# Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set

Source: https://onco.cc/key-papers/paper-klein-ccga3-mced-validation-ann-oncol-2021/  
OnCo record `paper-klein-ccga3-mced-validation-ann-oncol-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The methylation blood test now sold as Galleri detected half of all cancers and one in six stage I cancers in 4,077 people, while wrongly flagging one healthy person in 200, and named the organ correctly in 89% of positives.

## Summary

The third and final substudy of the Circulating Cell-free Genome Atlas validated a multi-cancer early detection test using cell-free DNA methylation sequencing with machine learning in 4,077 participants (2,823 cancer, 1,254 non-cancer confirmed at one year). Specificity for cancer signal detection was 99.5%; overall sensitivity was 51.5%, rising by stage (I 16.8%, II 40.4%, III 77.0%, IV 90.1%). Stage I to III sensitivity was 67.6% in 12 pre-specified cancers accounting for about two-thirds of US cancer deaths and 40.7% across all cancers. Cancer signals were detected across more than 50 cancer types and accuracy of cancer signal origin prediction was 88.7%.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Annals of Oncology
- Year: 2021
- DOI: 10.1016/j.annonc.2021.05.806
- Authors: Klein EA, Richards D, Cohn A, et al.
- Findings: Specificity 99.5%; overall sensitivity 51.5%.; Stage I sensitivity 16.8%; stage IV 90.1%.; Cancer signal origin correct in 88.7% of true positives.
- What it means: Methylation-based screening is real but weakest exactly where pancreatic cancer needs it, at stage I, which is why high-risk surveillance rather than population screening carries the field here.
- Caveats: Case-control validation, not a screening population.; Pancreas-specific stage I sensitivity is not given in the abstract.

## Sources

- Klein et al., Ann Oncol 2021: CCGA3 validation of the Galleri methylation test in 4,077 participants: https://doi.org/10.1016/j.annonc.2021.05.806
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34176681/

## Connected records

- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Cell-free DNA methylation tests](https://onco.cc/technologies/cfdna-methylation-testing/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Multi-cancer early detection (MCED)](https://onco.cc/technologies/mced/)
- drugs: [Galleri](https://onco.cc/drugs/galleri/)
- companies: [GRAIL](https://onco.cc/companies/grail/)
- terms: [CCGA: the Circulating Cell-free Genome Atlas behind the Galleri methylation test](https://onco.cc/terms/ccga-study/), [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/)
- journals: [Annals of Oncology](https://onco.cc/journals/annals-of-oncology/)

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