Tamoxifen sharply cuts the risk of breast cancer relapse, but it may be less effective in women who carry a relatively common genetic variation, according to researchers here.
The genetic alteration affects the level of cytochrome P4502D6 (or CYP2D6), a liver enzyme that is involved in metabolizing the drug, said Matthew Goetz, M.D., an oncologist at the Mayo Clinic here and colleagues. About one in 10 women in the U.S. have the variation.
CYP2D6 is "a crucial enzymatic step responsible for activating tamoxifen to a metabolite that is nearly one hundred times more potent than tamoxifen," Dr. Goetz colleagues reported in the Dec. 20 issue of the Journal of Clinical Oncology.
Women whose CYP2D6 gene is altered, he said, appear to be at higher risk of relapse when treated with five years of tamoxifen, which ordinarily reduces the risk of recurrence by nearly half in women with estrogen-receptor positive breast cancer.
Normally, the enzyme CYP2D6 converts tamoxifen to a metabolite called endoxifen that is a more potent anti-estrogen than tamoxifen itself, said study co-author James Rae, Ph.D., of the University of Michigan.
Rae and colleagues were the first to work out the link between CYP2D6 and the activation of endoxifen, but the clinical implications of the finding were unknown, he said.
If the enzyme were missing or present in lower-than-normal levels, it could affect how well tamoxifen would work to control relapse, he said.
To find out, the researchers looked at tumor and tissue samples from women who took part in the tamoxifen arm of a Phase III study of adjuvant therapy in women with resected estrogen-receptor positive breast cancer.
Of the 223 women for whom tissue samples were available, 137 had the wild-type CYP2D6 gene on both copies of chromosome 22, 40 had one wild-type chromosome and one with the genetic variant, and 13 were homozygous for the variant.
Univariate analysis showed that women who were homozygous for the variant were twice as likely as the others to see their cancer return: - For relapse-free time, the hazard ratio was 2.71, with a 95% confidence interval from 1.15 to 6.41, and a statistical significance of p=0.023.
- For disease-free survival, the hazard ratio was 2.44, with a 95% confidence interval from 1.22 to 4.90, and a statistical significance of p=0.012.
- There was a trend toward worse overall survival (the hazard ratio was 1.73) but it was not significant.
When nodal status and tumor size was factored into a multivariate analysis, women with the variant still tended to have worse relapse-free time and disease-free survival, but the trends lost significance, the researchers found.
The finding has "the potential to improve the ability of physicians to select the optimal hormonal therapy for the treatment or ERR-positive women," the researchers concluded, although more study is needed to nail down the effect of the genetic variations.
Primary source: Journal of Clinical Oncology
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