Baatjes K J, Conradie M, Apffelstaedt J P, Kotze M J
Department Surgical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive Tygerberg. South Africa.
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences Stellenbosch University, Tygerberg. South Africa.
Anticancer Agents Med Chem. 2017;17(13):1805-1813. doi: 10.2174/1871521409666170412124226.
Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures.
This review outlines key issues in the implementation of pharmacogenetics of cytochrome P450 and tamoxifen as a model for optimal use of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer.
Lessons learnt from the association between tamoxifen and CYP2D6 genotyping were applied to identify polymorphisms with the potential to change clinical decision-making in patients on aromatase inhibitors. The ability of next generation sequencing to supersede single-gene analysis was furthermore evaluated in a subset of breast cancer patients on aromatase inhibitors selected from a central genomics database.
Methodological flaws in major randomised controlled trials and continued referral to incorrect results in expert consensus statements are important factors delaying the implementation of CYP2D6 pharmacogenetics in tamoxifen treatment. This highlighted the importance of a clinical pipeline including comprehensive genotyping, to define the target population most likely to benefit from aromatase inhibitor pharmacogenetics.
The clinical utility of CYP2D6 genotyping is well-established in patients at increased risk of tamoxifen resistance due to cumulative risk. The pharmacogenetics of CYP19A1 requires further clarification in terms of bone risk assessment for appropriate use in the treatment algorithm of high-risk patients at the onset of aromatase inhibitors.
遗传学在乳腺癌内分泌治疗的药物代谢中起着重要作用。这些方面在服用他莫昔芬的患者中已得到广泛研究，但芳香化酶抑制剂的药物遗传学研究尚不充分。与他莫昔芬的保护作用相反，芳香化酶抑制剂与骨质流失和骨折风险增加有关。
本综述概述了细胞色素P450药物遗传学及他莫昔芬作为绝经后雌激素受体阳性乳腺癌患者优化使用芳香化酶抑制剂模型的实施中的关键问题。
应用从他莫昔芬与CYP2D6基因分型之间关联中吸取的经验教训，以识别可能改变服用芳香化酶抑制剂患者临床决策的多态性。此外，在从中央基因组数据库中选取的一部分服用芳香化酶抑制剂的乳腺癌患者中，评估了下一代测序取代单基因分析的能力。
主要随机对照试验中的方法学缺陷以及专家共识声明中持续引用错误结果是延迟CYP2D6药物遗传学在他莫昔芬治疗中实施的重要因素。这凸显了包括全面基因分型在内的临床流程对于确定最有可能从芳香化酶抑制剂药物遗传学中获益的目标人群的重要性。
CYP2D6基因分型的临床效用在因累积风险而有他莫昔芬耐药风险增加的患者中已得到充分确立。就骨风险评估而言，CYP19A1的药物遗传学需要进一步阐明，以便在开始使用芳香化酶抑制剂时在高危患者的治疗算法中适当应用。
