Enzyme Variation Influences Effectiveness of Breast Cancer Treatment
Reported October 12, 2009
(Ivanhoe Newswire) — Among women with early stage breast cancer, genetic variation of a certain enzyme appears to be associated with clinical outcomes for women treated with tamoxifen, according to a new study.
Researchers state, “Tamoxifen has been the gold standard for the last 25 years for endocrine treatment of breast cancer. It is estimated that the lives of half a million women have been saved with [supplemental] tamoxifen therapy.”
Tamoxifens ability to inhibit tumor growth is mediated by its metabolites, and the formation of active metabolites is brought about by the CYP2D6 enzyme.
“Approximately 100 CYP2D6 genetic variants have been identified, which manifest in the population in 4 distinct phenotypes, extensive (normal activity), intermediate (reduced activity), poor (no activity), and ultrarapid (high activity) metabolism . . . . Thus, it can be speculated that genotype-related differences in the formation of active metabolites influence therapeutic response to tamoxifen,” study authors wrote.
Werner Schroth, D.Phil., of the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology in Stuttgart, Germany, and colleagues conducted a study to determine whether CYP2D6 variation is associated with clinical outcomes in women receiving tamoxifen. The study included 1,325 patients who had diagnoses of stage I through III breast cancer between 1986 and 2005 and who were mainly postmenopausal. Last follow-up was in December 2008, and the median follow-up time was 6.3 years. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced or absent enzyme activity. Women were classified as having an extensive, extensive/intermediate, or poor CYP2D6 metabolism.
The researchers found higher breast cancer rates in patients with reduced or absent CYP2D6 function. “At 9 years of follow-up, the recurrence rates were 14.9 percent for extensive metabolizers, 20.9 percent for . . . extensive/intermediate metabolizers, and 29.0 percent for poor metabolizers, and all-cause mortality rates were 16.7 percent, 18.0 percent, and 22.8 percent, respectively,” the authors wrote. Compared with extensive metabolizers, extensive/intermediate metabolizers had a 40 percent increased risk of recurrence; poor metabolizers had nearly twice the risk.
“Compared with extensive metabolizers, those with decreased CYP2D6 activity . . . had worse event-free survival and disease-free survival, but there was no significant difference in overall survival.”
“Genotyping has the potential for identification of women who have the CYP2D6 poor metabolism phenotype and for whom the use of tamoxifen is associated with poor outcomes, thus indicating consideration of alternative forms of adjuvant endocrine therapy,” the authors concluded.
SOURCE: Journal of the American Medical Association (JAMA), October 6, 2009