Analyzing the clinical actionability of germline pharmacogenomic findings in oncology.
Analyzing the clinical actionability of germline pharmacogenomic findings in oncology.
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DOI：
10.1002/cncr.31382
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发表时间：
2018-07-15
期刊：
影响因子：
6.2
通讯作者：
O'Donnell PH
中科院分区：
文献类型：
--
作者：
Wellmann R;Borden BA;Danahey K;Nanda R;Polite BN;Stadler WM;Ratain MJ;O'Donnell PH
生殖系和肿瘤药物基因组学影响药物反应，但生殖系标记物较少指导肿瘤处方。我们假设临床上可操作的种系药物基因组关联的关键数量存在，代表着临床实施的机会。我们分析了影响因子为≥5的期刊中的125种肿瘤药物的阳性种系药物基因组学关联。对设计和基因分型质量、临床相关结果、统计学严格性和药物基因效应的证据进行了评估。来自高方法学质量的研究的关联被认为是潜在的临床可操作的，翻译摘要被写成医疗保健点临床决策支持(CDS)工具，并使用研究和评估指南评估(Agree)II工具进行正式评估。我们确定了173种出版物中56/125种(45%)肿瘤药物的种系药物基因组学结果。检测到12种药物的可操作相关性，包括6种与食品和药物管理局标签或已发表指南(卡培他滨/氟尿嘧啶/DPYD，伊立替康/UGT1A1，硫代嘌呤/硫鸟嘌呤/TPMT，他莫昔芬/CYP2D6)中的胚系药物基因组信息，以及其他6种新药物(天冬酰胺酶/NFACT2/HLA-DRB1，顺铂/ACYP2，阿霉素/ABCC2/RAC2，拉帕替尼/HLA-DQA1，Sunitinib/CYP3A5，长春新碱/CEP72)。使用Agree II，开发的CDS摘要在范围和目的(92.7±5.1)和发展的严谨性(87.6±7.4)方面得分较高(均数±标准差[SD]；最高得分=100)，在表达清晰度(58.6±25.1)和适用性(55.9±24.6)方面得分中等但稳健。总体平均指南质量评分为5.2±1.0(最高分=7分)。建议实施这12种药物的种系药物基因组CDS摘要。一些肿瘤学药物具有可操作的种系药物基因组信息，通过机构药物基因组实施证明了交付的合理性，以确定临床效用。
Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. We hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities. We analyzed 125 oncology drugs for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically-relevant outcomes, statistical rigor, and evidence of drug-gene effects. Associations from studies of high methodologic quality were deemed potentially clinically actionable, and translational summaries were written as point-of-care clinical decision support (CDS) tools and formally evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. We identified germline pharmacogenomic results for 56/125 (45%) oncology drugs across 173 publications. Actionable associations were detected for 12 drugs, including six with germline pharmacogenomic information within Food and Drug Administration labels or published guidelines (capecitabine/fluorouracil/DPYD, irinotecan/UGT1A1, mercaptopurine/thioguanine/TPMT, tamoxifen/CYP2D6), while six others were novel (asparaginase/NFACT2/HLA-DRB1, cisplatin/ACYP2, doxorubicin/ABCC2/RAC2, lapatinib/HLA-DQA1, sunitinib/CYP3A5, vincristine/CEP72). Using AGREE II, developed CDS summaries had high scores (mean ± standard deviation [SD]; maximum score=100) for Scope and Purpose (92.7 ± 5.1) and Rigour of Development (87.6 ± 7.4) and moderate, yet robust scores for Clarity of Presentation (58.6 ± 25.1) and Applicability (55.9 ± 24.6). Overall mean guideline quality score was 5.2 ± 1.0 (maximum score=7). Germline pharmacogenomic CDS summaries for these 12 drugs were recommended for implementation. A number of oncology drugs have actionable germline pharmacogenomic information, justifying delivery through institutional pharmacogenomic implementations, to determine clinical utility.
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影响因子：
3.7
作者：
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通讯作者：
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