Foundation Medicine Inc., Cambridge, Massachusetts, USA
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Oncologist. 2018 Jul;23(7):776-781. doi: 10.1634/theoncologist.2017-0493. Epub 2018 Mar 14.
In our recent study, of cases positive for epidermal growth factor receptor () exon 19 deletions using comprehensive genomic profiling (CGP), 17/77 (22%) patients with prior standard of care (SOC) testing results available were previously negative for exon 19 deletion. Our aim was to compare the detection rates of CGP versus SOC testing for well-characterized sensitizing point mutations (pm) in our 6,832-patient cohort.
DNA was extracted from 40 microns of formalin-fixed paraffin-embedded sections from 6,832 consecutive cases of non-small cell lung cancer (NSCLC) of various histologies (2012-2015). CGP was performed using a hybrid capture, adaptor ligation-based next-generation sequencing assay to a mean coverage depth of 576×. Genomic alterations (pm, small indels, copy number changes and rearrangements) involving were recorded for each case and compared with prior testing results if available.
Overall, there were 482 instances of exon 21 L858R (359) and L861Q (20), exon 18 G719X (73) and exon 20 S768I (30) pm, of which 103 unique cases had prior testing results that were available for review. Of these 103 cases, CGP identified 22 patients (21%) with sensitizing pm that were not detected by SOC testing, including 9/75 (12%) patients with L858R, 4/7 (57%) patients with L861Q, 8/20 (40%) patients with G719X, and 4/7 (57%) patients with S768I pm (some patients had multiple pm). In cases with available clinical data, benefit from small molecule inhibitor therapy was observed.
CGP, even when applied to low tumor purity clinical-grade specimens, can detect well-known pm in NSCLC patients that would otherwise not be detected by SOC testing. Taken together with exon 19 deletions, over 20% of patients who are positive for -activating mutations using CGP are previously negative by SOC mutation testing, suggesting that thousands of such patients per year in the U.S. alone could experience improved clinical outcomes when hybrid capture-based CGP is used to inform therapeutic decisions.
This study points out that genomic profiling, as based on hybrid capture next-generation sequencing, can identify lung cancer patients with point mutation in epidermal growth factor receptor (EGFR) missed by standard molecular testing who can likely benefit from anti-EGFR targeted therapy. Beyond the specific findings regarding false-negative point mutation testing for EGFR, this study highlights the need for oncologists and pathologists to be cognizant of the performance characteristics of testing deployed and the importance of clinical intuition in questioning the results of laboratory testing.
在我们最近的研究中，使用全面基因组分析（CGP）对表皮生长因子受体（）外显子 19 缺失呈阳性的病例进行分析，77 例中有 17 例（22%）先前有标准护理（SOC）检测结果的患者为外显子 19 缺失阴性。我们的目的是比较 CGP 与 SOC 检测在我们的 6832 例患者队列中对明确的敏感突变（pm）的检测率。
从各种组织学类型的 6832 例非小细胞肺癌（NSCLC）连续病例的 40 微米福尔马林固定石蜡包埋切片中提取 DNA（2012-2015 年）。CGP 采用杂交捕获、接头连接的基于下一代测序的检测方法进行，平均覆盖深度为 576×。记录了每个病例涉及的基因组改变（pm、小插入缺失、拷贝数变化和重排），并在有可用结果的情况下与先前的检测结果进行比较。
总体而言，有 482 例出现 外显子 21 L858R（359 例）和 L861Q（20 例）、外显子 18 G719X（73 例）和外显子 20 S768I（30 例）pm，其中 103 例有先前的 检测结果可供审查。在这 103 例患者中，CGP 发现了 22 例（21%）SOC 检测未检出的敏感突变（pm），包括 9/75（12%）L858R 患者、4/7（57%）L861Q 患者、8/20（40%）G719X 患者和 4/7（57%）S768I pm 患者（部分患者有多个 pm）。在有可用临床数据的病例中，观察到小分子抑制剂治疗的获益。
CGP，即使应用于低肿瘤纯度的临床级标本，也可以检测到非小细胞肺癌患者中已知的 pm，而 SOC 检测则无法检测到这些 pm。与外显子 19 缺失一起，使用 CGP 检测到的 -激活突变阳性患者中，有超过 20%的患者 SOC 突变检测呈阴性，这表明在美国每年有数千例这样的患者，如果使用基于杂交捕获的 CGP 来指导治疗决策，他们的临床结局可能会得到改善。
这项研究指出，基于杂交捕获的下一代测序的基因组分析可以识别出标准分子检测漏检的表皮生长因子受体（EGFR）点突变的肺癌患者，这些患者可能受益于抗 EGFR 靶向治疗。除了关于 EGFR 点突变检测假阴性的具体发现外，本研究还强调了肿瘤学家和病理学家需要了解所使用的检测性能特征，并认识到临床直觉在质疑实验室检测结果方面的重要性。
