Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma
<i>Background</i>: 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 EFI...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/13/3342 |
| _version_ | 1797528048540581888 |
|---|---|
| author | Chul Kim 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 Udayan Guha |
| author_facet | Chul Kim 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 Udayan Guha |
| author_sort | Chul Kim |
| collection | DOAJ |
| description | <i>Background</i>: 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. <i>Methods</i>: 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. <i>Results</i>: A total of 25 patients were included. We analyzed 534 samples by ddPCR (<i>n</i> = 25), 256 samples by NGS (<i>n</i> = 24) and 371 samples by eLB (<i>n</i> = 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 <i>EGFR</i> 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. <i>EGFR</i>/<i>ERBB2</i>/<i>MET/KRAS</i> amplifications, <i>EGFR</i> C797S, <i>PIK3CA</i> E545K, <i>PTEN</i> V9del, and <i>CTNNB1</i> S45P were key resistance mechanisms identified by NGS. <i>Conclusion</i>: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles. |
| first_indexed | 2024-03-10T09:52:36Z |
| format | Article |
| id | doaj.art-2f0bc14b4de5496a937750d19c0b4275 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:52:36Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2f0bc14b4de5496a937750d19c0b42752023-11-22T02:36:24ZengMDPI AGCancers2072-66942021-07-011313334210.3390/cancers13133342Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung AdenocarcinomaChul Kim0Liqiang Xi1Constance M. Cultraro2Fang Wei3Gregory Jones4Jordan Cheng5Ahmad Shafiei6Trinh Hoc-Tran Pham7Nitin Roper8Elizabeth Akoth9Azam Ghafoor10Vikram Misra11Nina Monkash12Charles Strom13Michael Tu14Wei Liao15David Chia16Clive Morris17Seth M. Steinberg18Hadi Bagheri19David T. W. Wong20Mark Raffeld21Udayan Guha22Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USALaboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USASchool of Dentistry, University of California, Los Angeles, Los Angeles, CA 90024, USAInivata, Cambridge CB21 6GS, UKSchool of Dentistry, University of California, Los Angeles, Los Angeles, CA 90024, USARadiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD 20892, USALaboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USALiquid Diagnostics LLC, San Clemente, CA 92673, USALiquid Diagnostics LLC, San Clemente, CA 92673, USAEZLife Bio Inc., Los Angeles, CA 91324, USADepartment of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USAInivata, Cambridge CB21 6GS, UKBiostatistics and Data Management Section, NCI, NIH, Bethesda, MD 20892, USARadiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD 20892, USASchool of Dentistry, University of California, Los Angeles, Los Angeles, CA 90024, USALaboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USAThoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA<i>Background</i>: 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. <i>Methods</i>: 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. <i>Results</i>: A total of 25 patients were included. We analyzed 534 samples by ddPCR (<i>n</i> = 25), 256 samples by NGS (<i>n</i> = 24) and 371 samples by eLB (<i>n</i> = 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 <i>EGFR</i> 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. <i>EGFR</i>/<i>ERBB2</i>/<i>MET/KRAS</i> amplifications, <i>EGFR</i> C797S, <i>PIK3CA</i> E545K, <i>PTEN</i> V9del, and <i>CTNNB1</i> S45P were key resistance mechanisms identified by NGS. <i>Conclusion</i>: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.https://www.mdpi.com/2072-6694/13/13/3342ctDNAEGFRosimertinibNSCLC |
| spellingShingle | Chul Kim 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 Udayan Guha Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma Cancers ctDNA EGFR osimertinib NSCLC |
| title | Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma |
| title_full | Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma |
| title_fullStr | Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma |
| title_full_unstemmed | Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma |
| title_short | Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma |
| title_sort | longitudinal circulating tumor dna analysis in blood and saliva for prediction of response to osimertinib and disease progression in egfr mutant lung adenocarcinoma |
| topic | ctDNA EGFR osimertinib NSCLC |
| url | https://www.mdpi.com/2072-6694/13/13/3342 |
| work_keys_str_mv | AT chulkim longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT liqiangxi longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT constancemcultraro longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT fangwei longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT gregoryjones longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT jordancheng longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT ahmadshafiei longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT trinhhoctranpham longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT nitinroper longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT elizabethakoth longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT azamghafoor longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT vikrammisra longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT ninamonkash longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT charlesstrom longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT michaeltu longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT weiliao longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT davidchia longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT clivemorris longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT sethmsteinberg longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT hadibagheri longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT davidtwwong longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT markraffeld longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma AT udayanguha longitudinalcirculatingtumordnaanalysisinbloodandsalivaforpredictionofresponsetoosimertinibanddiseaseprogressioninegfrmutantlungadenocarcinoma |