目的:缺乏反映治疗和复发的实时反应的生物标志物。我们评估了在子宫内膜癌(EC)和卵巢癌(OC)患者中检测无细胞循环肿瘤DNA(ctDNA)突变的临床价值。
方法:接受初次手术的EC/OC患者同意组织库和2年连续抽血。使用靶向基因组对肿瘤组织DNA和血浆ctDNA进行下一代测序以鉴定体细胞突变。
结果:在44例患者中(24例EC,17OC,2个同步子宫内膜和卵巢癌[SEOC]和1个宫颈腺癌[EA])在40个肿瘤组织中至少鉴定出一种体细胞突变(91%,20/24EC,所有OC/SEOC/EA),术前血浆ctDNA中有12例(27%)(6/24[25%]EC和6/17[35%]OC)。术前检测ctDNA突变与晚期相关,术前CA125升高,疾病复发。在5/12(42%)有术前ctDNA突变的患者中,检查/成像建议临床I期,但最终病理显示为II/III期。在ctDNA和CA125治疗期间评估连续时间点的11名患者中,ctDNA清除先于CA125正常化。13例患者出现复发性疾病(4EC,8OC,1个EA);8个术后检测到ctDNA突变,在临床/放射学/生物标志物进展前2-5个月发现ctDNA突变的复发时间为4。
结论:ctDNA可以反映更大的肿瘤体积/转移,EC和OC的治疗反应和复发。仔细选择患者对于将资源引导到最有可能受益的患者至关重要。考虑疾病负担和风险人群。
OBJECTIVE: Biomarkers reflecting real-time response to therapy and recurrence are lacking. We assessed the clinical value of detecting cell-free circulating tumor DNA (ctDNA) mutations in endometrial cancer (EC) and ovarian cancer (OC) patients.
METHODS: EC/OC patients undergoing primary surgery were consented for tissue banking and 2-year serial blood draws. Tumor tissue DNA and plasma ctDNA underwent next generation sequencing using a targeted gene panel to identify somatic mutations.
RESULTS: Of 44 patients (24 EC, 17 OC, 2 synchronous endometrial and ovarian carcinomas [SEOC] and 1 endocervical adenocarcinoma [EA]) at least one somatic mutation was identified in tumor tissue in 40 (91%, 20/24 EC, all OC/SEOC/EA), and in preoperative plasma ctDNA in 12 (27%) patients (6/24 [25%] EC and 6/17 [35%] OC). Detection of preoperative ctDNA mutations was associated with advanced stage, higher preoperative CA125, and disease recurrence. In 5/12 (42%) patients with preoperative ctDNA mutations, examination/imaging suggested clinical stage I however final pathology revealed stage II/III. In 11 patients where serial timepoints were assessed during treatment for ctDNA and CA125, ctDNA clearance preceded normalization of CA125. Thirteen patients developed recurrent disease (4 EC, 8 OC, 1 EA); 8 in whom ctDNA mutations were detected postoperatively, and 4 followed through time of recurrence with ctDNA mutations identified 2-5 months prior to clinical/radiologic/biomarker progression in 3.
CONCLUSIONS: ctDNA can reflect larger tumor volume/metastases, treatment response and recurrence in EC and OC. Careful patient selection is critical to direct resources to patients most likely to benefit, considering disease burden and risk group.