Volckmar Anna-Lena, Christopoulos Petros, Kirchner Martina, Allgäuer Michael, Neumann Olaf, Budczies Jan, Rempel Eugen, Horak Peter, Glade Julia, Goldschmid Hannah, Seker-Cin Huriye, Brandt Regine, Kriegsmann Mark, Leichsenring Jonas, Winter Hauke, Faehling Martin, Fischer Jürgen R, Heußel Claus Peter, Herth Felix, Brummer Tilman, Fröhling Stefan, Schirmacher Peter, Thomas Michael, Endris Volker, Penzel Roland, Kazdal Daniel, Bochtler Tilmann, Stenzinger Albrecht
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
Lung Cancer. 2021 Apr;154:131-141. doi: 10.1016/j.lungcan.2021.02.022. Epub 2021 Feb 19.
Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments.
Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively.
Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18-21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials.
酪氨酸激酶抑制剂（TKI）及其他靶向治疗的应用是胸部肿瘤学的一项主要进展，非小细胞肺癌（NSCLC）患者的生存期因此延长了数月至数年。高通量综合分子谱分析对于识别可能从这些新型治疗中获益的患者至关重要。
对4500例连续的晚期NSCLC福尔马林固定、石蜡包埋标本（n = 4172例患者）进行二代测序（NGS），自动提取DNA和RNA后分别并行检测突变和基因融合。
除了24.9%（n = 1040）的病例因表皮生长因子受体（EGFR）外显子18 - 21、BRAF、ROS1、间变性淋巴瘤激酶（ALK）、神经营养酪氨酸激酶受体（NTRK）和转染重排（RET）中存在典型改变而符合批准的靶向治疗条件外，另有n = 1260例患者（30.2%）在EGFR（n = 748）、BRAF（n = 135）、人表皮生长因子受体2（ERBB2）（n = 30）、原癌基因c-Kit（KIT）（n = 32）、磷脂酰肌醇-3激酶催化亚基α（PIK3CA）（n = 221）和β-连环蛋白1（CTNNB1）（n = 94）中显示罕见或非典型突变，靶向治疗对这些突变也可能有效。结合计算机评估进行的系统文献检索确定了n = 232例（5.5%）患者，根据现有证据，对这些患者进行靶向治疗试验是必要的（NCT 1级，即已发表的数据显示在同一肿瘤实体中有效）。总之，相当一部分NSCLC患者存在罕见或非典型改变，这些改变可能与从现有靶向药物中获得临床益处相关。对这些病例进行系统识别和个体化管理可以扩大精准肿瘤学在NSCLC中的适用性，并从已确立的分子靶点中延长临床获益。这些结果也可为临床试验提供参考。
