CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.
CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.
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DOI：
10.1158/1078-0432.ccr-12-2153
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发表时间：
2013-01-15
期刊：
影响因子：
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通讯作者：
Ingle JN
中科院分区：
文献类型：
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作者：
Goetz MP;Suman VJ;Hoskin TL;Gnant M;Filipits M;Safgren SL;Kuffel M;Jakesz R;Rudas M;Greil R;Dietze O;Lang A;Offner F;Reynolds CA;Weinshilboum RM;Ames MM;Ingle JN
关于CYP2D6基因型和他莫昔芬疗效存在争议。一项匹配的病例对照研究利用奥地利乳腺癌和结直肠癌研究组试验8进行，随机分配绝经后雌激素受体阳性乳腺癌妇女服用他莫昔芬5年（A组）或服用他莫昔芬2年后服用阿那曲唑3年（B组）。病例有疾病复发、对侧乳腺癌、第二次非乳腺癌或死亡。对于每个病例，从年龄、手术/放疗和TNM分期相似的同一治疗组中确定对照。对no （PM; *3, *4, *6）相关等位基因进行基因分型；减少（IM; *10, *41）；广泛的（EM：缺乏这些等位基因）CYP2D6代谢。常见的CYP2D6 *4等位基因处于Hardy Weinberg平衡。在A组治疗的前5年，携带2个不良等位基因（PM/PM: OR=2.45, 95% CI: 1.05-5.73, p=0.04）和携带1个不良等位基因（PM/IM或PM/EM: OR=1.67, 95% CI: 0.95-2.93, p=0.07）的女性比携带2个广泛等位基因（EM/EM）的女性发生事件的可能性更高。在3-5年，当患者继续服用他莫昔芬（A组）或改用阿那曲唑（B组）时，在A组的女性中，PM/PM相对于EM/EM （or = 2.40, 95% CI: 0.86-6.66, p=0.09）倾向于疾病事件发生的可能性更高，而在B组的女性中则相反（or = 0.28, 95% CI: 0.03-2.30）。在ABCSG8中，CYP2D6代谢降低的负面影响仅在他莫昔芬给药期间观察到，而在切换到阿那曲唑后没有观察到。
Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. 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. 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). In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.