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. 2025 Jun 3:S1556-0864(25)00751-8.
doi: 10.1016/j.jtho.2025.05.021. Online ahead of print.

Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Patients With Advanced Lung Squamous Cell Carcinoma Receiving Immunochemotherapy or Chemotherapy Alone

Fei Zhou  1 , Jiao Zhang  2 , Shengxiang Ren  3 , Jianhua Chen  4 , Feifei Li  2 , Ting Ma  2 , Yong Fang  5 , Qiming Wang  6 , Wenxiu Yao  7 , Renhua Guo  8 , Dongqing Lv  9 , Shundong Cang  10 , Xiaorong Dong  11 , Huijuan Wang  12 , Nong Yang  13 , Yun Fan  14 , Jiuwei Cui  15 , Ziping Wang  16 , Jianxing He  17 , Yu S Huang  2 , Weizhi Chen  2 , Li-Di Xu  2 , Caicun Zhou  18
Affiliations

Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Patients With Advanced Lung Squamous Cell Carcinoma Receiving Immunochemotherapy or Chemotherapy Alone

Fei Zhou et al. J Thorac Oncol. .

Abstract

Introduction: Although circulating tumor DNA (ctDNA) dynamics have been widely explored for therapeutic response assessment, standardized methodologies remain elusive. Here, we developed MinerVa-Delta, a novel approach to quantify ctDNA dynamics by calculating weighted mutation changes in samples with multiple tracked variants.

Methods: MinerVa-Delta was developed and analytically validated using serially diluted reference samples. The optimal cutoff was determined in a discovery cohort of 227 patients with advanced lung squamous cell carcinoma (LUSC) receiving programmed cell death protein 1 blockade plus chemotherapy or chemotherapy alone and further validated in an independent cohort of 97 patients with LUSC treated with chemotherapy alone. Variants were de novo called in pretreatment samples using a 769-gene next-generation sequencing panel, serving as a basis for personalized variant tracking in posttreatment plasma after two cycles of treatment. We applied MinerVa-Delta to evaluate prognosis and therapeutic response in advanced LUSC.

Results: Patients classified as molecular responders (MinerVa-Delta <30%) exhibited significantly improved outcomes compared with nonresponders (MinerVa-Delta ≥30%), with superior progression-free survival (hazard ratio = 0.19, p < 0.001) and overall survival (hazard ratio = 0.24, p < 0.001). MinerVa-Delta displayed consistent prediction performance in the validation cohort. Furthermore, MinerVa-Delta accurately identified radiologic stable disease patients, a clinically heterogeneous population, who could benefit from initial treatment.

Conclusions: Our findings suggest MinerVa-Delta is feasible for evaluating treatment response in patients with advanced LUSC. Integrating ctDNA profiling with conventional imaging could enhance response assessment, particularly in radiologic stable disease patients, enabling more precise therapeutic decision-making.

Keywords: Chemotherapy; Circulating tumor DNA; Lung squamous cancer; PD-1 blockade; Treatment response.

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Conflict of interest statement

Disclosure Dr. C. Zhou has received honoraria as a speaker for Lily China, Sanofi, Boehringer Ingelheim, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc., Amoy Diagnositics, and is an advisor for Innovent Biologics, Hengrui, Qilu, and TopAlliance Biosciences Inc. Mrs. J. Zhang, Mrs. F. Li, Mrs. T. Ma, Dr. YS. Huang, Dr. L.-D. Xu, and Dr. W. Chen are employees of Genecast Biotechnology Co., Ltd. The remaining authors declare no conflict of interest.