Alterations in CYP2D6 Enzyme Affect Efficacy of Tamoxifen

Matthew Goetz, MD

Genetic or drug-induced alterations of the enzyme CYP2D6 that result in reduced metabolism of tamoxifen are associated with a higher risk of recurrence and death in women with estrogen receptor—positive breast cancer who receive the drug. The results of the study were published in Clinical Cancer Research.

CYP2D6 is responsible for the metabolism of tamoxifen to create its active metabolite, endoxifen. The study’s authors noted that there has been controversy regarding whether the effectiveness of the tamoxifen is affected by alterations in CYP2D6. They conducted this study to independently determine whether the odds of death or recurrence differ by CYP2D6 genotype in patients who received 5 years of adjuvant tamoxifen. Additionally, the researchers wanted to determine whether there is a relationship between CYP2D6 genotype and outcomes in patients who received 2 years of tamoxifen followed by 3 years of anastrozole, compared with those who received 5 years of tamoxifen.

The researchers used data obtained from patients enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8, a prospective, multicenter, randomized, open-label trial that randomized 3901 surgically resected early-stage breast cancer patients within 6 weeks after surgery to receive either 5 years of tamoxifen (20 mg daily) or 2 years of tamoxifen (20 mg daily) followed by 3 years of anastrozole (1 mg daily).

Eligible patients were postmenopausal women aged ≤80 years and had histologically verified ductal or lobular breast carcinoma that was invasive or minimally invasive, endocrine-responsive, and Nottingham grade 1 or 2. Patients were not allowed to have previously received neoadjuvant chemotherapy, hormone therapy, or radiotherapy.

The researchers used an assay to determine which alleles were most closely associated with different types of CYP2D6 metabolism. They found that alleles *3, *4, and *6 were associated with no metabolism (PM), and alleles *10 and *41 were associated with reduced metabolism (IM). The absence of those alleles was associated with extensive metabolism (EM).

In the group of patients assigned to 5 years of tamoxifen, women had a higher likelihood of a recurrence or death if they had two poor alleles (PM/PM: odds ratio [OR] = 2.45; 95% CI, 1.05-5.73; P = .04) or one poor allele (PM/IM or PM/EM: OR = 1.67; 95% CI, 0.95-2.93; P = .07) compared with women with two extensive alleles (EM/EM).

In years 3 to 5, when patients in the study remained on tamoxifen or switched to anastrozole, patients with PM/PM tended toward a higher likelihood of experiencing recurrence or death relative to patients with EM/EM if they continued on tamoxifen (OR = 2.40; 95% CI, 0.86-6.66; P = .09), but the same was not true in women who switched to anastrozole (OR = 0.28; 95% CI, 0.03-2.30; P = 0.23).

“Our findings confirm that, in early breast cancer treated with tamoxifen, genetic alterations in CYP2D6 lead to a higher likelihood of recurrence and death,” said Matthew Goetz, MD, associate professor of Oncology at the Mayo Clinic in Rochester, Minnesota, and lead author of the study, in a statement.

Goetz said he believes that switching from tamoxifen to an aromatase inhibitor, the current recommendation, will give women with decreased CYP2D6 metabolism the greatest benefit. He said that women who are identified as poor metabolizers of CYP2D6 should probably avoid tamoxifen altogether and begin therapy with an aromatase inhibitor.

Additionally, Goetz’s research group is working with the National Cancer Institute to develop endoxifen, the active part of tamoxifen. If successfully developed, Goetz said it would not matter how tamoxifen gets metabolized.

Goetz MP, Suman VJ, Hoskin TL, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8. Clin Cancer Res. 2013;19(2):500-507.