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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 biomarkernegative group is confirmed, over 90% of patients
with stage II colon cancer will be reassured that
avoiding the unpleasantness of standard adjuvant therapy is unlikely to affect their outcome
adversely. No one expected that.
How would data sharing work best? We think
it should happen symbiotically, not parasitically.
Start with a novel idea, one that is not an obvious extension of the reported work. Second,
identify potential collaborators whose collected
data may be useful in assessing the hypothesis
and propose a collaboration. Third, work together 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 accrued 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.
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 surgically. However, many cases of colon cancer are
systemic at the time of diagnosis, and apparently curative surgery is followed at a later date
by tumor recurrence as a consequence of circulating tumor cells before the surgery. Adjuvant
medical therapies are designed to prevent recurrences after surgical resection.
The current standard for clinical prognostication 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 chemotherapy provides a minimal benefit1 that is usually 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 administration 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 different 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 patients with stage II colon cancer is “overtreatment,”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 selection of patients for additional treatment.
In this issue of the Journal, Dalerba and colleagues6 report on a novel approach to the problem 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 aggressive tumors, and they performed a bioinformatics 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;3 nejm.org January 21, 2016
The New England Journal of Medicine
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277
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-cell–like state. The CDX2 gene product was
the most clinically actionable of these genes,
since it is suitable for detection by means of immunohistochemical analysis.
The investigators performed a series of validation analyses involving multiple independent
data sets; this is a necessary approach for datamining 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 CDX2positive tumors, were associated with significantly lower rates of 5-year disease-free survival
(41% vs. 74%). Immunohistochemical analysis
was performed to evaluate CDX2 protein expression in colon cancers. This analysis of a validation 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 finding 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 CDX2negative cancers, as compared with CDX2-positive 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 increased rates of disease-free survival from 56%
to 91% among patients with stage II colon cancer 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 cancer and CDX2-negative tumors was small. This
retrospective study requires prospective confirmation with uniform interventions, which was
not necessarily the case in the different cohorts.
The immunohistochemical analysis was performed on tissue microarrays that facilitated
rapid throughput but may have underestimated
the heterogeneity of CDX2 expression throughout
278
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 approaches to treating the fundamental problem.
This study provides an opportunity for oncologists to move beyond what has been an inadequate method of selecting patients with stage II
colon cancer for adjuvant chemotherapy. In addition 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 Research 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 unmatched 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 September 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 biomarker in stage II and stage III colon cancer. N Engl J Med 2016;​
374:211-22.
7. Ebert MP, Tänzer M, Balluff B, et al. TFAP2E–DKK4 and chemoresistance 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 microRNA 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):​117790.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.
n engl j med 374;3 nejm.org January 21, 2016
The New England Journal of Medicine
Downloaded from nejm.org on April 28, 2017. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.