OBJECTIVES Potentially targetable genomic alterations have been identified in lung squamous cell carcinoma (LUSC), but none have yet translated into effective therapy. We examined potential benefits of next generation sequencing (NGS) in a cohort of consecutive LUSC patients with emphasis on distinctions between smokers and light/never smokers and implications for clinical trial enrollment. METHODS We retrospectively evaluated results from an internally developed NGS assay (OncoPanel) targeting ∼300 genes with a mean overall target coverage of >200x for consecutive LUSC seen at our institution over 30 months. RESULTS Tissue was obtained from 172 patients for targeted NGS. 42 (24 %) samples were insufficient for testing. Median age of tested patients was 66, including 87 % moderate/heavy versus 13 % light/never smokers; 66 % were stage IIIB or IV. Of 130 patients with evaluable NGS results, 49 (38 %) had at least 1 alteration qualifying for enrollment to a LungMAP treatment arm (PIK3CA, MET, FGFR family, cell cycle, or homologous recombination pathways) or for an approved therapy or other clinical trial (e.g. EGFR sensitizing mutations, MET exon 14 splice mutations, TSC1/2 mutation, or microsatellite instability). Therapeutic targets were enriched in light/never smokers (47 % vs 35 % moderate/heavy smokers). Unexpectedly, genomic features suggested an alternative diagnosis (metastatic cutaneous squamous carcinoma; mesothelioma) in 7 patients, including 35 % of never/light smokers. CONCLUSION NGS in a real-world LUSC cohort yields potentially targetable genomic alterations informing clinical trial enrollment and approved therapies and critical diagnostic insights. Our findings strongly support current guidelines recommending mutational profiling of LUSC arising in light/never smoking patients; the utility of sequencing in smokers with LUSC appears to be limited to identification of research targets.

中文翻译：

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下一代测序为肺鳞状细胞癌的诊断提供了依据，并确定了意想不到的治疗靶点。

目的已在肺鳞状细胞癌（LUSC）中发现了潜在的可靶向基因组改变，但尚未转化成有效的治疗方法。我们在连续的LUSC患者队列中研究了下一代测序（NGS）的潜在好处，重点是吸烟者与轻度/从未吸烟者之间的区别以及对临床试验入组的影响。方法我们回顾性评估了内部开发的NGS检测（OncoPanel）的结果，该检测针对约300个基因，在我们机构进行的30个月内连续LUSC的平均总目标覆盖率> 200x。结果从172例患者中获得了靶向NGS的组织。42（24％）个样本不足以进行测试。被测患者的中位年龄为66岁，其中中度/重度吸烟者为87％，轻度/从未吸烟者为13％。IIIB或IV期占66％。在130例NGS结果可评估的患者中，有49例（38％）至少有1项改变符合入组LungMAP治疗组的要求（PIK3CA，MET，FGFR家族，细胞周期或同源重组途径）或已获批准的治疗方法或其他临床方法试验（例如EGFR致敏突变，MET外显子14剪接突变，TSC1 / 2突变或微卫星不稳定性）。轻度/从未吸烟者中有治疗目标（47％vs 35％的中度/重度吸烟者）。出乎意料的是，基因组特征提示在7例患者中有另一种诊断方法（转移性皮肤鳞状细胞癌；间皮瘤），其中35％的从不吸烟或轻度吸烟者。结论在现实世界的LUSC队列中，NGS可能产生潜在的可靶向基因组改变，从而为临床试验入组，批准的疗法和关键的诊断见解提供了信息。我们的发现有力地支持了当前的指南，该指南建议在轻度吸烟/从不吸烟的患者中产生LUSC的突变谱。在LUSC吸烟者中测序的效用似乎仅限于确定研究目标。