The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l s

Improving Noninvasive Colorectal Cancer Screening

John M. Carethers, M.D.

Noninvasive colorectal cancer screening com-
menced historically with the use of guaiac-based
tests that require the addition of hydrogen per-
oxide to oxidize the presence of substances such
as blood in stool. Large, randomized, controlled
trials of these tests in a screened population
showed the detection of earlier-stage cancers that
could be curable, a reduction in mortality from
colorectal cancer, and durability in the avoidance
of colorectal cancer in persons who completed
colonoscopy with polypectomy after a positive
test.1 These benefits from guaiac-based screening
were present despite the poor sensitivity of such
tests, the requirement for diet alteration before
test completion for accuracy, and the recommen-
dation that they be performed annually.2
Fecal immunochemical testing (FIT) detects
human hemoglobin in stool and has shown im-
proved sensitivity and specificity as compared with
guaiac-based tests. FIT has also eliminated the
previous diet adjustments, but it is still recom-
mended that a FIT be conducted annually. The
addition of specified multitarget stool DNA
markers to FIT in the DeeP-C Study further im-
proved sensitivity for the detection of colorectal
cancer and added moderate sensitivity for the de-
tection of advanced adenomas, a known precursor
to colorectal cancer.3 However, specificity with that
multitarget stool DNA test was lower than with
FIT alone, which generated false positive results
and led to additional colonoscopy use.3 The multi-
target stool DNA test is recommended to be con-
ducted every 3 years and has provided an alterna-
tive to primary screening by colonoscopy for some
patients.
The overall prevalence of colorectal cancer
screening in the United States for combined
noninvasive and endoscopic methods in the pre–
Covid-19 era was approximately 69%,4 which
falls short of nationally stated goals of 80% or
more. Therefore, increasing the pool of persons
who undergo screening for colorectal cancer
should be a priority. Such increases can be ac-
complished by encouraging the use of screening
with the existing approved tests or by expand-
ing, enhancing, or improving tests over the cur-
rently available options,5,6 such that population-
wide use becomes easier and increased utilization
follows. Providing access to affordable, convenient
tests with high sensitivity and specificity can also
boost screening participation in underrepre-
sented groups.7 A premise of screening comple-
tion is that any noninvasive test that is positive
is linked to an automatic follow-up colonoscopy.
Two studies that are reported in this issue of
the Journal show promise with regard to increas-
ing the use of colorectal cancer screening. The
BLUE-C Study, conducted by Imperiale et al.,8
evaluated a next-generation multitarget stool DNA
test that consists of updated DNA biomarkers
from the first-generation test and compared this
new test with FIT in more than 20,000 participants
at average risk who were undergoing screening for
colorectal cancer. Although the study did not
directly compare the two multitarget stool DNA
tests, the next-generation test appeared to preserve
sensitivity for the detection of colorectal cancer
and had improvements in overall specificity for
the absence of any advanced neoplasia as com-
pared with the earlier test. The new multitarget

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 The n e w e ng l a n d j o u r na l
stool DNA test also preserved a 43.4% sensitivity
for the detection of advanced precancerous lesions.
The higher specificity (albeit still lower than the
specificity with FIT alone) should increase the de-
tection efficiency for users by reducing the oc-
currence of false positive results and thus lower-
ing the number of follow-up colonoscopies.
The ECLIPSE (Evaluation of the ctDNA LUNAR
Test in an Average Patient Screening Episode)
study, conducted by Chung et al.,9 used cell-free
DNA (cfDNA) from whole blood (also called “liq-
uid biopsy”) to detect genomic alterations, aber-
rant methylation, and DNA fragment changes in
nearly 7900 screened participants. Because the
assay uses blood, thus avoiding the collection of
stool, it may easily be prescribed and sent from
any caregiver’s office as part of a standard blood
draw, thus potentially increasing the use of colorec-
tal cancer screening in multiple diverse popula-
tions (under the assumption that patients undergo
a complete colonoscopy if they receive positive
results). The cfDNA assay, as compared with colo-
noscopy, showed a sensitivity of 83.1% for colorec-
tal cancer and a specificity of 89.6% for advanced
neoplasia, with a 13.2% sensitivity for advanced
adenomas. The sensitivities of the liquid-biopsy
assay for the detection of colorectal cancer and
advanced adenoma that were reported in this study
are lower than those reported for the multitarget
DNA stool assay; however, the specificities are
similar.
Screening for colorectal cancer saves lives.
Screening tests have evolved to include stool-
based, endoscopic and image-based, and blood-
based methods, with minimal thresholds for
sensitivity and specificity for colorectal cancer set
by the baseline characteristics of FIT. Although
multiple tests have been developed over time and
vary in cost-effectiveness for colorectal cancer
screening, the best screening test is the one that
gets completed by the patient. Most of the rec-
ommended tests, including the two newer tests
assessed in the studies now published in the
Journal, improve on the sensitivity and approach
the specificity of FIT, such that these tests ap-
1046 n engl j med 390;11
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of m e dic i n e
pear to be at least as effective as FIT. Adherence
to screening is a key factor, and ease of test use
may contribute to increased adherence. Cost-effec-
tiveness and the selection of the testing interval
may play roles in adherence, particularly in popu-
lations that already have lower rates of adherence
to colorectal cancer screening than the general
population. Adherence to screening varies accord-
ing to age group, including persons in the 45-to-
49-year age group who are now eligible for aver-
age-risk screening.10 It is hoped that these newer
tests will increase use and adherence and elevate
the percentage of the population undergoing
screening in order to reduce deaths from colorec-
tal cancer.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Division of Gastroenterology and Hepatology, De-
partment of Medicine, Moores Cancer Center, and the Herbert
Wertheim School of Public Health and Human Longevity Sci-
ence, University of California, San Diego, San Diego.
1. Carethers JM. Screening for colorectal cancer in African
Americans: determinants and rationale for an earlier age to
commence screening. Dig Dis Sci 2015;​60:​711-21.
2. Carethers JM. Stool-based screening tests for colorectal can-
cer. JAMA 2023;​329:​839-40.
3. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget
stool DNA testing for colorectal-cancer screening. N Engl J Med
2014;​370:​1287-97.
4. Fisher DA, Princic N, Miller-Wilson L-A, Wilson K, Fendrick
AM, Limburg P. Utilization of a colorectal cancer screening test
among individuals with average risk. JAMA Netw Open 2021;​
4(9):​e2122269.
5. Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget
stool RNA test for colorectal cancer screening. JAMA 2023;​330:​
1760-8.
6. Lo YMD. Cell-free DNA for colorectal cancer screening.
N Engl J Med 2024;​390:​1047-50.
7. Doubeni CA, Corley DA, Zhao W, Lau Y, Jensen CD, Levin
TR. Association between improved colorectal screening and ra-
cial disparities. N Engl J Med 2022;​386:​796-8.
8. Imperiale TF, Porter K, Zella J, et al. Next-generation multi-
target stool DNA test for colorectal cancer screening. N Engl J
Med 2024;​390:​984-93.
9. Chung DC, Gray DM II, Singh H, et al. A cell-free DNA
blood-based test for colorectal cancer screening. N Engl J Med
2024;​390:​973-83.
10. Carethers JM. Commencing colorectal cancer screening at
age 45 years in U.S. racial groups. Front Oncol 2022;​12:​966998.
DOI: 10.1056/NEJMe2400366
Copyright © 2024 Massachusetts Medical Society.
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