Multi Cancer Early Detection by Using Circulating Tumor DNA—The Galleri Test. Reply to Klein et al. The Promise of Multicancer Early Detection. Comment on “Pons-Belda et al. Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics 2021, 11, 2171”

Abstract

We recently published some concerns with new technologies which are based on circulating tumor DNA (ctDNA) for early cancer detection. Most of our published criticism, including a commentary in this journal, has focused on tests developed by the biotechnology company GRAIL (their commercial product is also known as The Galleri Test). Scientists from GRAIL provided explanations and rebuttals to our criticism. They also posed some questions. Here, we reiterate our position and provide rebuttals, explanations and answers to these questions. We believe that constructive scientific debates, like this one, can profoundly contribute to advancements in scientific fields such as early cancer detection.

C. elegans as a Powerful Tool for Cancer Screening

“…Importantly was the notable high sensitivity (100%) at stages 0-I [ 13 ]. This is in stark contrast to blood tumor markers CEA, CA15-3, and CA19-9 or liquid biopsy approach based on cfDNA/ctDNA such as Galleri by GRAIL (16.8% at stage I) ( Figure 2 ) [ 21 , 70 ].…”

“…Looking into more details, in 12 pre-specified cancer, the sensitivity of the test shows a wide variation depending on the cancer type, from 11.2% (prostate), 30.5% (breast), 74.8% (lung), 83.7% (pancreas), and 93.5% (liver/bile-duct) [ 20 ]. As semi-expected for any new technology development, the clinical research data from GRAIL have sparked debate as to whether cfDNA/ctDNA technologies could be practical in the clinic [ 21 ]. Pons-Belda et al emphasized that the most important parameter from the patient and physician’s points of view for a cancer screening test is the positive predictive value of the test (PPV) [ 21 , 22 ].…”

“…As semi-expected for any new technology development, the clinical research data from GRAIL have sparked debate as to whether cfDNA/ctDNA technologies could be practical in the clinic [ 21 ]. Pons-Belda et al emphasized that the most important parameter from the patient and physician’s points of view for a cancer screening test is the positive predictive value of the test (PPV) [ 21 , 22 ]. PPV is the risk value of having cancer if the test is positive.…”

“…PPV is the risk value of having cancer if the test is positive. The PPV depends on three parameters: test sensitivity, specificity, and disease prevalence within the screened population [ 21 ]. Due to technology limitations, Pons-Belda et al argued that screening for cancer using cfDNA/ctDNA would suffer from low sensitivity and low PPV.…”

“…Notably, patterns of volatiles organic compounds (VOCs) are produced by cancer cells and found in urine. A growing number of studies are linking different cancers to either an increase or decrease in levels of VOCs [ 18 , 21 , 26 , 31 , 32 , 33 ]. It is associated with the cancer smell, the end-product of metabolic changes producing patterns of volatile organic compounds (VOCs) observed in cancers [ 34 , 35 , 36 ].…”