Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) harbors one of the most mutated genomes. There are limited data on the genomic profile and its predictive potential for response to immunotherapy with PD-1 inhibitors in cSCC. Methods: This study retrospectively reviewed cSCC patients treated with PD-1 inhibitor monotherapy at a single institution. Clinical characteristics, treatment outcomes, PD-L1 expression, tumor mutation burden (TMB), and genomic profile in tumor and blood were analyzed. Logistic regression and a support vector classifier were used to validate identified biomarkers of significance. Results: Twenty-five patients were evaluable for response and had genomics tested in tumor and/or blood. Of the total, 80% of patients achieved an objective response: 40% complete response (CR), 32% partial response (PR) for more than 6 months, and 8% stable disease (SD) for more than 1 year; 20% of patients progressed on treatment. With a median follow-up of 21 months, progression-free survival (PFS) was 28 months in responders vs. 3 months in non-responders (p= 0.00001). Median PD-L1 was 25% in responders vs. 10% in non-responders (p= 0.39). There was no difference in median TMB between responders and non-responders. Eight gene mutations were significantly more frequent in non-responders than in responders:CDK12(p= 0.005),CTCF(p= 0.033),CTNNB1(p= 0.033),IGF1R(p= 0.038),IKBKE(p= 0.016),MLH1(0.033),QKI(p= 0.016), andTIPARP(p= 0.033). A support vector model of these genes classified responders and non-responders with an accuracy of 0.88 in the training data and 1.0 in the testing data. Conclusions: PD-1 inhibitor monotherapy produces an impressive response. Eight gene mutations were significantly more frequent in non-responders. PD-L1 and TMB were inconclusive in predicting treatment response to anti-PD-L1.
背景/目的：皮肤鳞状细胞癌（cSCC）具有高度突变的基因组特征。目前关于cSCC的基因组谱及其对PD-1抑制剂免疫治疗反应预测价值的数据有限。方法：本研究回顾性分析单中心接受PD-1抑制剂单药治疗的cSCC患者。分析临床特征、治疗结果、PD-L1表达、肿瘤突变负荷（TMB）以及肿瘤和血液中的基因组谱。采用逻辑回归和支持向量分类器验证具有显著意义的生物标志物。结果：25例患者可评估疗效并完成肿瘤和/或血液基因组检测。总体客观缓解率达80%，其中完全缓解（CR）40%，部分缓解（PR）32%（持续超过6个月），疾病稳定（SD）8%（持续超过1年）；20%患者出现疾病进展。中位随访21个月，缓解者的无进展生存期（PFS）为28个月，非缓解者为3个月（p=0.00001）。缓解者中位PD-L1表达为25%，非缓解者为10%（p=0.39）。两组间中位TMB无显著差异。CDK12（p=0.005）、CTCF（p=0.033）、CTNNB1（p=0.033）、IGF1R（p=0.038）、IKBKE（p=0.016）、MLH1（p=0.033）、QKI（p=0.016）和TIPARP（p=0.033）这8个基因突变在非缓解者中发生率显著更高。基于这些基因构建的支持向量模型在训练数据中对缓解者与非缓解者的分类准确率达0.88，测试数据中达1.0。结论：PD-1抑制剂单药治疗疗效显著。8个基因突变在非缓解者中显著富集。PD-L1和TMB在预测抗PD-1治疗反应方面尚无定论。
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