Stockley Tracy L, Oza Amit M, Berman Hal K, Leighl Natasha B, Knox Jennifer J, Shepherd Frances A, Chen Eric X, Krzyzanowska Monika K, Dhani Neesha, Joshua Anthony M, Tsao Ming-Sound, Serra Stefano, Clarke Blaise, Roehrl Michael H, Zhang Tong, Sukhai Mahadeo A, Califaretti Nadia, Trinkaus Mateya, Shaw Patricia, van der Kwast Theodorus, Wang Lisa, Virtanen Carl, Kim Raymond H, Razak Albiruni R A, Hansen Aaron R, Yu Celeste, Pugh Trevor J, Kamel-Reid Suzanne, Siu Lillian L, Bedard Philippe L
Laboratory Medicine Program, University Health Network, Toronto, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Genome Med. 2016 Oct 25;8(1):109. doi: 10.1186/s13073-016-0364-2.
The clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM).
Patients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients' molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated.
From March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response.
Few advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate.
NCT01505400 (date of registration 4 January 2012).
肿瘤组织分子谱分析指导晚期实体瘤患者治疗的临床实用性尚不清楚。我们的目的是评估基因组改变的频率、体细胞变异的临床“可操作性”、参与针对特定突变或其他临床试验的情况，以及玛格丽特公主癌症中心（PM）晚期实体瘤患者分子谱分析的结果。
前瞻性纳入年龄≥18岁、体能状态良好且有存档肿瘤组织的晚期实体瘤患者。使用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）热点 panel 或靶向二代测序（NGS）panel 检测存档福尔马林固定石蜡包埋肿瘤组织中的DNA。根据临床可操作性对体细胞变异进行分类，并将一份注释报告纳入电子病历。为肿瘤学家提供其患者分子谱分析结果的汇总表以及可用的特定突变临床试验。评估在分析结果发布后参与基因型匹配与基因型不匹配临床试验的情况以及根据实体瘤疗效评价标准（RECIST）v1.1标准的反应。
2012年3月至2014年7月，纳入1893例患者，1640例接受检测。中位随访18个月后，1640例接受检测的患者中有245例（15%）随后参与了277项治疗性临床试验，其中84例（5%）参与了89项基因型匹配试验。与基因型不匹配试验（9%）相比，接受基因型匹配试验治疗的患者总体缓解率更高（19%；p＜0.026）。在多变量模型中，基因型试验匹配（p = 0.021）和女性性别（p = 0.034）是与治疗反应可能性增加相关的唯一因素。
在一项前瞻性机构分子谱分析试验中纳入的晚期实体瘤患者中，很少有患者随后接受基因型匹配的治疗性试验。在这项非随机比较中，早期临床试验的基因型富集与客观肿瘤缓解率增加相关。
NCT01505400（注册日期2012年1月4日）
