Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER) : development and independent validation studies
Copyright © 2023. Published by Elsevier Ltd..
BACKGROUND: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas.
PATIENTS AND METHODS: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world.
RESULTS: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance.
CONCLUSION: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
Annals of oncology : official journal of the European Society for Medical Oncology - 34(2023), 5 vom: 01. Mai, Seite 486-495 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Gao, Q [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Biomarkers, Tumor |
|---|
| Anmerkungen: |
Date Completed 02.05.2023 Date Revised 12.05.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.annonc.2023.02.010 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM353551910 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM353551910 | ||
| 003 | DE-627 | ||
| 005 | 20231226060250.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.annonc.2023.02.010 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1178.xml |
| 035 | |a (DE-627)NLM353551910 | ||
| 035 | |a (NLM)36849097 | ||
| 035 | |a (PII)S0923-7534(23)00087-X | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Gao, Q |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER) |b development and independent validation studies |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.05.2023 | ||
| 500 | |a Date Revised 12.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023. Published by Elsevier Ltd. | ||
| 520 | |a BACKGROUND: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas | ||
| 520 | |a PATIENTS AND METHODS: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world | ||
| 520 | |a RESULTS: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance | ||
| 520 | |a CONCLUSION: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cell-free DNA (cfDNA) | |
| 650 | 4 | |a machine learning | |
| 650 | 4 | |a methylation | |
| 650 | 4 | |a multi-cancer early detection | |
| 650 | 7 | |a Cell-Free Nucleic Acids |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 700 | 1 | |a Lin, Y P |e verfasserin |4 aut | |
| 700 | 1 | |a Li, B S |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, G Q |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, L Q |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, B Y |e verfasserin |4 aut | |
| 700 | 1 | |a Lou, W H |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, W C |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, D |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Q L |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Y |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, J M |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, W J |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, P |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, P H |e verfasserin |4 aut | |
| 700 | 1 | |a He, M J |e verfasserin |4 aut | |
| 700 | 1 | |a Qiao, G B |e verfasserin |4 aut | |
| 700 | 1 | |a Chuai, S K |e verfasserin |4 aut | |
| 700 | 1 | |a Zang, R Y |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, T Y |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, L J |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, J |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Q |e verfasserin |4 aut | |
| 700 | 1 | |a Su, X F |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Z D |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, X Q |e verfasserin |4 aut | |
| 700 | 1 | |a Nian, W Q |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, S |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, J |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, S L |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Z H |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Annals of oncology : official journal of the European Society for Medical Oncology |d 1990 |g 34(2023), 5 vom: 01. Mai, Seite 486-495 |w (DE-627)NLM012606308 |x 1569-8041 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2023 |g number:5 |g day:01 |g month:05 |g pages:486-495 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.annonc.2023.02.010 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2023 |e 5 |b 01 |c 05 |h 486-495 | ||