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, 100 (9), 642-8

Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

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Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

Rinaa S Punglia et al. J Natl Cancer Inst.

Abstract

Background: Adjuvant endocrine treatment with aromatase inhibitors improves disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor-positive breast cancer. This difference could be due to differences in tamoxifen metabolism because levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6).

Methods: We created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized 5-year disease-free survival for patients with the wild-type CYP2D6 genotype (wt/wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in breast cancer patients who were not selected by CYP2D6 genotype were derived from the Breast International Group 1-98 trial. Genotype frequencies and the hazard ratio for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR(*4/*4) = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen. We explored the impact of CYP2D6(*4) heterozygosity on disease-free survival for wt/wt patients by studying a range of effect (ie, recurrence on tamoxifen) estimates, from no effect of the single mutation (Eff(wt/*4) = 0, recurrence rate in wt/*4 patients same as that in wt/wt patients) to complete effect (Eff(wt/*4) = 1 recurrence rate in wt/*4 patients same as that in *4/*4 patients).

Results: With HR(*4/*4) = 1.86 and Eff(wt/*4) = 0.5, the 5-year disease-free survival of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, that is, essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR(*4/*4) estimates, disease-free survival with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Eff(wt/*4) ratios.

Conclusions: Modeling suggests that among patients who are wild type for CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer, particularly those who have with concerns about either the relative toxicity or the increased cost of aromatase inhibitors.

Figures

Figure 1
Figure 1
Model results for disease-free survival in the unselected population and in each genotypic subgroup. For these analyses, we assumed a hazard ratio of recurrence in homozygous mutation carriers (*4/*4) of 1.86 (HR*4/*4 = 1.86) and that the increased hazard ratio in heterozygotes (wt/*4) was half that in *4/*4 homozygotes. The thick gray line represents the aromatase inhibitor strategy in the unselected population. The thick black line represents in the tamoxifen strategy in the unselected population. The tamoxifen strategy in the wild-type (wt/wt) subgroup is shown as black circles, in the wt/*4 subgroup as a thin dashed black line, and in the *4/*4 subgroup as a thin solid black line.
Figure 2
Figure 2
Two-way sensitivity analysis for the wild-type (wt/wt) subgroup. The hazard ratio of recurrence among the homozygous mutation carriers (HR*4/*4) is plotted on the x-axis, and proportion of HR*4/*4 attributed to heterozygotes (Effwt/*4) is plotted on the y-axis. The gray zone represents the combinations of Effwt/*4 and HR*4/*4 for which aromatase inhibitors optimize 5-year disease-free survival for wt/wt patients. The white zone represents the combinations of Effwt/*4 and HR*4/*4 for which tamoxifen optimizes 5-year disease-free survival for these patients. The asterisk marks the combination of HR*4/*4 and calculated Effwt/*4—2.6 and 0.316, respectively—that corresponds to updated but unadjusted estimates from the North Central Cancer Treatment Group trial data.

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