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NEW ORLEANS, Mar 26 (Reuters Health) - Women with breast cancer who have certain variations in drug metabolizing genes may be less likely to survive than other patients, Duke University researchers reported here at the American Association for Cancer Research meeting.
Almost everyone carries the two genes, which play a role in the breakdown of chemotherapy drugs. A third gene may also be implicated in survival, said lead investigator William Petros, director of the clinical pharmacology lab at Duke's Medical Center in Durham, North Carolina.
The work is groundbreaking because "there are very few examples, perhaps if any, where you could predict drug metabolism and patient survival in a cancer population," Petros said.
He and his colleagues examined stored blood samples from 86 women with breast cancer who came to the medical center between 1988 and 1991. None of the women had received chemotherapy before, and all gave samples before they began their treatment.
The researchers analyzed the women's DNA and found that women with variations in the CYP3A4 and CYP3A5 genes (common in most people) were not able to metabolize the chemotherapy drug cyclophosphamide. To be an effective tumor-killer, cyclophosphamide needs to be metabolized. So these women had high blood concentrations of the drug, but it was not active.
Their median survival was 12 to 18 months, compared with almost 3 years for the women who did not have a variation in those two genes.
Survival was also decreased for women who had one or two copies of a gene called GSTM1. GSTM1 helps normal cells flush anti-cancer drugs out, thus protecting them from being killed along with the tumor cells. But it is also often found in cancer cells and if it's working too much, it might flush the cancer drug out of the malignant cells, too. Women who had two nonfunctioning versions of the GSTM1 gene were at a survival advantage compared to those with one or two functioning versions of the gene.
Petros said the Duke team will verify the significance of all three gene variations over the next few months, and then they hope to begin tests in humans.
Patients would be tested for these genes before chemotherapy, a dose will be determined based on those results, and then their blood will be sampled during therapy to make sure appropriate drug levels are being maintained.
"Hopefully, we could tailor the dose of drugs we're giving to avoid adverse events and optimize their chance for effectiveness," Petros said.
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