Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Biostatistics, University of Arkansas for Medical Science, Little Rock, AR 72205, USA.
Int J Mol Sci. 2023 May 17;24(10):8873. doi: 10.3390/ijms24108873.
Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.
子宫浆液性癌（USC）和癌肉瘤（CS）是子宫内膜癌的罕见、高度侵袭性变体。目前尚无可靠的肿瘤生物标志物可用于指导 USC/CS 患者的治疗反应或检测早期复发。使用液滴数字聚合酶链反应（ddPCR）等超敏技术鉴定的循环肿瘤 DNA（ctDNA）可能代表一种用于识别隐匿性疾病的新型平台。我们探讨了使用个性化 ctDNA 标志物监测 USC 和 CS 患者的方法。在手术时和/或治疗过程中采集 USC/CS 患者的肿瘤和血浆样本，通过临床级别的下一代测序（NGS）平台（即 Foundation Medicine）和液滴数字 PCR 仪器（Raindance，ddPCR）评估肿瘤特异性体细胞结构变异（SSV）。通过液滴数字 PCR 定量血浆样本中的 ctDNA 水平，并将其与临床发现相关联，包括 CA-125 血清和/或计算机断层扫描（CT）扫描结果。基于基因组分析的检测方法在所有 USC/CS 患者中确定了用于 ctDNA 分析的突变“驱动”靶基因。在多个患者中，纵向 ctDNA 检测能够在 CA-125 或 CT 扫描临床可检测到复发性肿瘤之前检测到癌细胞的存在。初始治疗后持续无法检测到 ctDNA 与无进展生存期和总生存期延长相关。在一名 USC 患者中，CA-125 和 TP53 突变但不是 PIK3CA 突变在复发时在血浆中变得不可检测，这表明应该使用多个定制探针来监测 ctDNA。使用基于肿瘤信息的检测进行纵向 ctDNA 检测可能会发现残留肿瘤的存在，预测治疗反应，并识别 USC/CS 患者的早期复发。通过 ctDNA 监测识别疾病的持续性和/或复发可能会更早地治疗复发性疾病，并有可能改变 USC 和 CS 患者的治疗管理实践。需要在前瞻性纳入治疗试验的 USC/CS 患者中进行 ctDNA 验证研究。
