Department of Medicine, Division of Medical Oncology, University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital, Miami, FL 33131, United States.
Caris Life Sciences, Phoenix, AZ 85040, United States.
Oncologist. 2024 Nov 4;29(11):e1480-e1491. doi: 10.1093/oncolo/oyae168.
TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach.
Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts.
Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors.
TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.
TROP2（TACSTD2）的表达与一些实体瘤的总生存期（OS）降低有关，并且 TROP2 靶向抗体药物偶联物（ADC）Sacituzumab govitecan 已在乳腺癌和尿路上皮癌中获得批准。我们旨在探索与各种实体瘤中 TACSTD2 基因表达相关的多组学图谱，以确定最有可能从这种方法中获益的患者。
根据 Caris Life Sciences（凤凰城，AZ）的下一代 DNA 测序、全转录组测序和免疫组织化学结果，将乳腺癌（N=11246）、结直肠癌（N=15425）、肝细胞癌（N=433）、胰腺癌（N=5488）和尿路上皮癌（N=4125）肿瘤按 TACSTD2 基因表达分为四组。从保险索赔中获得生存数据，并为分子定义队列计算 Kaplan-Meier 估计。
几种致病性突变与 TACSTD2 高肿瘤相关，包括乳腺癌、结直肠癌、胰腺癌和肝细胞癌中的 TP53；胰腺癌和结直肠癌中的 KRAS；尿路上皮癌中的 ARID1A 和 FGFR3；以及肝细胞癌中的 CTNNB1。TACSTD2 低乳腺癌肿瘤中 CCND1 和 FGF/R 家族成员基因的拷贝数扩增更为丰富。TACSTD2 高通常与更多的免疫细胞浸润和更大的 T 细胞炎症评分相关。与 TACSTD2 低肿瘤相比，TACSTD2 高的乳腺癌、结直肠癌和胰腺癌患者的总生存期明显缩短。这种情况仅限于微卫星稳定的结直肠癌和 KRAS 突变型胰腺癌患者。TACSTD2 高的乳腺癌患者在接受免疫检查点抑制剂治疗后，总生存期也明显恶化。
TACSTD2 的表达与关键驱动改变和更活跃的免疫微环境相关，这表明在各种实体瘤中，TROP2 靶向 ADC 联合免疫疗法可能具有联合治疗策略。
Zotero 插件
