Robinson H R, Lakritz S, Pavlick D C, Davis S L, Lieu C H, Eule C J, Graham L S, Spiess P E, Li R, Kamat A M, Grivas P, Jacob J M, Bratslavsky G, Basnet A, Wong K A, Lin D I, Necchi A, Ross J S, Lam E T
Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA.
Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA.
ESMO Open. 2025 Jun;10(6):105312. doi: 10.1016/j.esmoop.2025.105312. Epub 2025 Jun 10.
Squamous cell carcinoma (SCC) of unknown primary (SCCUP) refers to any SCC for which the primary tumor origin cannot be identified despite guideline-directed evaluation. Although strategies employing comprehensive genomic profiling (CGP) to identify targets for non-SCC carcinomas of unknown primary (CUPs) have shown benefit, the genomic landscape in SCCUP remains poorly defined. Here we describe results of CGP in patients with SCCUP to identify potential therapy targets and characteristic biomarkers.
Cases of advanced SCCUP were identified in the FoundationCORE® database by review of clinical history and pathology records. Samples underwent DNA extraction and sequencing to identify genomic alterations (GAs), microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic mutational signatures, and viral reads. Programmed death-ligand 1 (PD-L1) expression was determined by immunohistochemistry.
443 SCCUP cases were identified. Common presentation sites included lymph nodes (41.1%), liver (15.6%), and soft tissue (15.1%). A mean of 6.5 GAs were observed per case. The most frequent non-targetable GAs involved TP53 (62.5%), CDKN2A (37.0%), CDKN2B (19.6%), KMT2D (18.3%), and TERT (16.0%); the most frequent GAs potentially targetable in biomarker-driven trials included PIK3CA (27.3%), PTEN (15.1%), MTAP (13.1%), KRAS (10.4%), and NOTCH1 (8.4%). Among all SCCUP cases, 2.0% had MSI-high (MSI-H) status and 33.9% had TMB ≥10 mutations/megabase. Among 204 cases with available PD-L1 testing, 39.2% were low-positive [tumor proportion score (TPS) 1%-49%] and 29.9% were high-positive (TPS ≥50%). SCCUP cases presenting with liver involvement had fewer GAs per tumor and lower TMB compared with other SCCUP cases. In contrast, cases presenting with inguinal, pelvic, or retroperitoneal involvement were more likely to demonstrate evidence of human papilloma virus (HPV) infection and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) genomic signatures.
CGP of this SCCUP cohort identified GAs that may guide consideration of molecularly targeted therapy via tumor-agnostic indications and/or treatment in biomarker-driven trials. SCCUPs frequently exhibit biomarkers associated with response to immune checkpoint inhibitors.
原发灶不明的鳞状细胞癌（SCCUP）是指尽管经过指南指导的评估仍无法确定原发肿瘤起源的任何鳞状细胞癌。虽然采用综合基因组分析（CGP）来识别原发灶不明的非鳞状细胞癌（CUPs）靶点的策略已显示出益处，但SCCUP的基因组格局仍未明确界定。在此，我们描述了SCCUP患者的CGP结果，以识别潜在的治疗靶点和特征性生物标志物。
通过回顾临床病史和病理记录，在FoundationCORE®数据库中识别晚期SCCUP病例。对样本进行DNA提取和测序，以识别基因组改变（GAs）、微卫星不稳定性（MSI）状态、肿瘤突变负荷（TMB）、基因组突变特征和病毒读数。通过免疫组织化学测定程序性死亡配体1（PD-L1）表达。
共识别出443例SCCUP病例。常见的表现部位包括淋巴结（41.1%）、肝脏（15.6%）和软组织（15.1%）。每例平均观察到6.5个GAs。最常见的不可靶向GAs涉及TP53（62.5%）、CDKN2A（37.0%）、CDKN2B（19.6%）、KMT2D（18.3%）和TERT（16.0%）；在生物标志物驱动试验中最常见的潜在可靶向GAs包括PIK3CA（27.3%）、PTEN（15.1%）、MTAP（13.1%）、KRAS（10.4%）和NOTCH1（8.4%）。在所有SCCUP病例中，2.0%为微卫星高度不稳定（MSI-H）状态，33.9%的肿瘤突变负荷≥10个突变/兆碱基。在204例可进行PD-L1检测的病例中，39.2%为低阳性[肿瘤比例评分（TPS）1%-49%]，29.9%为高阳性（TPS≥50%）。与其他SCCUP病例相比，出现肝脏受累的SCCUP病例每个肿瘤的GAs较少且TMB较低。相比之下，出现腹股沟、盆腔或腹膜后受累的病例更有可能显示人乳头瘤病毒（HPV）感染和载脂蛋白B mRNA编辑催化多肽样（APOBEC）基因组特征的证据。
该SCCUP队列的CGP识别出了一些GAs，这些GAs可能通过不考虑肿瘤来源的适应症和/或生物标志物驱动试验中的治疗来指导分子靶向治疗的考虑。SCCUP经常表现出与免疫检查点抑制剂反应相关的生物标志物。
