ctDNA-based detection of molecular residual disease in stage I-III non-small cell lung cancer patients treated with definitive radiotherapy.

Background

Sensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT.

Methods

A total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient's plasma samples.

Results

Pre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p<0.0001).

Conclusion

Personalized, longitudinal ctDNA monitoring can detect recurrence early in patients with unresectable NSCLC patients undergoing curative radiation and potentially risk-stratify patients who might benefit most from treatment intensification.

Informations de copyright

Copyright © 2023 Lebow, Shaverdian, Eichholz, Kratochvil, McCune, Murciano-Goroff, Jee, Eng, Chaft, Kris, Kalashnikova, Feeney, Scalise, Sudhaman, Palsuledesai, Malhotra, Krainock, Sethi, Aleshin, Liu, Shepherd, Wu, Simone, Gelblum, Johnson, Rudin, Gomez, Razavi, Reis-Filho, Isbell, Li and Rimner.

Déclaration de conflit d'intérêts

NS reports research funding from Novartis. DG reports research funding from Astra Zeneca and Varian and receives Honoraria from Johnson and Johnson, MedLearning Gropu, and GRAIL. YM-G reports travel, accommodation, and expenses from AstraZeneca and Loxo Oncology/Eli Lilly. She acknowledges honoraria from Virology Education and Projects in Knowledge for a CME program funded by an educational grant from Amgen. She acknowledges associated research funding to the institution from Mirati Therapeutics, Loxo Oncology at Eli Lilly, Elucida Oncology, Taiho Oncology, Hengrui USA, Ltd/Jiangsu Hengrui Pharmaceuticals, Luzsana Biotechnology, and Endeavor Biomedicines. She acknowledges royalties from Rutgers University Press and Wolters Kluwer. She acknowledges food/beverages from Endeavor Biomedicines. YM-G acknowledges receipt of training through an institutional K30 grant from the NIH CTSA UL1TR00457. She has received funding from a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation, endowed by Dr. Charles M. Baum and Carol A. Baum. She is also funded by the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, the Andrew Sabin Family Foundation, the Society for MSK, and a Paul Calabresi Career Development Award for Clinical Oncology NIH/NCI K12 CA184746. JJ has a patent licensed by MDSeq Inc. JC has served as a consultant for Astra Zeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, and Janssen as well as received research funding to her institution from Astra Zeneca, Bristol-Myers Squib, Genentech, and Merck. MGK receives personal fees from Novartis, Sanofi-Genzyme, AstraZeneca, Pfizer, Janssen, and Daiichi-Sankyo. He has also received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, and AstraZeneca. MGK has received travel support from AstraZeneca, Pfizer, and Genentech as well as editorial support from Hoffman La-Roche. EK, JF, CBS, SS, CCP, MMa, MK, HS, AA, and MCL reported employment and stock ownership or option at Natera, Inc outside the submitted work. MCL reported receiving grants funding to Mayo Clinic from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro, and travel support from AstraZeneca, Genomic Health and Ionis, outside the submitted work. AS has stock ownership in ArcellX and Doximity. AW reports research support from CivaTech Oncology, Inc, Honoraria from Nanovi A/S, serves on the Scientific Advisory Board of Simphotek, Inc, and has stock in Simphotek, Inc. CS reports Honoraria from Varian and Novocure and serves in a Leadership position for the Proton Collaborative Group, American Society for Radiation Oncology, NRG Oncology, American Radium Society, and Annals of Palliative Medicine. DG reports research funding to her institution from Merck. CR reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics, outside the submitted work. DG reports grants to his institutions from Varian, AstraZeneca, Merck, and Bristol Myers Squibb, personal fees from Varia, AstraZeneca, Merck, US Oncology, Bristol Myers Squibb, Relfexion, WebMD, Vindico, and Medscape; and has served on the advisory board for AstraZeneca; he has also received Honoraria from Johnson and Johnson, MedLearning Group, and GRAIL. PR received institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences, ArcherDx and Consultation/Ad board/Honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, and Tempus. JR-F is a paid consultant of Goldman Sachs, Paige.AI and REPARE Therapeutics, a member of the Scientific Advisory Board of Goldman Sachs, Paige.AI and Volition RX, and ad hoc member of the scientific advisory board of Roche, Genetech, Roche Tissue Diagnostics, Ventana, Novartis, InVicro and GRAIL. JR-F reports receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Astrazeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the scope of this study. JR-F is funded in part by the Breast Cancer Research Foundation, by a Susan G Komen Leadership grant, and by the NIH/NCI P50 CA247749 01 grant. JI reports equity in LumaCyte, LLC and has served as an uncompensated member of a steering committee for Genentech. BL has served as an uncompensated advisor and consultant to Amgen, Genentech, Boehringer Ingelheim, Lilly, AstraZeneca, Daiichi Sankyo. He has received research grants to his institution from Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health and Bolt Biotherapeutics. He has received academic travel support from MORE Health, and Jiangsu Hengrui Medicine. He is an inventor on two institutional patents at MSK US62/685,057, US62/514,661 and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. AR reports research funding from Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Merck, and Pfizer and serves in Leadership Positions for the International Thymic Malignancies Group and International Mesothelioma Interest group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.