Inherited Variants Of Three Genes Affect Treatment Response And Outcome.(breast cancer)

2001 APR 5 - (NewsRx.com & NewsRx.net) -- In findings that support potential tailored therapy for patients with cancer and possibly other diseases, Duke University Medical Center researchers and colleagues report finding that inherited variants in three genes are associated with response to high-dose chemotherapy and overall survival in advanced breast cancer.

If future studies show that these genetic variants can predict response and outcome, a simple blood test and genetic analysis might help physicians select the best treatment options for each patient, the researchers said.

Besides breast cancer, this pre-treatment genotyping might be useful to tailor treatments for numerous other diseases, given the three genes' broad involvement in drug processing pathways, said lead author William Petros, assistant clinical professor of medicine at Duke Comprehensive Cancer Center.

"Despite giving doses based on patients' height and weight, the blood concentrations of drugs vary widely, and we think that's genetically based," said Petros, who prepared the results for presentation March 26, 2001, at the annual meeting of the American Association for Cancer Research. "In cancer treatment, factors that affect blood concentration can affect the thin line between effectiveness and intolerable toxicity. The link we've found between these three genes and patient response is potentially translatable to other situations and may be clinically applicable, but confirmatory studies need to be done," Petros said.

The researchers from Duke and a collaborating company, PPGx of La Jolla, California, (a fully owned subsidiary of DNA Sciences, Fremont, California) discovered that inherited variations in two genes, called CYP3A4 and CYP3A5, were associated with poorer response to high-dose chemotherapy treatment and poorer survival. Variants of a third gene, called GSTM1, provided a better response and longer average survival, they reported.

"CYP3A4 and CYP3A5 play important roles in the metabolism of over half of the drugs used clinically, not just drugs used in treating cancer, while GSTM1 detoxifies and removes drugs that get inside cells," Petros said. "Whether the variations are 'good' or 'bad' would depend on the drug being given."

Researchers reviewed the records of 86 patients with metastatic or inflammatory breast cancer who had been treated as part of a Duke clinical trial between 1988 and 1991. The scientists also extracted DNA from each patient's stored white blood cells, which had been collected prior to any treatment, and shipped the DNA to PPGx, where scientists analyzed each sample for 22 variants, or single nucleotide polymorphisms, in 12 drug metabolism genes.