Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm.

Oscar D Pons-Belda,Eleftherios P Diamandis,Amaia Fernandez-Uriarte

doi:10.3390/diagnostics11122171

Oscar D Pons-Belda, Eleftherios P Diamandis + Show 1 more

Open Access

https://doi.org/10.3390/diagnostics11122171

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Abstract

Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail’s clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10–15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail’s new data confirm the low sensitivity for early cancer detection (<30% for Stage I–II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.

Highlights

Circulating fetal DNA was originally discovered by clinical chemist Dr Dennis Lo in the 1990’s (Figure 1), who found that in the serum/plasma of pregnant women there is 5–10% of circulating free DNA of fetal origin [1]
Dennis Lo and others identified cell-free DNA in the serum of patients with cancer. Some of this DNA is of tumor origin, termed circulating tumor DNA
It has been hypothesized that it may be possible to use what is widely known as a “liquid biopsy” for the diagnosis and prognosis of cancer by analyzing circulating tumor DNA (ctDNA). ctDNA has emerged as the latest and a highly promising new cancer biomarker for diverse clinical applications [3,4,5]

Summary

Introduction

Circulating fetal DNA was originally discovered by clinical chemist Dr Dennis Lo in the 1990’s (Figure 1), who found that in the serum/plasma of pregnant women there is 5–10% of circulating free DNA (cfDNA) of fetal origin [1]. Dennis Lo and others identified cell-free DNA in the serum of patients with cancer. Some of this DNA is of tumor origin, termed circulating tumor DNA (ctDNA). In a 2016 study of 230 stage 2 colon cancer patients, 100% of those who had detectable ctDNA right after the Diagnostics 2021, 11, 2171 cal breast cancer biomarker) and circulating tumor cells in tracking disease progression and regression. The patient is treated initially with certain therapy while he/she is monitored with liquid biopsy for the presence and intensity of mutations in ctDNA. Larger amounts of ctDNA correlate with larger tumors, advanced tumors, or later-stage tumors

Early Cancer Diagnosis

Experimental Data from Grail That Support our Predictions

Findings

Conclusions