PO.CL01.15 · 临床研究
Early ctDNA quantification by ctFE outperforms Max VAF for survival stratification across locally advanced and oligometastatic NSCLC treated with radiotherapy
作者与单位
摘要 Abstract
Background: Personalizing chemoradiotherapy (chemoRT) for locally advanced non-small cell lung cancer (LA-NSCLC) is limited by the lack of early biomarkers that inform response during treatment. Current circulating tumor DNA (ctDNA) molecular residual disease assays predict post-treatment outcomes but lack mid-treatment utility. ctDNA burden estimation has traditionally relied on variant-centric metrics such as maximum variant allele fraction (Max VAF), which rely on mutation-specific signals and may be confounded by histology-dependent shedding variability, allelic imbalance, and clonal hematopoiesis. Here we present circulating tumor fraction estimate (ctFE), a machine-learning composite score that integrates VAF distributions, copy-number alterations, and germline B-allele frequency deviations to approximate global tumor burden using a widely available, tumor-naïve clinical platform.
Methods: A burden-based ctFE threshold was derived using pre-treatment plasma from a prospective phase II clinical trial of MR-guided hypofractionated chemoRT (LA-WU, n=26), locked, and applied unchanged to early mid-treatment samples (day 10-14). To test scalability and generalizability, its prognostic performance was validated in two real-world cohorts: 94 LA-NSCLC patients receiving definitive chemoRT (LA-RW) and 309 oligometastatic NSCLC patients receiving consolidative RT (OM-RW). ctFE and Max VAF were compared as continuous predictors across cohorts.
Results: ctFE consistently outperformed Max VAF. In LA-WU, pre-treatment ctFE was associated with overall survival (OS HR=1.15, p=0.04) and progression-free survival (PFS HR=1.84, p=0.009), whereas Max VAF was not. Mid-treatment ctFE remained prognostic for PFS (HR=1.14, p=0.026). Early ctFE dynamics defined three molecular response groups with marked OS separation: consistently low, responder, and nonresponder groups (median OS 60.8 vs 13.0 vs 2.9 months, respectively; p<0.001). In multivariable models including both biomarkers, higher ctFE remained independently associated with worse survival in LA-RW (OS HR=1.88, p=0.010) and OM-RW (OS HR=1.37, p=0.040; PFS HR=1.45, p=0.008), whereas Max VAF did not. The locked ctFE threshold stratified OS across all cohorts (LA-WU HR=5.93; LA-RW HR=9.08; OM-RW HR=2.26; all p<0.001).
Conclusion: ctFE provides clinically meaningful pre- and mid-treatment risk stratification and consistently outperforms Max VAF across locally advanced and oligometastatic NSCLC cohorts. We show that ctFE is a biologically informative, clinically generalizable and scalable ctDNA burden metric measurable using a tumor-naïve, off-the-shelf assay, supporting its practical utility in biomarker-adapted radiotherapy strategies.
利益披露 Disclosure
A. Hashmi, None..
J. Linford, None.
P. S. Chauhan,
Cancer related biomarker Patent.
K. Parikh,
Mayo Clinic Employment.
Mayo Clinic CCATS ).
ASCO Conquer Cancer Foundation ).
ImmunityBio Independent Contractor.
AstraZeneca Independent Contractor.
Rigel Independent Contractor.
DAVA Independent Contractor.
Regeneron Independent Contractor.
OncLive Other, Educational faculty/speaker honoraria.
Curio Other, Educational faculty/speaker honoraria.
Ideology Other, Educational faculty/speaker honoraria.
CEA Other Intellectual Property, Educational faculty/speaker honoraria.
R. Ben-Shachar,
Tempus Labs AI, Inc. Employment, Stock.
J. Guittar,
Tempus AI Employment, Stock Option.
M. Pillai,
Tempus AI Employment, Stock Option.
J. Patel,
Tempus Labs AI, Inc. Employment, Stock.
M. Bergsagel, None.
N. P. Semenkovich,
N/A Patent, Other Intellectual Property.
Acuta Capital Management Independent Contractor.
K. R. Olivier,
PurMinds Neuropharma (via Mayo Clinic Ventures) ), Other Intellectual Property, Other, Relationship with potential future royalties related to psychedelic therapy development.
UpToDate Other, Honorarium.
S. S. Park,
NCI (R21 CA259236) ).
Mayo Lawrence W. and Marilyn W. Matteson Fund ).
NaNotics Independent Contractor, ), Other, Honoraria.
D. Owen,
AstraZeneca ).
