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CANCER SCREENING & EARLY DETECTION: A methylation based ctDNA assay from GRAIL delivered sensitivity 93% for stage IV cancer, falling to 43% for stage II and 18% for stage I disease


April 14, 2020


CANCER SCREENING & EARLY DETECTION A methylation based ctDNA assay from GRAIL delivered sensitivity 93% for stage IV cancer, falling to 43% for stage II and 18% for stage I disease. Specificity was impressive at 99.3%. If individual cancers sequentially transit stages I to IV, earlier detection will saves lives. However, animal models and human studies suggest this may not always be the case. We are moving closer to pivotal trials that address this.

Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA

M.C. Liu et al

Annals of Oncology DOI: https://doi.org/10.1016/j.annonc.2020.02.011


Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity.

Participants and methods

The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization.


Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%.


cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.


Projected Reductions in Absolute Cancer–Related Deaths from Diagnosing Cancers Before Metastasis, 2006–2015

Christina A. Clarke, Earl Hubbell, Allison W. Kurian, Graham A. Colditz, Anne-Renee Hartman and Scarlett Lin Gomez

CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION Published OnlineFirst March 30, 2020; DOI: 10.1158/1055-9965.EPI-19-1366



New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer–related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages.


We obtained stage-specific incidence and survival data from the Surveillance, Epidemiology, and End


rogram for 17 cancer types for all persons diagnosed ages 50 to 79 years in 18 geographic regions between 2006 and 2015. For a hypothetical cohort of 100,000 persons, we estimated cancer-related deaths under assumptions that cancers diagnosed at stage IV were diagnosed at earlier stages. Results: Stage IV cancers represented 18% of all estimated diagnoses but 48% of all estimated cancer-related deaths within 5 years. Assuming all stage IV cancers were diagnosed at stage III, 51 fewer cancer-related deaths would be expected per 100,000, a reduction of 15% of all cancer-related deaths. Assuming one third of metastatic cancers were diagnosed at stage III, one third diagnosed at stage II, and one third diagnosed at stage I, 81 fewer cancer-related deaths would be expected per 100,000, a reduction of 24% of all cancer-related deaths, corresponding to a reduction in all-cause mortality comparable in magnitude to eliminating deaths due to cerebrovascular disease.


Detection of multiple cancer types earlier than stage IV could reduce at least 15% of cancer-related deaths within 5 years, affecting not only cancer-specific but all-cause mortality.


Detecting cancer before stage IV, including modest shifts to stage III, could offer substantial population benefit.