PO.CL01.22 · 临床研究

肿瘤知情的循环肿瘤DNA可识别出尽管接受了包含原发性肉眼完全切除的最佳一线治疗仍具有最高复发风险的高级别浆液性卵巢癌患者

Tumor-informed circulating tumor DNA identifies high-grade serous ovarian cancer patients at highest risk for recurrence despite optimal first-line treatment with primary macroscopic complete resection

编号 1061 展板 1 时间 4/19 02:00–05:00 区域 Section 42 主讲 Magdalena Postl

分会场 Circulating Tumor Cells, Metastasis, and Dissemination Biology 1

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作者与单位 Authors & Affiliations

Magdalena Postl¹, Christina Victoria Tauber², Valentina Glueck³, Mira Maria Gliga², Nuria Segui⁴, Karen Howarth⁴, Miguel Alcaide⁴, Lucia Oton⁴, Gerda Hofstetter⁵, Isabelle Maurer², Alexander Burges², Sven Mahner², Mirjana Kessler², Melina Danisch¹, Stephan Polterauer¹, Nicole Concin¹, Christoph Grimm¹, Fabian Trillsch²

¹Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria,²Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, LMU University Hospital, LMU Munich, Munich, Germany,³Department of Obstetrics and Gynecology, Klinikum Starnberg, Starnberg, Germany,⁴SAGA Dx, Morrisville, NC,⁵Department of Pathology, Medical University of Vienna, Vienna, Austria

摘要 Abstract

中文摘要

背景：由外科医生目视评估的肿瘤肉眼完全切除是高级别浆液性卵巢癌（HGSOC）最重要的预后因素。目前缺乏针对术后分子残留病灶（MRD）的客观检测手段，包括血清学和影像学评估。肿瘤知情的循环肿瘤DNA（ctDNA）作为识别高复发风险患者的新方法已显示出前景。方法：这项前瞻性双中心研究纳入了接受初次减瘤手术（PDS）、六个周期化疗及维持治疗的晚期HGSOC患者（pts）（2021年7月至2024年9月）。通过对肿瘤组织进行全基因组测序识别结构变异，用于设计个体化多重dPCR检测以检测MRD。血浆样本采集时间点为：围手术期（术前、术后第[d]2天和第10天）、化疗期间（C1、C3、C6）以及每3个月（mo）一次直至疾病进展或随访（FU）满24个月。CA-125也相应进行分析（临界值35 kU/L）。统计方法包括卡方检验和log-rank检验、多因素Cox模型以及针对无进展生存期（PFS）的Kaplan-Meier估计。结果：在中位随访时间15.4个月期间，33/84例患者（39%）发生复发，中位PFS为12.0个月。基线时77/82例患者（94%）检测到ctDNA，术后63/74例患者（85%）检测到ctDNA。在术后第10天，肿瘤完全切除的患者ctDNA水平显著低于术后有残留病灶的患者（p=0.0018）。肿瘤完全切除的患者中位ctDNA水平在术前与术后第10天之间下降了94%（p=0.0247），但术后有肿瘤残留的患者则无此下降（p=0.891）。在肿瘤完全切除的患者亚组中，与ctDNA水平持续存在（C1：80%，C6：30%）相比，C1（20%）和C6（70%）时的ctDNA清除与显著更低的复发风险相关，且在C6时相关性更强（C1：HR=3.39，p=0.0470；C6：HR=52.21，p<0.0001）。C6时ctDNA阳性组的中位复发时间为10.7个月，而ctDNA阴性组为21.3个月。该效应在术后第10天（p=0.273）或有残留肿瘤的患者中未观察到。ctDNA在预后方面优于CA-125，因为C1或C6时的CA-125水平未能预测复发（C1：p=0.189；C6：p=0.165）。在多因素分析中，C6时ctDNA持续存在（HR=14.58，p<0.0001）和术后残留肿瘤被确认为独立预后标志物。结论：肿瘤知情的ctDNA分析能够进一步准确地对尽管接受了肉眼完全切除的初次手术仍具有高复发风险的HGSOC患者进行分层。C6时的ctDNA评估可能提供一个机会窗口，用于在化疗后直接进行风险分层的治疗调整，从而实现新的个体化维持治疗策略。

