colors representing different sample types. *SNV* single nucleotide variant, *CNV* copy number variation, PD progressive disease, *MSI* microsatellite instability, *MSS* microsatellite stable, *MSI-H* microsatellite instability-high, *VAF* variant allele frequency, *cfDNA* cell-free DNA, *ttDNA* tumor tissue DNA

**Fig. 2** Clonal evolution dynamics before and after the treatment. A Variant allele frequency values of ttDNA, baseline-cfDNA, and PD-cfDNA were visualized in eight patients harboring single nucleotide variants and small indels: GC025, GC050, GC058, GC070, GC085, GC099, GC116, and GC177. B Copy number values of ttDNA, baseline-cfDNA, and PD-cfDNA were visualized in three patients harboring copy number variations: GC047, GC081, and GC116. PD progressive disease, *ttDNA* tumor tissue DNA, *cfDNA* cell-free DNA

**Fig. 3** PFS according to DNA concentration and VAF. A Patients with a high cfDNA concentration (> 17.27 ng/µL) tended to have shorter PFS (P = 0.0502). B Patients with a high ctDNA concentration (> 4.38 ng/µL) at 110–160 bp had significantly shorter PFS (P = 0.016). C Among patients with any mutations in the baseline-cfDNA (N = 36), those with higher maximal VAF values (> 0.1045) demonstrated significantly worse PFS (P = 0.022). D Patients with a higher sum of VAF values (> 0.2071) had significantly shorter PFS (P = 0.028). E Among patients harboring *TP53* mutations (N = 24), those with high *TP53* VAF values (> 0.1014) showed significantly worse PFS (P = 0.022). PD progressive disease, *cfDNA* cell-free DNA, *PFS* progression-free survival

그림 출처: PubMed Central 공개 논문 (PMC12174237)

Conflict of interest statement

Declarations. Conflict of interest: Kyung DS, Ko WY, and Kim H-P are employees of IMBdx, Inc. The other authors declare no conflicts of interest.

그 밖의 정보