Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer

Moding, Everett J.; Liu, Yufei; Nabet, Barzin Y.; Chabon, Jacob J.; Chaudhuri, Aadel A.; Hui, Angela B.; Bonilla, Rene F.; Ko, Ryan B.; Yoo, Christopher H.; Gojenola, Linda; Jones, Carol D.; He, Jianzhong; Qiao, Yawei; Xu, Ting; Heymach, John V.; Tsao, Anne S.; Liao, Zhongxing; Gomez, Daniel R.; Das, Millie; Padda, Sukhmani K.; Ramchandran, Kavitha; Neal, Joel W.; Wakelee, Heather A.; Loo, Billy W.; Lin, Steven H.; Alizadeh, Ash A.; Diehn, Maximilian

doi:10.1038/s43018-019-0011-0

Cited by 246 publications

(210 citation statements)

References 27 publications

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“…This study prospectively evaluated the value of ctDNA kinetics as a therapeutic biomarker during ICB treatment on a large scale. Previously, smaller studies and retrospective analyses have shown consistent findings that early on-treatment reduction in ctDNA levels identifies a favorable risk subset of patients treated with ICB [13][14][15][16][17][18][19][20][21] . Due to the size and mature follow up of our study, we were able to evaluate the generalizability of our findings across the predefined INSPIRE cohorts (SCCHN, TNBC, HGSOC, malignant melanoma and MST).…”

Section: Discussionmentioning

confidence: 75%

“…Despite its potential, ctDNA has not yet been clinically implemented for patients treated with ICB 12 . Proof-of-principle studies suggest that ctDNA quantification and on-treatment changes could assist in prognostication and response monitoring [13][14][15][16][17][18][19][20][21] , but the robustness of these findings have been limited by small cohort sizes, heterogeneous treatment regimens and variable ctDNA detection methodologies.…”

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confidence: 99%

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Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab

et al. 2020

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Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab

et al. 2020

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“…All will guide administration of EGFR-Tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib to lung cancer patients [18]. (iii) Surrogates of therapeutic efficacy: ctDNA dynamics is able to predict benefit of immunotherapy [54] and may also correlate with chemoradiation efficacy in lung cancer patients [55]. (iv) Identification of localized lung cancer at high risk of disease relapse: compared to conventional histopathological criteria in identifying post-therapeutic localized lung cancer patients suitable for personalized adjuvant therapeutic setting, cancer personalized profiling by deep sequencing (CAPP-seq) ctDNA analysis is able to detect post-surgical minimal or molecular residual disease (MRD), thereby identifying patients bearing the lowest disease burden eligible for adjuvant therapy [21,56].…”

Section: Clinical Application Of Ctdnamentioning

confidence: 99%

Liquid Biopsy Analysis of Circulating Tumor Biomarkers in Lung Cancer

Lin¹

2021

Lung Cancer - Modern Multidisciplinary Management

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Risk stratification, prognostication and longitudinal monitoring of therapeutic efficacy in lung cancer patients remains highly challenging. It is imperative to establish robust surrogate biomarkers for identifying eligible patients, predicting and effectively monitoring clinical response as well as timely detecting emerging resistance to therapeutic regimens. Circulating tumor biomarkers, analyzed by liquid biopsy, are primarily composed of nucleic acid-based circulating tumor DNA (ctDNA) and an aneuploid cell-based category of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs). Unlike ctDNA, cancer cells are the origin of all categories of various tumor biomarkers. Involvement of aneuploid CTCs and CTECs in tumorigenesis, neoangiogenesis, tumor progression, cancer metastasis and post-therapeutic recurrence has been substantially investigated. Both CTCs and CTECs possessing an active interplay and crosstalk constitute a unique category of cellular circulating tumor biomarkers. These cells concurrently harbor the intact cancer-related genetic signatures and full tumor marker expression profiles in sync with disease progression and therapeutic process. Recent progress in clinical implementation of non-invasive liquid biopsy has made it feasible to frequently carry out ctDNA analysis and unbiased detection of a full spectrum of non-hematologic circulating rare cells including CTCs and CTECs in lung cancer patients, regardless of variation in heterogeneous cell size and cancer cell surface anchor protein expression. In situ phenotypic and karyotypic comprehensive characterization of aneuploid CTCs and CTECs, in combination with single cell-based genotyping and improved ctDNA analyses, will facilitate and benefit multidisciplinary management of lung cancer.

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“…Fusions [85] as well as deficiencies in the splicing machinery [86] also induce neoantigen release and their detection in cfDNA might be an alternative indirect correlate for immunogenicity in plasma. In contrast to the quantitative assessment of mutant fragments in plasma as blood TMB, the level of cfDNA itself was proposed as early monitoring marker under ICI treatment, since the dynamic changes in cfDNA quantities might predict long-term outcome [87, 88].…”

Section: Genomic Markersmentioning

confidence: 99%

Liquid Biopsies to Evaluate Immunogenicity of Gynecological/Breast Tumors: On the Way to Blood-Based Biomarkers for Immunotherapies

Keup

Kasimir‐Bauer

2020

Breast Care

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Background: Despite the assumption of breast cancer (BC) as a cold, non-immunogenic tumor, immune checkpoint inhibitor (ICI) therapy is favorable for a subgroup of patients. Immunohistochemical assessment of the programmed cell death ligand 1 (PD-L1) is the only approved companion diagnostic for anti-PD-L1 therapy in metastatic triple-negative BC; however, challenges regarding the standardization of PD-L1 scoring in tumor tissue still remain. Consequently, to select patients most likely to respond to ICI, blood-based biomarkers are urgently needed. Summary and Key Messages: Liquid biopsy, comprising circulating immune cells, circulating tumor cells and extracellular vesicles, as well as their surface proteins, is of high potential, and these analytes were already shown to be molecular correlates or regulators of the evasion from antitumoral immune reaction. Liquid biopsy, also enabling the evaluation of tumor mutational burden (TMB), microsatellite instability, and the T-cell receptor repertoire, allows serial sampling for monitoring purposes and reflects intra-tumoral heterogeneity which qualifies as marker for immunogenicity. Only a very few studies have already elucidated the potential of these analytes as biomarkers under ICI therapy. Nonetheless, the topic is of growing interest and has high relevance for the future. However, for clinical implementation, these multifarious analytes first need to pass robust standardization and validation procedures.

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Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer

Cited by 246 publications

References 27 publications

Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab

Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab

Liquid Biopsy Analysis of Circulating Tumor Biomarkers in Lung Cancer

Liquid Biopsies to Evaluate Immunogenicity of Gynecological/Breast Tumors: On the Way to Blood-Based Biomarkers for Immunotherapies

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