ID of Subtypes, Mutations in CRC Increases Survival
January Gastroenterology (doi: 10.1053/ j.gastro.2014.09.038 and doi: 10.1053/ j.gastro.2014.09.041)
Dr. Daniel C. Chung is associate professor, department of medicine,
Harvard Medical School, Boston, and director, Hi-Risk Gastrointes-
tinal Cancer Clinic, Massachusetts General Hospital, also in Bos-
ton. He has no conficts of interest.
It is now recognized that colon cancer is quite heterogeneous on a genetic level, and the clinical features as- sociated with each of these genetic subtypes are equally heterogeneous. The two current studies addressed
the question of whether long-term prognosis differs among these genetic subtypes. Colon tumors were first divided
into five distinct categories, based upon
a panel of multiple molecular markers.
One study analyzed more than 2,700
colon cancers of all stages, whereas the
other examined more than 2,700 stage
III tumors from a North Central Cancer
Treatment Group adjuvant chemotherapy trial.
Similar patterns emerged. Tumors
with the least favorable prognosis were
the so-called “serrated” tumors that are
DNA mismatch-repair (MMR) proficient
and are positive for a BRAF mutation.
Tumors with deficient MMR (MSI-H),
whether sporadic or associated with
Lynch syndrome, consistently exhibited
the most favorable prognosis and high-
est rates of long-term survival.
These studies provide strong evidence that links survival with specific
tumor genotypes, regardless of stage or
treatment, and establish the significance
of molecular genotyping for prognostic
purposes. There are other important
reasons to perform tumor genotyping,
including the identification of unrecognized Lynch syndrome. However, the
therapeutic implications of tumor genotyping remain less clear, as meaningful
targeted therapies for each of the specific subgroups are still lacking. In particular, effective targeting of the BRAF
oncogene in serrated tumors remains
an important priority. More refined
molecular classifications are likely to
emerge in the future, and the opportunities to offer more precise and personalized approaches to management should
increase in parallel. n
Key clinical point: Genetic factors
in colon cancer determine long-term
prognosis, but tumors are heterogeneous and the factors are complex.
Major finding: Tumors with the
least favorable prognosis in both
studies were serrated and DNA mismatch-repair proficient and positive
for a BRAF mutation. Tumors with
deficient MMR (MSI-H), whether
sporadic or associated with Lynch
syndrome, consistently exhibited
the most favorable prognosis and
highest rates of long-term survival.
Data source: Tumor material from
the North Central Cancer Treatment
Group adjuvant chemotherapy trial
was analyzed and Cox regression
models were used to estimate
hazard ratios, 95% confidence intervals, and associations for each
subtype with specific diseases and
overall mortality, all of which were
adjusted for age, sex, body mass, diagnosis year, and smoking history.
Disclosures: The investigators for
both studies reported no relevant
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