Via NIH Press - Researchers have found links between an individual's 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 moleculesknown as reactive oxygen species, or free radicals. Reactive oxygen species areproduced by normal cellular processes and the action of some chemotherapy drugs.The findings represent the first preliminary evidence pointing toward a mechanismand 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 diagnostictest may be developed that determines whether a patient has certain genetic variationsthat may modify the effect of certain chemotherapies," said study author SharonGlynn, Ph.D., of NCI’s Center for Cancer Research.

"In the future, such tests may be used to guide the treatment of patients withthe SOD2 variation, ensuring that they receive a therapy that is more effectivethan 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 motherand the other inherited from the father. These gene copies can vary from oneanother.

Some variations in genes play an important role in how a gene is expressedor how its protein product functions. The variant identified by the researchers in the SOD2 gene affects both the structureand the function of the encoded protein, an enzyme known as manganese superoxidedismutase (MnSOD) and affects the ability of MnSOD to reach its proper locationin the cell and its activity level. MnSOD normally functions inside cellularcompartments known as mitochondria and helps protect cells from damage causedby reactive oxygen species formed during cellular metabolism. Excessive levelsof reactive oxygen species can be toxic to cells. Indeed, some anticancer drugsdepend on increased production of reactive oxygen species to kill cancer cells.

Furthermore, some studies have indicated that, because MnSOD neutralizes reactiveoxygen species, it can modify the effects of chemotherapy drugs. For example,in laboratory and animal models, increased activity of MnSOD protects cells againstthe toxic effects of doxorubicin, which is a widely used anticancer drug. In the new study, the research team investigated whether the variation affectedsurvival in two separate groups of women with breast cancer: 248 women in theUnited 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 womento determine their genotype, meaning which types of the SOD2 gene they had.

Theresearchers found that, among patients who received chemotherapy, those who hadone 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 didnot receive chemotherapy. Next, the team looked at the relationship between SOD2 genotype and the typeof chemotherapy the women received. The data were analyzed according to whichof three types of commonly used chemotherapy drugs were administered: doxorubicin,5-fluorouracil, or cyclophosphamide. Both doxorubicin and cyclophosphamide generatereactive oxygen species in cancer cells during treatment.

The researchers determinedthat the presence of a particular variant was associated with decreased survivalof patients treated with chemotherapy regimens that contained any of the threedrugs. However, the most significant effects were found with the drug cyclophosphamide.Women with a distinct variant form of SOD2 and who received cyclophosphamide-containingchemotherapy had the poorest survival. The research team says more work is necessary to confirm these findings and toexamine the precise mechanism by which a genotype influences the response ofcancer cells to cyclophosphamide. The team plans to examine the influence ofseveral variations on the resistance to other chemotherapies.

For more information on Dr. Ambs’ research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=6100. NCI leads the National Cancer Program and the NIH effort to dramatically reducethe burden of cancer and improve the lives of cancer patients and their families,through research into prevention and cancer biology, the development of new interventions,and the training and mentoring of new researchers. For more information aboutcancer, please visit the NCI Web site at http://www.cancer.gov or call NCI'sCancer Information Service at 1-800-4-CANCER (1-800-422-6237).