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Article

Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma

1
Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA
2
Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA
3
School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90024, USA
4
Inivata, Cambridge CB21 6GS, UK
5
Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD 20892, USA
6
Liquid Diagnostics LLC, San Clemente, CA 92673, USA
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EZLife Bio Inc., Los Angeles, CA 91324, USA
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Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA
9
Biostatistics and Data Management Section, NCI, NIH, Bethesda, MD 20892, USA
*
Authors to whom correspondence should be addressed.
Current address: Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC 20007, USA.
Current address: Bristol-Meyers Squibb, Lawrence Township, NJ 08648, USA.
Academic Editor: Álvaro González
Cancers 2021, 13(13), 3342; https://doi.org/10.3390/cancers13133342
Received: 31 May 2021 / Revised: 24 June 2021 / Accepted: 29 June 2021 / Published: 3 July 2021
(This article belongs to the Collection Cancer Biomarkers)
ctDNA assay is a promising non-invasive method to detect genomic alterations associated with lung cancer. In this prospective study of 25 patients with EGFR-mutant lung adenocarcinoma receiving osimertinib, ctDNA progression predated radiographic progression by 118 days in 11 of 20 patients with disease progression. Saliva-based ctDNA analysis and plasma NGS detected additional patients with ctDNA progression preceding clinical progression, suggesting the potential complementary roles of different ctDNA detection methodologies. Baseline mutant ctDNA level predicted progression-free survival while tumor volume measurements by volumetric CT did not. Serial ctDNA analysis of plasma and saliva is a clinically useful tool to monitor response and resistance to osimertinib.
Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles. View Full-Text
Keywords: ctDNA; EGFR; osimertinib; NSCLC ctDNA; EGFR; osimertinib; NSCLC
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Figure 1

MDPI and ACS Style

Kim, C.; Xi, L.; Cultraro, C.M.; Wei, F.; Jones, G.; Cheng, J.; Shafiei, A.; Pham, T.H.-T.; Roper, N.; Akoth, E.; Ghafoor, A.; Misra, V.; Monkash, N.; Strom, C.; Tu, M.; Liao, W.; Chia, D.; Morris, C.; Steinberg, S.M.; Bagheri, H.; Wong, D.T.W.; Raffeld, M.; Guha, U. Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma. Cancers 2021, 13, 3342. https://doi.org/10.3390/cancers13133342

AMA Style

Kim C, Xi L, Cultraro CM, Wei F, Jones G, Cheng J, Shafiei A, Pham TH-T, Roper N, Akoth E, Ghafoor A, Misra V, Monkash N, Strom C, Tu M, Liao W, Chia D, Morris C, Steinberg SM, Bagheri H, Wong DTW, Raffeld M, Guha U. Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma. Cancers. 2021; 13(13):3342. https://doi.org/10.3390/cancers13133342

Chicago/Turabian Style

Kim, Chul, Liqiang Xi, Constance M. Cultraro, Fang Wei, Gregory Jones, Jordan Cheng, Ahmad Shafiei, Trinh Hoc-Tran Pham, Nitin Roper, Elizabeth Akoth, Azam Ghafoor, Vikram Misra, Nina Monkash, Charles Strom, Michael Tu, Wei Liao, David Chia, Clive Morris, Seth M. Steinberg, Hadi Bagheri, David T. W. Wong, Mark Raffeld, and Udayan Guha. 2021. "Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma" Cancers 13, no. 13: 3342. https://doi.org/10.3390/cancers13133342

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