Editorials

the benefit from adjuvant treatment was within
the biomarker-negative group, the patients with
the most primitive tumors. The findings have
generated a new hypothesis that is now ready for
testing in a prospective randomized clinical trial.
If the hypothesis that nearly all the benefit
from adjuvant chemotherapy is in the biomarker-
negative group is confirmed, over 90% of patients
with stage II colon cancer will be reassured that
avoiding the unpleasantness of standard adju-
vant therapy is unlikely to affect their outcome
adversely. No one expected that.
identify potential collaborators whose collected
data may be useful in assessing the hypothesis
and propose a collaboration. Third, work to-
gether to test the new hypothesis. Fourth, report
the new findings with relevant coauthorship to
acknowledge both the group that proposed the
new idea and the investigative group that ac-
crued the data that allowed it to be tested. What
is learned may be beautiful even when seen from
close up.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

How would data sharing work best? We think
it should happen symbiotically, not parasitically.
Start with a novel idea, one that is not an obvi-
ous extension of the reported work. Second,
1. Dalerba P, Sahoo D, Paik S, et al. CDX2 as a prognostic bio-
marker in stage II and stage III colon cancer. N Engl J Med 2016;
374:211-22.
DOI: 10.1056/NEJMe1516564
Copyright 2016 Massachusetts Medical Society.

Prognostic Subgroups among Patients with Stage II Colon

Cancer
C.Richard Boland, M.D., and Ajay Goel, Ph.D.

Colon cancer has traditionally been treated sur-
gically. However, many cases of colon cancer are
systemic at the time of diagnosis, and appar-
ently curative surgery is followed at a later date
by tumor recurrence as a consequence of circu-
lating tumor cells before the surgery. Adjuvant
medical therapies are designed to prevent recur-
rences after surgical resection.
The current standard for clinical prognostica-
tion relies principally on pathological staging. In
early-stage colon cancers (stages I and II), all the
tumor is contained within the wall of the colon.
Less than 10% of patients with stage I disease
have a recurrence, and adjuvant chemotherapy is
not administered because it provides no benefit.
Approximately 20% of patients with stage II colon
cancers have a recurrence, and adjuvant chemo-
therapy provides a minimal benefit1 that is usu-
ally considered to be not worth the toxic effects
of the drugs. Furthermore, among patients with
stage II disease, there is quite a range of rates of
5-year survival (as low as 60%), depending on
the incremental depth of tumor invasion.2 Stage
III colon cancers have regional lymph-node
metastases; cancer recurs in more than 50% of
patients, and multiple clinical studies have shown
significant increases in survival with the admin-
istration of adjuvant chemotherapy.2 Patients
with distant metastases (stage IV colon cancer)
receive a variety of more intensive regimens that
are not usually curative. Rectal tumors are dif-
ferent and are not part of this discussion.
The use of adjuvant chemotherapy in patients
with stage II colon cancer remains controversial
because recurrence never develops in the vast
majority of these patients.1 Treatment of all pa-
tients with stage II colon cancer is overtreat-
ment,3 since only a small subgroup of patients
derives any therapeutic benefit, whereas in others
there is harm, a poorer quality of life, and no net
benefit.4 Prior studies to identify the subgroup
of patients with high-risk stage II colon cancer
have not been robust,5 and the lack of prognostic
and predictive criteria underscores the need to
discover biomarkers that can facilitate the selec-
tion of patients for additional treatment.
In this issue of the Journal, Dalerba and col-
leagues6 report on a novel approach to the prob-
lem of identifying patients with colon cancer
who might benefit from adjuvant chemotherapy.
They reasoned that the presence of a stem-cell
like state would be associated with more ag-
gressive tumors, and they performed a bioin-
formatics search for a gene-expression signature
obtained from populations of stem cells and
progenitor cells. By mining a large preexisting

