CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

Abstract

Background Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. Methods A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism. Findings The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05–5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95–2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3–5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86–6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03–2.30). Conclusion In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

“…The meta-analysis of the association between the variant/variant genotype (or inferred poor metabolizer phenotype) and breast cancer recurrence or mortality, as compared with the wild-type/wild-type genotype (or inferred extensive or ultrametabolizer phenotype), included 21 of the 31 studies. In 16 (76%) of these 21 studies, researchers extracted DNA from nonneoplastic tissue (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), and in 5 of them (24%) they extracted DNA from tumor-infiltrated tissue (26-28, 46, 72). The summary estimates of association with and without bias analysis are reported in Table 3 and displayed in Figure 1.…”

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

“…Goetz et al [27] , have proven a statistically important incidence of negative events within carriers of poor CYP2D6 variants, while the two other studies failed to confirm such an association. Although they favour against a CYP2D6 genetic testing prior to tamoxifen therapy, it should be mentioned that both studies showed a substantial departure from the Hardy-Weinberg equilibrium regarding the frequency of allele*4 [25,26] .…”

“…It is important to mention that the three latest large studies refer exclusively to postmenopausal women with ER positive breast cancer disease [25][26][27] . Goetz et al [27] , have proven a statistically important incidence of negative events within carriers of poor CYP2D6 variants, while the two other studies failed to confirm such an association.…”

“…The possibility of such an event was significantly higher when poor alleles were present and only during the period of tamoxifen administration. It should be noted that *4 was present in 58.45% of all non-EM cases [27] .…”

Pharmacogenetic testing of allelic variants of the CYP2D6 gene in hormone positive breast cancer

“…Однако этот эффект не наблюдался у больных, переведенных на анастрозол после 2-лет-него приема тамоксифена. Эти данные позволяют предположить, что влияние генотипа CYP2D6 может быть замаскировано, если пациенты получают тамок-сифен непродолжительное время или другие препара-ты помимо тамоксифена, тем самым изменяя риск развития рецидива [43].…”