Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.
Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.
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DOI：
10.1038/s41598-016-0021-4
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发表时间：
2016-12-23
影响因子：
4.6
通讯作者：
Bryce AH
中科院分区：
文献类型：
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作者：
Borad MJ;Egan JB;Condjella RM;Liang WS;Fonseca R;Ritacca NR;McCullough AE;Barrett MT;Hunt KS;Champion MD;Patel MD;Young SW;Silva AC;Ho TH;Halfdanarson TR;McWilliams RR;Lazaridis KN;Ramanathan RK;Baker A;Aldrich J;Kurdoglu A;Izatt T;Christoforides A;Cherni I;Nasser S;Reiman R;Cuyugan L;McDonald J;Adkins J;Mastrian SD;Valdez R;Jaroszewski DE;Von Hoff DD;Craig DW;Stewart AK;Carpten JD;Bryce AH
DNA聚焦面板测序已迅速用于评估晚期/难治性癌症的治疗靶点。综合基因组分析（IGP）利用DNA/RNA与肿瘤/正常比较，符合临床实验室改进修正案（CLIA）的设置，使单个分析能够提供：治疗靶点优先级，新靶点发现/应用和全面的生殖系评估。采用符合clia的IGP对35例晚期/难治性癌症患者进行了前瞻性研究。可行性评估通过估计时间到结果（TTR），优先考虑/分配假定的治疗靶点，评估药物可及性，确定生殖系改变，以及评估患者对数据使用/报告的偏好/观点。使用生物智能/途径分析确定治疗靶点，并由基因组肿瘤委员会进行解释。75%的病例含有1-3个治疗靶向突变/例（中位79个具有潜在功能意义的突变/例）。获得clia验证结果的中位时间为116天，其中21/22例患者实现了clia验证目标。13例患者采用FDA批准的药物（n = 9）、临床试验（n = 3）和单例IND （n = 1）进行IGP定向治疗。初步临床疗效5例（部分缓解2例，病情稳定3例）。尽管存在广泛应用的障碍，包括需要更广泛的治疗方法，但clia框架中的IGP在抗癌治疗靶点的选择/优先排序方面是可行的和有价值的。
DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1–3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.