n engl j med 374;3nejm.org January 21, 2016 277

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 The n e w e ng l a n d j o u r na l
database of colon cancers, they found 16 genes
in which expression was inversely related to the
stem-celllike state. The CDX2 gene product was
the most clinically actionable of these genes,
since it is suitable for detection by means of im-
munohistochemical analysis.
The investigators performed a series of vali-
dation analyses involving multiple independent
data sets; this is a necessary approach for data-
mining research. The first analysis confirmed
an inverse relationship between CDX2 expression
and patient outcome in which CDX2-negative
colon tumors (in 6.9% of the patients in the
discovery data set), as compared with CDX2-
positive tumors, were associated with signifi-
cantly lower rates of 5-year disease-free survival
(41% vs. 74%). Immunohistochemical analysis
was performed to evaluate CDX2 protein expres-
sion in colon cancers. This analysis of a valida-
tion data set in which 13% of the patients had
CDX2-negative tumors confirmed 5-year survival
rates of 48% among patients with CDX2-negative
tumors, as compared with 71% among patients
with CDX2-positive tumors. However, this find-
ing was not sufficient to prove that the subgroup
of patients with a worse natural history would
benefit from adjuvant chemotherapy; they could
be less responsive to treatment.
The investigators focused on patients with
stage II colon cancer and confirmed that CDX2-
negative cancers, as compared with CDX2-posi-
tive cancers, were associated with significantly
lower rates of survival (48 to 51% vs. 80 to 87%).
Finally, they used an expanded database to show
that the administration of chemotherapy in-
creased rates of disease-free survival from 56%
to 91% among patients with stage II colon can-
cer and from 37% to 74% among patients with
stage III colon cancer.
This was not a perfect or definitive study. In
spite of the rigorous bioinformatics analysis, the
number of patients who had stage II colon can-
cer and CDX2-negative tumors was small. This
retrospective study requires prospective confir-
mation with uniform interventions, which was
not necessarily the case in the different cohorts.
The immunohistochemical analysis was per-
formed on tissue microarrays that facilitated
rapid throughput but may have underestimated
the heterogeneity of CDX2 expression throughout
278 n engl j med 374;3nejm.org January 21, 2016
The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
the tumor. Furthermore, these findings raise the
important question of what mechanism might
be at work in silencing CDX2; the answer to this
question could lead to the discovery of new ap-
proaches to treating the fundamental problem.
This study provides an opportunity for oncolo-
gists to move beyond what has been an inade-
quate method of selecting patients with stage II
colon cancer for adjuvant chemotherapy. In addi-
tion to genetic targets, hypermethylation of the
gene encoding transcription factor AP-2 epsilon
(TFAP2E)7 and altered expression of specific micro
RNAs8 are among the growing list of DNA-based
and epigenetic biomarkers that have shown
prognostic and predictive promise in stage II
colon cancer.9,10 A combination of genetic and
epigenetic marker panels will be assessed for
their ability to enhance the prediction of disease
course in oncology.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Center for Gastrointestinal Research, and the Center
for Epigenetics, Cancer Prevention and Genomics, Baylor Re-
search Institute, and the Baylor Charles A. Sammons Cancer
Center, Baylor University Medical Center all in Dallas.
1. Marshall JL. Risk assessment in Stage II colorectal cancer.
Oncology (Williston Park) 2010;24:Suppl 1:9-13.
2. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal
cancer. N Engl J Med 2005;352:476-87.
3. Kneuertz PJ, Chang GJ, Hu CY, et al. Overtreatment of young
adults with colon cancer: more intense treatments with un-
matched survival gains. JAMA Surg 2015;150:402-9.
4. Lewis C, Xun P, He K. Effects of adjuvant chemotherapy on
recurrence, survival, and quality of life in stage II colon cancer
patients: a 24-month follow-up. Support Care Cancer 2015 Sep-
tember 9 (Epub ahead of print).
5. Benson AB III, Schrag D, Somerfield MR, et al. American
Society of Clinical Oncology recommendations on adjuvant
chemotherapy for stage II colon cancer. J Clin Oncol 2004;22:
3408-19.
6. Dalerba P, Sahoo D, Paik S, et al. CDX2 as a prognostic bio-
marker in stage II and stage III colon cancer. N Engl J Med 2016;
374:211-22.
7. Ebert MP, Tnzer M, Balluff B, et al. TFAP2EDKK4 and che-
moresistance in colorectal cancer. N Engl J Med 2012;366:44-53.
8. Zhang JX, Song W, Chen ZH, et al. Prognostic and predictive
value of a microRNA signature in stage II colon cancer: a mi-
croRNA expression analysis. Lancet Oncol 2013;14:1295-306.
9. Carethers JM, Jung BH. Genetics and genetic biomarkers in
sporadic colorectal cancer. Gastroenterology 2015;149(5):1177-
90.e3.
10. Okugawa Y, Grady WM, Goel A. Epigenetic alterations in
colorectal cancer: emerging biomarkers.Gastroenterology 2015;
149(5):1204-25.e12.
DOI: 10.1056/NEJMe1514353
Copyright 2016 Massachusetts Medical Society.