NEDLANDS, AustraliaIf the implications of an Australian study
are validated in further prospective studies, microsatellite
instability (MSI) could potentially predict those patients with
Dukes C and possibly Dukes B colorectal cancer who will
respond best to chemotherapy.
Patients with MSI appear to derive very good survival benefit
from chemotherapy, Hany Elsaleh, MBBS, said at the recent
annual meeting of the American Society of Clinical Oncology.
Conversely, he reported that p53 mutation in the tumor predicts a
very poor response to chemotherapy.
The study, conducted by Dr. Barry Iacopetta and Dr. Elsaleh at the
Sir Charles Gairdner Hospital and the University of Western
Australia, Nedlands, put several hypotheses on the table for
One was whether the response to chemotherapy could differ between
phenotypes, since it is known that genetic alterations differ within
colon carcinomas. Also, since the frequency of these genetic
alterations seems to differ between the proximal and distal regions
of the colon, could site of origin also determine treatment outcome?
The testing of genetic alterations may allow us to identify
patients who benefit from therapy and those who dont, Dr.
Microsatellite instability is a disorder of DNA mismatch repair, Dr.
Elsaleh explained. This results in changes in the length of
repetitive nucleotide sequences scattered throughout the genome.
MSI is found both in hereditary nonpolyposis colorectal cancer and
sporadic colorectal cancer, and is found mostly in the proximal
colon, he said.
The aims of the study were to identify the prevalence of MSI
and p53 mutations in a large consecutive series of single-staged,
surgical-margin-negative Dukes C colorectal carcinomas,
Dr. Elsaleh said. Improvement in cancer-specific survival was
measured, as well as the potential influence of chemotherapy on the
disease. Survival was the primary endpoint, and adjuvant chemotherapy
status was defined on an intention to treat basis.
Dr. Elsaleh and his colleagues looked at 891 consecutive Dukes
C colorectal cancer patients (median age, 67.6 years) over a 14-year
period. The median follow-up was 6.5 years. Of the total, 30% (n =
272) received adjuvant chemotherapy consisting of
5-fluorouracil/levamisole. By the end of the study, 55% had died of
In the chemotherapy vs non-chemotherapy group, tumor site,
histological grade, p53 mutation, and MSI were balanced. The only
major differences between the two groups were age and gender. The
average age of those receiving chemotherapy was 60 vs 71 for those
not on chemotherapy.
Because of younger age at presentation, slightly more males received
chemotherapy than females.
Looking at all the cases, a 10% survival benefit was seen in the
chemotherapy group. When MSI and p53 were analyzed, it was apparent
that there were differences in the response to chemotherapy depending
on these factors. Patients whose tumors showed MSI had a much better
response to chemotherapy, compared with those receiving chemotherapy
whose tumors were MSI negative (96% survival vs 37% at 5 years).
Dr. Elsalehs view is that previous reports of prognostic value
for MSI were primarily due to the predictive effect of MSI for good
response to chemotherapy, as there was no survival benefit seen in
having MSI in the non-chemotherapy-treated group.
Because MSI was seen primarily in the proximal colon (20% vs 1%),
this prompted us to look at the effect of chemotherapy in the
proximal group vs the distal group, Dr. Elsaleh said. What they
found was that the proximal group had a 25% absolute survival benefit
at 5 years with chemotherapy. When the cancer was confined to the
distal colon, the chemotherapy resulted in only a marginal 1% benefit
at 5 years.
Since MSI is most common in the proximal colon and p53 mutations
occur more often in the distal area, Dr. Elsaleh and his colleagues
concluded that perhaps the site where the cancer occurs would predict
Gender differences too were looked at in the study. Females were
found to have a 20% absolute survival benefit from chemotherapy at
the 10-year projections compared to males.
So there are potentially differences in the genetic alteration
profile of tumors based not only on site but also on gender. This may
also contribute to gender differences observed in the response to
chemotherapy, Dr. Elsaleh said.
The data on the predictive value of the p53 mutation was also
interesting, he said. It did not have prognostic significance when
the treatment and nontreatment group were compared. However, as a
predictive marker, Dr. Elsaleh said, it can help to identify patients
who are not deriving benefit from chemotherapy.
Patients with normal p53 derived a survival benefit, but not
those with mutant p53.
A multivariate analysis of the treatment group found that gender,
p53, and MSI were independent predictors of survival benefit from chemotherapy.
The prospect of using tumor-related genetic alterations to
identify differences in biological response to treatment is
attractive, and if this defines distinct entities, then it will
assist us to reclassify this disease. This will only be possible when
the predictive values of genetic biomarkers are tested in prospective
studies, Dr. Elsaleh concluded.