|Genetic Variant Associated with Resistance to Chemotherapy Drug in Women with Breast Cancer
Researchers have found links between an individualís genetics and their response
to treatment with chemotherapy. The findings, by researchers at the National
Cancer Institute (NCI), part of the National Institutes of Health, and colleagues,
show how a genetic variant, located in the SOD2 gene, may affect how a person
responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used
in the treatment of breast and other cancers.
The SOD2 gene produces a key protein that protects cells from damage by molecules
known as reactive oxygen species, or free radicals. Reactive oxygen species are
produced by normal cellular processes and the action of some chemotherapy drugs.
The findings represent the first preliminary evidence pointing toward a mechanism
and a potential biomarker for cyclophosphamide resistance in breast cancer patients.
The study appeared online June 9, 2009, in Clinical Cancer Research.
"This study shows how, with the progress of individualized medicine, a diagnostic
test may be developed that determines whether a patient has certain genetic variations
that may modify the effect of certain chemotherapies," said study author Sharon
Glynn, Ph.D., of NCIís Center for Cancer Research.
"In the future, such tests may be used to guide the treatment of patients with
the SOD2 variation, ensuring that they receive a therapy that is more effective
than cyclophosphamide-based therapies," added senior author Stefan Ambs, Ph.D.,
also of the Center for Cancer Research.
Most genes in human cells are present in two copies — one inherited from the mother
and the other inherited from the father. These gene copies can vary from one
another. Some variations in genes play an important role in how a gene is expressed
or how its protein product functions.
The variant identified by the researchers in the SOD2 gene affects both the structure
and the function of the encoded protein, an enzyme known as manganese superoxide
dismutase (MnSOD) and affects the ability of MnSOD to reach its proper location
in the cell and its activity level. MnSOD normally functions inside cellular
compartments known as mitochondria and helps protect cells from damage caused
by reactive oxygen species formed during cellular metabolism. Excessive levels
of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs
depend on increased production of reactive oxygen species to kill cancer cells.
Furthermore, some studies have indicated that, because MnSOD neutralizes reactive
oxygen species, it can modify the effects of chemotherapy drugs. For example,
in laboratory and animal models, increased activity of MnSOD protects cells against
the toxic effects of doxorubicin, which is a widely used anticancer drug.
In the new study, the research team investigated whether the variation affected
survival in two separate groups of women with breast cancer: 248 women in the
United States and 340 women in Norway. Some of the women received chemotherapy,
and some did not receive chemotherapy. The team first analyzed DNA from the women
to determine their genotype, meaning which types of the SOD2 gene they had. The
researchers found that, among patients who received chemotherapy, those who had
one form had decreased survival and those with another form had the poorest survival.
In contrast, the genotype of SOD2 did not affect survival among those who did
not receive chemotherapy.
Next, the team looked at the relationship between SOD2 genotype and the type
of chemotherapy the women received. The data were analyzed according to which
of three types of commonly used chemotherapy drugs were administered: doxorubicin,
5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generate
reactive oxygen species in cancer cells during treatment. The researchers determined
that the presence of a particular variant was associated with decreased survival
of patients treated with chemotherapy regimens that contained any of the three
drugs. However, the most significant effects were found with the drug cyclophosphamide.
Women with a distinct variant form of SOD2 and who received cyclophosphamide-containing
chemotherapy had the poorest survival.
The research team says more work is necessary to confirm these findings and to
examine the precise mechanism by which a genotype influences the response of
cancer cells to cyclophosphamide. The team plans to examine the influence of
several variations on the resistance to other chemotherapies.
For more information on Dr. Ambsí research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=6100.
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Reference: Glynn SA, Boersma BJ, Howe TM, et al. A Mitochondrial Target Sequence
Polymorphism in MnSOD Predicts Inferior Survival in Breast Cancer Patients Treated
with Cyclophosphamide. Online June 9, 2009. Clinical Cancer Res.