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Women at high risk for breast cancer who have undergone a hysterectomy appear to benefit from taking tamoxifen to prevent breast cancer, according to an extended follow-up of the Italian Randomized Tamoxifen Trial. The initial findings from the Italian trial showed no significant reduction in breast cancer risk with tamoxifen use. However, the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Treatment /Prevention Trial found that tamoxifen reduced the risk of estrogen receptor-positive breast cancer. Umberto Veronesi, M.D., of the European Institute of Oncology in Milan, and colleagues randomly assigned 5,408 healthy women who had a hysterectomy to receive tamoxifen or a placebo for 5 years. After 11 years of follow-up, 136 women developed breast cancer–74 in the placebo group and 62 in the tamoxifen group. Among low-risk women, rates of breast cancer were similar in the tamoxifen and placebo groups. But for women at high risk, breast cancer rates were lower for those taking tamoxifen. Women taking tamoxifen experienced more side effects, including hot flashes and heart problems, than women in the placebo group. "A complete assessment of the baseline cardiovascular risk should become an important component of counseling women on the use of tamoxifen, particularly in the prevention setting," the authors write.

Breast Cancer Treatment : Selecting Patients

Breast cancer patients who carry the wild-type gene required for tamoxifen metabolism may have comparable risk of recurrence when taking tamoxifen or an aromatase inhibitor, according to modeling data. Cytochrome P450 2D6 (CYP2D6) converts tamoxifen into its metabolically active form called endoxifen. The enzymes encoded by different variants of the CYP2D6 gene metabolize tamoxifen at different rates. For example, women who carry two copies of the CYP2D6*4 allele have less endoxifen in their blood than women who carry two copies of the wild-type allele for CYP2D6. The lower serum concentration of endoxifen may make tamoxifen less effective for the women with the CYP2D6 *4 allele. However, two large randomized trials, which did not test women for their CYP2D6 genotype, showed that breast cancer survivors who take aromatase inhibitors reduce their risk of recurrence more than those taking tamoxifen.

To estimate whether women with wild-type CYP2D6 might derive more clinical benefit from tamoxifen than from aromatase inhibitors, Rinaa Punglia, M.D., of the Dana-Farber Cancer Institute in Boston and colleagues created a mathematical model. The researchers used estimates about the risk of recurrence from past randomized trials. Punglia and colleagues calculated that women with wild-type CYP2D6 who take tamoxifen would have approximately the same reduction in the risk of recurrence as was seen for the whole population of women who took aromatase inhibitors in the clinical trial. Therefore, women with wild-type CYP2D6 genotype may derive as much benefit from tamoxifen as from aromatase inhibitors. "Our model raises the possibility that tailored therapy based on pharmacogenomics could be considered for such women," the authors write. In an accompanying editorial, Daniel Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor and colleagues review what is known about tamoxifen metabolism and CYP2D6 allele types and their impact on the risk of recurrence for breast cancer patients. The editorialists comment that the conclusions by Punglia and colleagues are important because they have brought the field of pharmacogenomics to the attention of breast cancer physicians. However, the analysis was based on limited data and on modeling assumptions and must be viewed with caution. "We do not recommend routine CYP2D6 genotyping for all patients who are considering tamoxifen, although we recognize that there are already selected circumstances in which such knowledge might be helpful," they write.