NEW ORLEANSNew findings reported at the 92nd Annual
Meeting of the American Association for Cancer Research (AACR) support an
emerging view that genetic mutations not only contribute to cancer etiology but
even to individual variability in response to cancer treatment.
Small changes in a patient’s genetic makeup, for exampleeven
the substitution of a single letter in the genetic codecan positively or
negatively affect treatment response, according to several reports at the
meeting. These findings point the way to a future of truly
"personalized" cancer treatment, as pharmacogenetics will make it
possible to tailor therapy to the genetic characteristics of a patient or the
"I am a zealot for this concept," said Jeffrey Trent,
MD, of the NIH’s National Human Genome Research Institute. "We will
begin to individualize patient treatment, based on genetic information. As to
how genetics is impacting individual patients, I would say the future is
One study from Duke University Medical Center linked three
previously identified genetic variations to length of survival in patients with
metastatic breast cancer treated with several different agents. In one case,
having the variation was beneficial, while having the other two variations
The genes in this study mediate enzymes involved in the
metabolism of many chemotherapy agents, said lead investigator William P.
Petros, PharmD, assistant clinical professor of medicine at Duke and director
of the Clinical Pharmacology Lab.
Dr. Petros and his colleagues stored white blood cell samples
from 86 chemotherapy-naïve women with metastatic or inflammatory breast cancer
before they began therapy with high-dose cyclophosphamide, cisplatin
(Platinol), and car-mustine (BCNU).
DNA analysis showed that women with variations in the CYP3A4
and CYP3A5 genes were less able to activate cyclophosphamide, thus making this
agent less efficacious. The median survival of these women was 12 to 18 months,
compared with almost 3 years for women who did not have a variation in these
two genes, Dr. Petros reported.
Furthermore, there were ethnic differences in the frequency of
the variations. Few whites (12%) had the CYP3A4/CYP3A5 variations, compared
with approximately 50% of blacks. Interestingly, the length of survival among
blacks was about half that of white patients.
Survival was increased for women with no normal copies of a
gene called GSTM1, compared with those who had one or two copies of the gene.
In healthy white blood cells, this gene helps detoxify chemotherapy agents,
thus protecting them from cytotoxicity. This gene may also detoxify
chemotherapy agents in tumor cells, preventing the drug from working, Dr.
The median survival for patients with both GSTM1 deletions was
3.8 years, compared to 1.8 years for patients with one or both GSTM1 copies.
"In this case, having a mutation was a good thing," Dr. Petros said.
At a press conference, Dr. Petros said that genotype will
dictate how drug dosages are figured for these agents, leading to less toxicity
and better efficacy, and also may become factors to consider when evaluating
outcomes of clinical trials.
Investigators from the University of Aberdeen, Scotland, also
studied ethnic differences in chemotherapy response. They found a genetic
mutation (C3435T) in all 10 ethnic groups they studied (1,280 subjects).
However, the mutation was more common among Asians and whites than among
persons of African descent.
The C3435T mutation results from the change of a single letter
in the genetic code, reducing the expression of P-glycoprotein (PGP). PGP is
known as the multidrug-resistance protein because it pumps chemotherapeutic
agents out of tumor cells. The newly discovered mutation appears to be
responsible for impaired PGP, making the cell less effective at eliminating the
Future studies will determine whether cancer patients with the
PGP mutation respond better to chemotherapy. "If so, we will have
identified a way to make therapy better for some patients. A patient’s PGP
mutation status can help select the treatment regimen that is most likely to be
effective," said lead investigator Howard L. McLeod, PharmD, currently at
Washington University School of Medicine, St. Louis.
In a third study, researchers found individual variation in the
expression of two enzymes that regulate the activity of gemcitabine (Gemzar).
In cells, gemcita-bine is phosphorylated to active metabolites by deoxycytidine
kinase (dCK), the rate-limiting enzyme in the biotransformation of nucleoside
analogs, while active metabolites of gemcitabine are inactivated through
dephosphorylation by 5´-nucleotidase (5´-NT) (see Figure). Because
these two enzymes act as opposing on-off switches for gemcita-bine, their
ratios may influence drug cytotoxicity and thus help explain differences in
patient response to the drug.
Italian researchers found that ratios of these two enzymes
varied considerably in tumor specimens of non-small-cell lung cancer (NSCLC).
The study suggests that researchers may someday be able to optimize treatment
for NSCLC by evaluating the pharmacogenetics of drug-metabolizing systems
before chemotherapy is begun, said Romano Danesi, MD, PhD, University of Pisa.