Lohinai Zoltan, Megyesfalvi Zsolt, Dome Balazs, Weiss Glen J
National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
Transl Oncol. 2019 Dec;12(12):1539-1548. doi: 10.1016/j.tranon.2019.08.004. Epub 2019 Aug 31.
Molecular underpinnings that may prognosticate survival could increase understanding of small cell lung cancer (SCLC) tumor behavior. Here, we report the clinicopathological characteristics and biomarker profiles of short-term (ST) versus long-term (LT) survival in patients with metastatic SCLC.
Of the 876 consecutive metastatic SCLC patients receiving standard of care therapy, 44 met the definition of LT and 91 for ST, respectively. Available FFPE tumor tissue blocks were analyzed by next-generation sequencing (NGS). Analysis included gene mutations, copy number variations, mRNA expression, and protein expression by immunohistochemistry, followed by correlation with clinicopathological characteristics.
There were no statistically significant and clinically relevant differences in cases with or without FFPE according to major clinicopathological variables in ST and LT. However, according to NGS, five mutually exclusive gene mutations were identified (E1A binding protein P300 [EP300] p.N217S; p.E152K; human epidermal growth factor receptor 4 [ERBB4] p.E317K; BRCA1, DNA repair associated [BRCA1] p.E1661N, and epidermal growth factor receptor [EGFR] p.V742A). Comparing LT vs. ST survivals, a twofold increase was found in the average predicted number of drugs per patient off compendium. We found high SSTR2 mRNA expressions in all LT patients (vs. two [20%] ST patients), which may reflect more benign neuroendocrine tumor characteristics.
Consolidation radiation therapy and higher predicted drug sensitivity for off compendium were associated with LT compared to ST patients in SCLC. NGS profiling of extreme survivals may improve classification of SCLC and possibly identify clinically relevant new targets.
可能预示生存情况的分子基础有助于增进对小细胞肺癌（SCLC）肿瘤行为的理解。在此，我们报告转移性SCLC患者短期（ST）与长期（LT）生存的临床病理特征及生物标志物谱。
在876例接受标准治疗的连续性转移性SCLC患者中，分别有44例符合LT定义，91例符合ST定义。对可用的福尔马林固定石蜡包埋（FFPE）肿瘤组织块进行二代测序（NGS）分析。分析包括基因突变、拷贝数变异、mRNA表达以及免疫组化检测的蛋白表达，随后与临床病理特征进行相关性分析。
根据ST和LT的主要临床病理变量，有或无FFPE的病例之间在统计学上无显著且临床相关的差异。然而，根据NGS，鉴定出五个相互排斥的基因突变（E1A结合蛋白P300 [EP300] p.N217S；p.E152K；人表皮生长因子受体4 [ERBB4] p.E317K；DNA修复相关的BRCA1 [BRCA1] p.E1661N以及表皮生长因子受体[EGFR] p.V742A）。比较LT与ST生存情况，发现每位患者超出汇编的平均预测药物数量增加了两倍。我们在所有LT患者中发现高SSTR2 mRNA表达（相比之下，2例[20%] ST患者有该表达），这可能反映出更良性的神经内分泌肿瘤特征。
与ST患者相比，SCLC患者的LT与巩固放疗及更高的超出汇编预测药物敏感性相关。极端生存情况的NGS分析可能改善SCLC的分类，并有可能识别出临床相关的新靶点。
