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CYP2D6 Genotyping Fails to Predict Effectiveness of Tamoxifen

Online First
Alice Goodman

According to 2 large breast cancer trials, CYP2D6 genotyping was not predictive of the effectiveness of tamoxifen in postmenopausal women. Thus, the results of these studies are not generalizable to premenopausal women.

CYP2D6 genotyping has been a focus of research interest, but studies have been inconclusive as to the value of testing. In theory, certain CYP2D6 genotypes and phenotypes would be associated with breast cancer outcomes on treatment with tamoxifen; that is, tamoxifen would be less effective in poor and intermediate metabolizers of endoxifen (a metabolite of tamoxifen) and more effective in extensive metabolizers of endoxifen.

The 2 studies—ATAC and BIG 1-98—were published in the Journal of the National Cancer Institute (JNCI) online on March 6, 2012.

ATAC was a prospective clinical trial that compared effectiveness and safety of the aromatase inhibitor anastrozole versus tamoxifen in postmenopausal women with hormone receptor–positive early-stage breast cancer. Tumor samples from 1203 women were genotyped for CYP2D6. At a median follow-up of 10 years, no significant associations were found in the tamoxifen-treated group between the CYP2D6 genotype for poor metabolizers versus extensive metabolizers for distant recurrence or for any recurrence. As might be expected, no associations were found between the CYP2D6 genotype and recurrence in the patients who received anastrozole.

BIG 1-98 randomized postmenopausal women with hormone-sensitive, operable, invasive breast cancer to 5 years of treatment with tamoxifen monotherapy versus letrozole monotherapy. The findings were similar to those of ATAC, with no significant association found between CYP2D6 metabolism phenotypes and breast cancer–free interval in women treated with tamoxifen.

The authors of BIG 1-98 also studied new-onset or worsening hot flushes during the first 2 years of tamoxifen therapy. They wrote, the results “suggest that CYP2D6 testing is not justified to determine whether tamoxifen should be given to postmenopausal women, nor to withhold treatment with an aromatase inhibitor. The presence or absence of hot flushes should not be used in the clinical setting to estimate tamoxifen efficacy.”

In an accompanying editorial in the same issue of JNCI, Catherine M. Kelly, MD, and Kathleen I. Pritchard, MD, wrote: “The fact that these two studies confirm each other suggests that this matter has likely been laid to rest.” They noted that the findings suggest that the vast industry of CYP2D genotype testing was premature, that patients underwent additional and unnecessary tests and charges related to genotyping, and that therapy was adjusted according to genotyping test results without firm evidence.

Both editorial writers wrote that the lessons learned from these 2 large trials include the need for large confirmatory studies of therapeutic agents and biomarkers. Results of ATAC and BIG 1-98 illustrate that laboratory observations that raise hypotheses must be independently validated in order to guide clinical practice.

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Last modified: April 27, 2020