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PO.CL01.07 · 临床研究

Analytical and clinical sensitivity of tumor-informed and tumor-naïve ctDNA residual disease detection during neoadjuvant immune checkpoint inhibition in resectable cancers

海报缩略图：Analytical and clinical sensitivity of tumor-informed and tumor-naïve ctDNA residual disease detection during neoadjuvant immune checkpoint inhibition in resectable cancers
编号 1129 展板 10 时间 4/19 02:00–05:00 区域 Section 44 主讲 Paul Lee, BS
分会场 Liquid Biopsies: Circulating Nucleic Acids 1
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作者与单位

Paul K. Lee1, Blair V. Landon1, Ezgi Oner1, Jaime Wehr1, Qiong Meng1, Amna Jamali1, Mimi Najjar2, Gavin Pereira1, Samira Hosseini-Nami1, Rachel Keogh1, Chen Hu1, Ronan J. Kelly3, Joshua E. Reuss4, Patrick M. Forde5, Mark Sausen6, Vincent K. Lam1, Robert B. Scharpf1, Noushin Niknafs1, Valsamo (Elsa) Anagnostou1

1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD,2Cleveland Clinic, Cleveland, OH,3Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX,4Department of Hematology/Oncology, Georgetown University, Washington, DC,5Trinity St. James’s Cancer Institute, Trinity College Dublin, Dublin, Ireland,6Labcorp, Baltimore, MD

摘要 Abstract

Background: Circulating tumor DNA (ctDNA) has become a key biomarker for minimally invasive detection of residual disease during neoadjuvant immunotherapy. However, its integration into routine clinical decision-making remains limited by modest sensitivity and the practical constraints of current assays. Methods: We performed multi-modality matched tumor, white blood cell (WBC), and cell-free DNA (cfDNA) next-generation sequencing (NGS) of 520 biospecimens (56 tumor, 105 WBC, 359 plasma) from 32 patients with operable gastroesophageal (GE) cancer (NCT03044613) and 30 patients with resectable pleural mesothelioma (PM; NCT03918252). ctDNA residual disease analyses were performed at baseline, before each cycle of neoadjuvant immunotherapy, and preoperatively. For the tumor-informed approach, whole genome sequencing (WGS) data of matched tumor, WBC, and cfDNA (80x, 40x, and 30x coverage) were integrated through a random forest machine learning model and calibrated using a reference set of noncancerous cfDNA to determine cfDNA tumor fraction (TF). In parallel, we performed orthogonal tumor-naïve, fixed-gene-panel targeted error-correction NGS of cfDNA and WBC (30,000x), filtering germline and clonal hematopoiesis variants. Results: Overall, the tumor-informed assay showed significantly higher sensitivity, evidenced by a higher ctDNA detection rate at all evaluated timepoints compared to the tumor-naïve assay. In the GE cohort, the tumor-informed assay detected ctDNA for 22 of 25 (88%), 20 of 25 (80%), 18 of 26 (69%), and 5 of 21 (24%) patients at baseline, cycle 2, cycle 3, and preoperatively, respectively. By contrast, 13 of 30 (43%), 12 of 30 (40%), 11 of 30 (37%), and 5 of 25 (20%) had detectable ctDNA by the tumor-naïve assay at corresponding timepoints. In detectable cases, cfDNA TFs were highly concordant between approaches (R = 0.85, p < 0.001). In the PM cohort, 12 of 26 (46%), 11 of 25 (44%), 7 of 21 (33%), and 13 of 25 (52%) had ctDNA detected by the tumor-informed assay at baseline, cycle 2, cycle 3, and preoperatively, respectively. Having demonstrated higher analytical sensitivity with the tumor-informed approach in the GE cohort, we applied the tumor-naïve approach only in cases with detectable ctDNA by the tumor-informed assay. Of these, 6 of 14 (43%), 6 of 13 (46%), 5 of 8 (63%), and 7 of 15 (47%) had ctDNA detected at corresponding timepoints. cfDNA TFs were concordant at timepoints when ctDNA was detectable by both approaches (R = 0.63, p = 0.002). Tumor-informed ctDNA residual disease preoperatively was associated with shorter progression-free survival (log-rank, p = 0.0059). Conclusion: Tumor-informed WGS-based liquid biopsies reliably measure ctDNA residual disease during neoadjuvant immunotherapy, demonstrating greater sensitivity compared to a tumor-naïve approach, supporting their clinical value.
利益披露 Disclosure
P. K. Lee, None.. B. V. Landon, None.. E. Oner, None.. J. Wehr, None.. Q. Meng, None.. A. Jamali, None.. M. Najjar, None.. G. Pereira, None.. S. Hosseini-Nami, None. R. Keogh, Merck Sharp & Dohme Travel. C. Hu, Belay Diagnostics Other, Consultant. Johnson & Johnson Other, Consultant. R. J. Kelly, Astellas Other, Consultant. AstraZeneca Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Daiichi Sankyo Other, Consultant. Eisai Other, Consultant. Eli Lilly ), Other, Consultant. EMD Serono Other, Consultant. Exact Sciences Other, Consultant. Grail Other, Consultant. Ipsen Other, Consultant. Merck Other, Consultant. Novartis Other, Consultant. Novocure Other, Consultant. Phillips Other, Consultant. Takeda Other, Consultant. Toray Other, Consultant. Amgen Other, Consultant. Beigene Other, Consultant. Cardinal Health Other, Consultant. Exact Sciences, Illumina, OncoHost Other, Consultant. J. E. Reuss, AstraZeneca ), Other, Consultant. Bristol Myers Squibb Other. Daiichi Sankyo Other, Consultant. Seagen Other, Consultant. Gilead Other, Consultant. Janssen Other, Consultant. Novocure Other, Consultant. Regeneron ), Other, Consultant. Summit Therapeutics Other, Consultant. Pfizer Other, Consultant. Lilly Other, Consultant. Natera Other, Consultant. Merck Other, Consultant. EMD Serono Other, Consultant. Genentech/Roche ), Other, Consultant. Boehringer Ingelheim Other, Consultant. Verastem ). Nuvalent ). Arcus ). Revolution Medicines, Amgen, Duality Bio ). P. M. Forde, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. Novartis ), Other, Consultant. Regeneron ), Other, Consultant. Kyowa ). BioNTech ), Other, Consultant. AbbVie Other, Consultant. Amgen Other, Consultant. Ascendis Other, Consultant. ChromaCode Other, Consultant. Daiichi Sankyo Other, Consultant. F-Star Other, Consultant. Genelux Other, Consultant. Gilead Other, Consultant. Gilead Other, Consultant. iTeos Other, Consultant. Novocure Other, Consultant. Tavotek Other, Consultant. Teva, Genentech, Sanofi, Surface, Janssen, G1, Merck Other, Consultant. Polaris, Flame Other, Data and Safety Monitoring Board. M. Sausen, Labcorp Employment, Stock. V. K. Lam, Anheart Therapeutics Other, Consultant. Takeda Other, Consultant. Seattle Genetics ), Other, Consultant. Bristol Myers Squibb ), Other, Consultant. AstraZeneca ), Other, Consultant. Guardant Health Other, Consultant. GlaxoSmithKline ). Merck ). Iovance Biotherapeutics Other, Consultant. R. B. Scharpf, Delfi Diagnostics Stock, Patent, Other, Founder, Consultant. Artemyx Stock, Other, Founder, Consultant. N. Niknafs, None. V. Anagnostou, AstraZeneca ), Other, Consultant. Bristol Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Consultant. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. ThermoFisher Other, Honoraria. Guardant Health Other, Honoraria.

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