Science - USA (2020-05-01)

SCIENCE sciencemag.org 1 MAY 2020 • VOL 368 ISSUE 6490 461

DATA: LENNON

ET AL

., SCIENCE

, 28 APRIL, DOI: 10.1126/SCIENCE.ABB9601

D

etecting many kinds of cancers early,

with a simple blood test for DNA shed

by tumor cells, is a seductive prospect.

Such tests, often called liquid biop-

sies, are now stepping out of the lab.

This week, a pioneering real-world

study confirms some of their promise—and

highlights a potential drawback that may

soon confront physicians, regulators, and the

public: a small but not insignificant number

of alarming but false detections.

In the first trial of such a test in a large,

general population, instead of in groups

with known tumors or at high risk of cancer,

researchers screened nearly

10,000 women with Cancer-

SEEK, an assay for circulat-

ing tumor DNA developed at

Johns Hopkins University. It

detected 26 previously un-

known tumors, they reported

online in Science this week

and at a virtual session of

an American Association for

Cancer Research meeting on

28 April.

Observers say the results

are promising, but leave

key questions unanswered.

“I’m very impressed with

this paper. They did all the

right things. But it does

not mean the assay should

be put on the market and

sold,” says breast cancer re-

searcher Daniel Hayes of the

University of Michigan, Ann Arbor. It’s not

yet clear that the early warnings saved the

women’s lives. And 101 of the women who

had a positive test and received follow-up

imaging turned out not to have cancer;

22 of them underwent fruitless invasive

tests such as an endoscopy.

The earlier cancer is detected, the better—

but not always, as some tumors may never

grow enough to need any treatment. And

false alarms can lead to needless anxiety and

unnecessary procedures. Such concerns fuel

debates over the frequency and worth of ex-

isting screening methods such as mammo-

grams and colonoscopies, and the concerns

are amplified for cancer blood tests because

they promise to make it easy to screen mil-

lions of healthy people.

To explore those issues with an early ver-

sion of CancerSEEK, the Geisinger Health

System in Pennsylvania recruited women

between the ages of 65 and 75 who had no

known cancer history. CancerSEEK pulls cir-

culating DNA from a blood sample and looks

for mutations in 16 genes known to drive

the growth of various cancers. It combines

this information with established protein

biomarkers for some cancers. If a woman’s

test was positive, an expert panel decided

whether she should get a second blood test to

confirm the initial finding and rule out mo-

lecular changes in her blood that might have

fooled the first test. If the positive test ap-

peared real, the woman was invited to under-

go full-body imaging.

During participants’ first

year in the study, dubbed

DETECT-A, the Hopkins test

picked up 10 types of can-

cer in 26 women, roughly

double the number found

with conventional screen-

ing. Seven of the cancers,

such as ovarian, have no ap-

proved screening test and

are often deadly because

they are rarely found early.

Seventeen of the 26 women

had early-stage cancers that

had not spread far, beyond

nearby muscle and lymph

nodes. Most of the 26 had

surgery or are undergoing

treatment and 12 are in re-

mission, suggesting they did

benefit from the test.

The DETECT-A study “makes great

strides in its approach,” says ovarian cancer

researcher David Huntsman of the Univer-

sity of British Columbia, Vancouver. But

more data attesting to an overall survival

benefit from testing are needed, he and oth-

ers stress, before the blood test should be

approved for widespread use.

The 101 false positives is a modest num-

ber given the scale of the study, Huntsman

and Hayes say. But the test also had false

negatives. Conventional screening over the

DETECT-A study’s first year of follow-up

found breast, lung, and colon cancers in

24 women whose CancerSEEK test was nega-

tive. Tumors in 46 more women became ap-

parent through symptoms or other reasons.

The Hopkins team views its test, which it

has continued to improve, as “additive and

complementary” to standard screening, says

Nickolas Papadopoulos, who led the study

with Kenneth Kinzler and Bert Vogelstein.

Some public health experts have worried

that if a blood test were available, people

might shun these other, proven screens.

But participating in the study didn’t deter

the women from continuing mammograms.

And in a follow-up survey completed by

nearly 6900 women, only 0.3% said they re-

gretted participating in the study, including

only one of 120 with a false positive or nega-

tive result. The DETECT-A study “suggests

that multicancer blood-based screening is

safe and feasible,” says oncologist Minetta

Liu of the Mayo Clinic.

Liu is part of an academic group running

studies of another blood test, developed by

the biotech Grail, which looks at patterns of

methyl groups on cell-free DNA to detect can-

cers. In a March paper in the Annals of Onco-

logy and at the virtual cancer meeting, Grail

shared the latest results from a study that

enrolled 15,000 people, some with newly di-

agnosed cancer and others with no evidence

of the disease. Its test for 50 cancers had a de-

tection rate of 44% for early- to midstage can-

cer and also determined the site of the known

cancer in 93% of cases, which could reduce

the need for full-body imaging. In December

2019, the company launched PATHFINDER,

a prospective study of 6200 people—all older

than 50 and 70% at elevated risk for cancer.

“This is an important next step toward the

commercialization of our test,” says Grail

spokesperson Kelsey Grossman.

As for when CancerSEEK might reach

the clinic, a startup company called Thrive

owns the rights to further develop the test.

It raised $110 million last year and is plan-

ning a large follow-up trial designed to

earn regulatory approval. Questions persist

about how officials and expert groups that

set screening guidelines, such as the U.S.

Preventive Services Taskforce, will weigh

early cancer detection tests. Will decade-

plus studies that show survival benefits

be required, for example, as they were for

other screening methods such as mammo-

grams and lung scans for smokers? Or can

proxies, such as data showing the tests find

more early cancers than existing screening

methods, satisfy the various groups? “That

is what everybody in the field is grappling

with now,” Papadopoulos says. j

Cancer DNA blood test gets real-world trial

Early detection test spots tumors in 26 women, but also produces false positives

BIOMEDICINE

By Jocelyn Kaiser

NEWS | IN DEPTH

Mixed signals

One-year follow-up results of the

DETECT-A study of nearly 10,000

women, ages 65 to 75.

WOMEN

Initial blood test 9911

Cancers detected

with blood test

26

Cancers detected with

standard screening

24

Cancers detected

with neither approach

46

Total cancers detected 96

Imaging based on false

blood test

101

Invasive diagnostics

after false blood test

22