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. 2025 Aug 4;15(8):1609-1629.
doi: 10.1158/2159-8290.CD-24-1704.

Integrating ctDNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer

Everett J Moding  1   2 , Mohammad Shahrokh Esfahani  2   3 , Cheng Jin  1 , Angela B Hui  1   2 , Barzin Y Nabet  2 , Yufei Liu  4 , Jacob J Chabon  2 , Michael S Binkley  1   2 , David M Kurtz  3 , Emily G Hamilton  2 , Aadel A Chaudhuri  5 , Chih Long Liu  3 , Zhe Li  1 , Rene F Bonilla  1 , Alice L Jiang  1 , Brianna C Lau  1 , Pablo Lopez  4 , Jianzhong He  4 , Yawei Qiao  4 , Ting Xu  4 , Luyang Yao  4 , Saumil Gandhi  4 , Zhongxing Liao  4 , Millie Das  3   6 , Kavitha J Ramchandran  3 , Sukhmani K Padda  3 , Joel W Neal  3 , Heather A Wakelee  3 , Michael F Gensheimer  1 , Billy W Loo Jr  1 , Ruijiang Li  1   2 , Steven H Lin  4 , Ash A Alizadeh  2   3   7 , Maximilian Diehn  1   2   7
Affiliations

Integrating ctDNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer

Everett J Moding et al. Cancer Discov. .

Abstract

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies.

Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534.

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Conflict of interest statement

E.J.M. has served as a paid consultant for Guidepoint and GLG. M.S.E. has served as a paid consultant for Foresight Diagnostics. B.Y.N. is currently an employee and stockholder at Roche/Genentech. A.A.C. has served as an advisor/consultant for Roche, Tempus Labs, Geneoscopy, and Oscar Health, and has received speaker honoraria from Roche, Varian Medical Systems, and Foundation Medicine. M.Das has received research funding from Novartis, Abbvie, United Therapeutics, CellSight, Varian, and Verily and has served as a consultant for Astra Zeneca, Beigene, Sanofi, and Jazz Pharmaceuticals. S.K.P. has received research funding from BioAlta and has served as a consultant for AstraZeneca, Nanobiotix, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Mirati Therapeutics, and Genentech. J.W.N. has served as an advisor/consultant for ARIAD/Takeda, AstraZeneca, Genentech/Roche, Lilly, Exelixis, Loxo, and Jounce. J.W.N. has received research funding from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, ARIAD/Takeda, and Nektar. H.A.W. has served on the advisory board for AstraZeneca, Xcovery, Janssen, Mirati, Merck, Takeda, and Genentech/Roche and has received compensation from AstraZeneca, Xcovery, Janssen, and Mirati. H.A.W. has received research funding from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Xcovery. S.H.L. receives grant funding from STCube Pharmaceuticals, Nektar Therapeutics, and Beyond Spring Pharmaceuticals, has served as a consultant for XRAD Therapeutics, has served on the advisory board for AstraZeneca and Creatv Microtech, and is a co-founder, scientific advisor and has stock options for Scenexo, Inc. A.A.A. and M.Diehn are co-inventors on patent applications related to CAPP-Seq. M.S.E., D.M.K., A.A.A., and M. Diehn are co-inventors on a patent application related to CIRI. M.S.E., J.J.J., D.M.K., A.A.A., and M. Diehn are co-inventors on a patent application related to the SNV score. A.A.A. has equity in CiberMed and Foresight Diagnostics and has served as a consultant for Roche, Genentech, Chugai, and Pharmacyclics. M.Diehn has equity in CiberMed and Foresight Diagnostics, has received research funding from AstraZeneca, Genentech, Illumina, and Varian Medical Systems, and has served as a paid consultant for Roche, AstraZeneca, Novartis, Genentech, Boehringer Ingelheim, BioNTech, Gritstone Oncology, Illumina, and RefleXion. The other authors declare no competing interests.

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