Serial Tumor-Agnostic Plasma Profiling with a Compact NGS Panel During First-Line Therapy for Newly Diagnosed Metastatic Colorectal Cancer
4 affiliations
- 1Institute of Personalized Oncology, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- 2City Clinical Hospital Named After S.S. Yudin, Moscow Healthcare Department, 129090 Moscow, Russia
- 3Center of Genetics and Life Sciences, Sirius University of Science and Technology, 354340 Sirius Federal Territory, Russia
- 4Department of Oncology and Palliative Medicine Named After Academician A.I. Savitsky, Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
Abstract
Plasma circulating tumor DNA (ctDNA) profiling may complement tissue hotspot testing and reveal molecular changes during treatment of metastatic colorectal cancer (mCRC). We prospectively studied 39 patients with newly diagnosed unresectable mCRC receiving first-line therapy. Cell-free DNA was collected before treatment and after two and four cycles and analyzed using a 10 kb, 10-gene hybrid-capture sequencing panel with molecular barcodes and error correction. Baseline oncogenic variants were detected in 32 of 35 evaluable patients (91.4%). Compared with routine tissue PCR for shared RAS/BRAF targets, plasma testing showed 84.2% sensitivity (16/19) and 100% specificity (19/19) in the intention-to-test cohort, compared with 88.2% sensitivity (15/17) and 100% specificity (17/17) among technically evaluable samples. Three activating KRAS variants (L19F, A59T, and A146T) lay outside the tissue assays’ target regions; patients carrying these alterations received anti-EGFR therapy. Patients with metastases in two or more organs had more detectable oncogenic alterations than those with one metastatic site (median, three versus two; adjusted q = 0.00184; rank-biserial correlation = 0.687). Serial sampling revealed divergent trajectories of individual variants in nine patients. Early reductions in plasma variant allele frequencies tended to be greater among partial responders, although associations with radiological response were not significant after multiple testing correction. Compact tumor-agnostic plasma sequencing provides complementary molecular information, but its clinical utility requires further validation.
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BibTeX
@article{zakharova2026serial,
title = {{Serial Tumor-Agnostic Plasma Profiling with a Compact NGS Panel During First-Line Therapy for Newly Diagnosed Metastatic Colorectal Cancer}},
author = {Galina Zakharova and Oleg Zauzolkov and Anna Khristichenko and Vladimir Lyadov and Ivan Gaziev and Nina Shaban and Anna Emelyanova and Marina Sekacheva and Marina Lyadova and Anton Buzdin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219633},
url = {https://www.mdpi.com/1422-0067/27/21/9633},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Serial Tumor-Agnostic Plasma Profiling with a Compact NGS Panel During First-Line Therapy for Newly Diagnosed Metastatic Colorectal Cancer
AU - Galina Zakharova
AU - Oleg Zauzolkov
AU - Anna Khristichenko
AU - Vladimir Lyadov
AU - Ivan Gaziev
AU - Nina Shaban
AU - Anna Emelyanova
AU - Marina Sekacheva
AU - Marina Lyadova
AU - Anton Buzdin
PY - 2026
DA - 2026/10/28
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219633
UR - https://www.mdpi.com/1422-0067/27/21/9633
AB - Plasma circulating tumor DNA (ctDNA) profiling may complement tissue hotspot testing and reveal molecular changes during treatment of metastatic colorectal cancer (mCRC). We prospectively studied 39 patients with newly diagnosed unresectable mCRC receiving first-line therapy. Cell-free DNA was collected before treatment and after two and four cycles and analyzed using a 10 kb, 10-gene hybrid-capture sequencing panel with molecular barcodes and error correction. Baseline oncogenic variants were detected in 32 of 35 evaluable patients (91.4%). Compared with routine tissue PCR for shared RAS/BRAF targets, plasma testing showed 84.2% sensitivity (16/19) and 100% specificity (19/19) in the intention-to-test cohort, compared with 88.2% sensitivity (15/17) and 100% specificity (17/17) among technically evaluable samples. Three activating KRAS variants (L19F, A59T, and A146T) lay outside the tissue assays’ target regions; patients carrying these alterations received anti-EGFR therapy. Patients with metastases in two or more organs had more detectable oncogenic alterations than those with one metastatic site (median, three versus two; adjusted q = 0.00184; rank-biserial correlation = 0.687). Serial sampling revealed divergent trajectories of individual variants in nine patients. Early reductions in plasma variant allele frequencies tended to be greater among partial responders, although associations with radiological response were not significant after multiple testing correction. Compact tumor-agnostic plasma sequencing provides complementary molecular information, but its clinical utility requires further validation.
SN - 1422-0067
ER -