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