查看英文原文 English abstract

Background: Complete macroscopic tumor resection estimation as visualized by the surgeon is the foremost prognostic factor in high-grade serous ovarian cancer (HGSOC). Objective measures of postoperative molecular residual disease (MRD) are lacking, including serologic and radiologic evaluation. Tumor-informed circulating tumor DNA (ctDNA) has shown promise as a new approach to identify patients at higher risk for relapse. Methods: This prospective bicentric study included advanced HGSOC patients (pts) undergoing primary debulking surgery (PDS), six cycles of chemotherapy and maintenance therapy (07/2021 - 09/2024). Whole-genome sequencing of tumor tissue identified structural variants, used to design personalized multiplex dPCR assays to detect MRD. Plasma samples were collected: perioperatively (preop, postop day[d]2 and d10), during chemotherapy (C1, C3, C6) and every 3 months (mo) until progression or 24 mo of follow up (FU). CA-125 was analyzed accordingly (cutoff 35 kU/L). Statistics included chi-square and log-rank tests, multivariate Cox model and Kaplan-Meier estimates for progression-free survival (PFS). Results: 33/84 pts (39%) experienced relapse with a median PFS of 12.0 mo during a median FU time of 15.4 mo. ctDNA was detected in 77/82 pts (94%) at baseline and in 63/74 pts (85%) postoperatively. At postop d10, pts with complete tumor resection had significantly lower ctDNA levels than pts with postop residual disease ( p =0.0018). Median ctDNA level decreased by 94% between preop and postop d10 in pts with complete tumor resection ( p =0.0247), but not in pts with postop tumor residuals ( p =0.891). Within the pt subgroup with complete tumor resection, ctDNA clearance at C1 (20%) and C6 (70%) was associated with significantly lower recurrence risk compared to persistent ctDNA levels (C1: 80%, C6: 30%) with a stronger association at C6 (C1: HR=3.39, p =0.0470, C6: HR= 52.21, p <0.0001). Median time to recurrence in the C6 ctDNA positive group was 10.7 mo compared to 21.3 mo in the ctDNA negative group. This effect was not observed at postop d10 ( p =0.273) or for pts with residual tumor. ctDNA outperformed CA-125 for prognosis, as CA-125 levels at C1 or C6 failed to predict recurrence (C1: p =0.189; C6: p =0.165). In a multivariate analysis, ctDNA persistence at C6 (HR=14.58, p <0.0001) and postoperative residual tumor were confirmed as independent prognostic markers. Conclusion: Tumor-informed ctDNA analysis can further accurately stratify HGSOC pts at high risk of recurrence despite primary surgery with complete macroscopic resection. ctDNA assessment at C6 may provide an opportunity window for risk-stratified treatment adjustments directly after chemotherapy, enabling new personalized maintenance strategies.

利益披露 Disclosure

M. Postl, None.. C. V. Tauber, None.. V. Glueck, None.. M. M. Gliga, None. N. Segui, SAGA Dx Employment, Other, Shareholder. K. Howarth, SAGA Dx Employment, Other, Shareholder. M. Alcaide, SAGA Dx Employment, Other, Shareholder. L. Oton, SAGA Dx Employment, Other, Shareholder. G. Hofstetter, None.. I. Maurer, None.. A. Burges, None. S. Mahner, AbbVie Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. AstraZeneca Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Clovis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Daiichi Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Eisai Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. GlaxoSmithKline Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Hubro Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Immunogen Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Medac Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. MEDiSTRAVA (Inizio Co.) Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. MSD Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Novartis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Nykode Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Olympus Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. PharmaMar Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Pfizer Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Roche Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Seagen Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Sensor Kinesis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. Teva, Tesaro Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support. M. Kessler, None.. M. Danisch, None.. S. Polterauer, None. N. Concin, AbbVie Other, Consulting/Advisory. MSD Other, Consulting/Advisory, Educational fees. ImmunoGen Other, Consulting/Advisory. Seagen Other, Consulting/Advisory. Akesobio Other, Consulting/Advisory. EISAI Other, Consulting/Advisory. GSK Travel, Other, Consulting/Advisory. AstraZeneca Other, Consulting/Advisory. Mersana Other, Consulting/Advisory. Seattle Genetics Other, Consulting/Advisory. eTheRNA immunotherapies NV Other, Consulting/Advisory. Kartos Other, Consulting/Advisory, Educational fees. Daiichi-Sankyo Other, Consulting/Advisory. Chorus Group Other, Consulting/Advisory. Pharma& Other, Consulting/Advisory. Amgen Travel. Genmab Travel. Roche Travel. Medtronic Travel. Medscape Oncology, TouchIME, FOMF, Med Media Verlag und Mediaservice GmbH, MEDahead, Springer Verlag, NSGO, NOGGO, OEGGG Akademie, DOC Congress, Müller Media Other, Educational fees. C. Grimm, AstraZeneca ), Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Eisai ), Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Meda Pharma Other, Receipt of grants/research supports. Roche Other, Receipt of grants/research supports, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Abbvie Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Celgene Other, Receipt of honoraria or consultation fees. Clovis Other, Receipt of honoraria or consultation fees. GSK Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. MSD Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. PharmaMar Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Vifor Pharma Other, Receipt of honoraria or consultation fees. Sandoz Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau. Amgen Other, Participation in a company sponsored speaker’s bureau. F. Trillsch, AbbVie ). AstraZeneca ). Eisai ). GSK ). ImmunoGen ). MSD ). Regeneron ). Roche ). SAGA diagnostics ).

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