Practice Update: Oncology

Direct Detection of Early-

Stage Cancers Using

Circulating Tumor DNA

Science Translational Medicine

Take-home message

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The authors developed a targeted error correction sequencing (TEC-Seq) approach

for the noninvasive detection of early-stage tumors. The technique uses massively

parallel sequencing to detect sequence changes in circulating cell-free DNA of 58

cancer-related genes encompassing 81 kb. The technique was used to analyze

the plasma of 44 healthy individuals and detected genomic changes related to

clonal hematopoiesis in 16% of them but no alterations in driver genes related to

solid cancers. Analysis of plasma from patients with known cancers and stage I or

II disease showed somatic mutations in 71% of patients with colorectal cancer, 59%

of patients with breast cancer, 59% of patients with lung cancer, and 69% of patients

with ovarian cancer. Higher amounts of circulating tumor DNA before surgery in

patients with resectable colorectal cancers were associated with an increased risk

of disease recurrence and a decreased overall survival.

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Noninvasive means of cancer detection could have huge implications for screening

and surveillance. This approach may be broadly applicable for cancer screening

for detecting early cancers noninvasively.

Abstract

Early detection and intervention are likely to be

the most effective means for reducing morbidity

and mortality of human cancer. However, devel-

opment of methods for noninvasive detection of

early-stage tumors has remained a challenge.

We have developed an approach called tar-

geted error correction sequencing (TEC-Seq)

that allows ultrasensitive direct evaluation of

sequence changes in circulating cell-free DNA

using massively parallel sequencing. We have

used this approach to examine 58 cancer-re-

lated genes encompassing 81 kb. Analysis of

plasma from 44 healthy individuals identified

genomic changes related to clonal hematopoie-

sis in 16% of asymptomatic individuals but no

alterations in driver genes related to solid can-

cers. Evaluation of 200 patients with colorectal,

breast, lung, or ovarian cancer detected somatic

mutations in the plasma of 71, 59, 59, and 68%,

respectively, of patients with stage I or II disease.

Analyses of mutations in the circulation revealed

high concordance with alterations in the tum-

ors of these patients. In patients with resectable

colorectal cancers, higher amounts of preoper-

ative circulating tumor DNA were associated

with disease recurrence and decreased over-

all survival. These analyses provide a broadly

applicable approach for noninvasive detec-

tion of early-stage tumors that may be useful

for screening and management of patients with

cancer.

Direct detection of early-stage cancers using

circulating tumor DNA.

Sci Transl Med

2017

Aug 16;9(403)eaan2415, J Phallen, M Sausen,

V Adleff, et al.

www.practiceupdate.com/c/57205

COMMENT

By Erin Schenk

MD, PhD

Expanding Potential for Circulating Tumor DNA

outinely in my clinic, I meet patients who struggle to understand how their can-

cer could spread so far with so few symptoms. In one way or another they ask,

“Doctor, isn’t there a test that could have found this earlier?” One day, the answer

may be a blood test for circulating tumor DNA (ctDNA). Using cutting-edge methods of

next-generation sequencing, Phallen and colleagues describe the detection of ctDNA,

which could result in earlier cancer diagnoses.

ctDNA is the tumor-derived subset of cell-free DNA (cfDNA). For decades, cfDNA has

been a recognized entity within the blood stream and is thought to be primarily derived

from cells undergoing apoptosis.

2,3

Patients with cancer have higher levels of cfDNA, and

currently available ctDNA testing is focused on the detection of actionable mutations

in metastatic disease such as EGFR T790M or BRAF V600E.

Other groups previously

demonstrated ctDNA as a powerful tool in detecting the recurrence of colon, lung, or

pancreatic cancer, but these approaches first sequenced the tumor tissue to guide sub-

sequent ctDNA surveillance.

5-7

Phallen and colleagues developed a ctDNA detection

method independent of mutations within the tumor, resulting in a blood test to screen

for the presence of cancer at earlier stages of diagnosis.

The authors first chose a panel of 58 genes commonly mutated in multiple cancers

and developed a novel method of cfDNA amplification with high fidelity to detect rare

mutations in the ctDNA fraction.

They analyzed plasma samples from 200 patients with

lung, breast, colorectal, or ovarian cancer, and 68% were stage I or II. The false-positive

rate for this approach was very low, and no mutations were detected in 44 healthy vol-

unteers. Higher levels of cfDNA were found in patients with more advanced disease,

and 78% had a detectable mutation. Even in early-stage disease, 62% had a detecta-

ble mutation in the 58-gene panel. Phallen and colleagues assessed the prognostic

capacity of ctDNA in the 31 colorectal cancer patients who underwent surgical resec-

tion, including 4 stage IV patients who had concurrent resection of hepatic metastases.

Patients with no or a low burden of ctDNA mutations experienced significantly longer

progression-free survival and overall survival compared with patients with more detect-

able ctDNA mutations. These trends held true even when excluding stage IV patients.

This proof-of-concept study holds great promise for cfDNA analysis as a screening tool

for the early detection of cancer and with possible predictive power to guide treatment

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