Varian ).
UpToDate Other, Honorarium.
D. M. Routman,
RadOncQuestions.com, LLC Independent Contractor, Other, Paid educational content/question bank work.
K. N. Lee, None..
A. D. Sherry, None.
A. S. Mansfield,
Novartis ).
Verily ).
Antoni van Leeuwenhoek Kanker Instituut Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
AXIS Medical Education Inc Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
BeiGeneChugai Pharmaceutical Co Ltd Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Chugai Pharmaceutical Co Ltd Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Ideology Health LLC Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Immunocore Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Intellisphere LLC Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Janssen Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
Johnson & Johnson Global Services Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
MJH Life Sciences Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
University of Miami Int’l Mesothelioma Symposium Other, Support for educational/meeting activities (typically honoraria/travel/meeting support).
AbbVie Independent Contractor.
AstraZeneca Independent Contractor.
Bristol Myers Squibb (BMS) Independent Contractor.
Genentech Independent Contractor.
Gilead Independent Contractor.
Janssen Independent Contractor.
Sanofi Genzyme Independent Contractor.
D. Morgensztern,
Celgene Independent Contractor.
BMS Independent Contractor.
BMS Independent Contractor.
R. Govindan,
Merck Independent Contractor.
Inivata Independent Contractor.
C. G. Robinson,
Radialogica g., Board of Directors, non-salaried role), Other Business Ownership.
Varian Medical Systems Independent Contractor.
AstraZeneca Independent Contractor.
EMD Serono Independent Contractor.
Quantaras Independent Contractor.
Not specified (patent filings related to cardiac arrhythmia treatment) Patent, Other Intellectual Property.
Varian Medical Systems ).
Merck ).
C. Bergom,
National Institutes of Health ).
Susan G. Komen Foundation ).
Innovation Pathways ).
S. N. Waqar,
SWOG–Clinical Trials Partnership ).
AstraZeneca Independent Contractor.
AbbVie Inc ).
Ariad Pharmaceuticals ).
Genentech ).
Millennium Pharmaceuticals Inc ).
Immunomedics, Inc. ).
Roche ).
Astellas Pharma Inc ).
Daiichi Sankyo ).
Cullinan Pearl ).
Verastem Inc ).
GlaxoSmithKline (GSK) ).
Janssen Research & Development LLC ).
Elevation Oncology ).
Loxo Oncology ).
Takeda Pharmaceuticals ).
B. Pellini Ferreira,
Bristol Myers Squibb (BMS) ), Travel, Other, Steering committee member.
BMS Foundation / Robert A. Winn Diversity in Clinical Trials Awards Program Independent Contractor, ).
Merck ), Other, Speaker honoraria.
AstraZeneca Independent Contractor, Other, Speaker honoraria.
Amgen Other, Speaker honoraria.
Boehringer Ingelheim Other, Speaker honoraria.
Foundation Medicine Independent Contractor, Other, Speaker honoraria.
Regeneron Independent Contractor, Travel, Other, Speaker honoraria.
Oncohost Independent Contractor, Other, Speaker honoraria.
Binaytara Foundation Other, Speaker honoraria.
MJH Life Sciences Other, Speaker honoraria.
Intellisphere LLC Other, Speaker honoraria.
Bayer Independent Contractor.
Catalyst Independent Contractor.
Gilead Independent Contractor, Travel.
Guardant Health Independent Contractor.
Illumina Independent Contractor.
Merus Independent Contractor.
MSD Travel.
G. R. Vlacich, None.
A. A. Chaudhuri,
Droplet Biosciences Stock, Other Business Ownership, Other Intellectual Property.
Tempus AI Independent Contractor, Other Business Ownership, ), Other Intellectual Property.
LiquidCell Dx g., Board of Directors, non-salaried role), Other Business Ownership, Other Intellectual Property.
Biocognitive Labs Other Business Ownership, Other Intellectual Property.
Geneoscopy Independent Contractor, Stock Option.
Roche Independent Contractor, ), Other, Honoraria.
NuProbe Independent Contractor.
Illumina Independent Contractor, ).
Invitae Independent Contractor.
Myriad Genetics Independent Contractor.
Daiichi Sankyo Independent Contractor.
AstraZeneca Independent Contractor.
AlphaSights Independent Contractor.
DeciBio Independent Contractor.
Guidepoint Independent Contractor.
Foundation Medicine Other, Honoraria.
Agilent Other, Honoraria.
Binaytara Foundation Other, Honoraria.
Dava Oncology Other, Honoraria.