PO.CL01.07 · 临床研究

利用液体活检和尿液蛋白质组学早期检测BCG治疗的NMIBC的治疗失败与疾病播散

Early detection of treatment failure and disease dissemination inBCG-treated NMIBC using liquid biopsies and urine proteomics

编号 1139 展板 20 时间 4/19 02:00–05:00 区域 Section 44 主讲 Iver Nordentoft

分会场 Liquid Biopsies: Circulating Nucleic Acids 1

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作者与单位 Authors & Affiliations

Trine Strandgaard¹, Tine Ginnerup Andreasen¹, Iver Nordentoft¹, Nathalie Demuth Fryd², Philippe Lamy³, Julie Pedersen Harrits¹, Boris Oklander⁴, Danielle Afterman⁴, Tal Katz-Ezov⁴, Imane Bourzgui⁴, Jørn Jakobsen⁵, Kristian Juul⁵, Jørgen Bjerggaard Jensen¹, Lars Dyrskjøt¹

¹Department of Clinical Medicine, Aarhus University, Aarhus, Denmark,²Department of Urology, Aarhus University Hospital, Aarhus N, Denmark,³Department of Molecular Medicine,, Aarhus University Hospital, Aarhus, Denmark,⁴Veracyte, Inc., Haifa, Israel,⁵Ferring Pharmaceuticals, A/S, Kastrup, Denmark

摘要 Abstract

中文摘要

仅约40%的非肌层浸润性膀胱癌（NMIBC）患者对卡介苗（BCG）治疗有反应。虽然免疫细胞耗竭已被认为与BCG耐药相关，但早期疾病播散（即隐匿性肌层浸润性疾病）也可能导致BCG治疗失败。我们评估了对尿液和血浆样本进行系列分析能否揭示免疫耗竭、残留病灶及早期播散的迹象，从而预测BCG疗效。在一项纳入102例BCG治疗的NMIBC患者的前瞻性队列中（中位随访28个月；入组于2024年4月结束），采用全基因组DNA测序（WGS），从配对的白膜层与肿瘤或尿沉渣（UPEL）DNA中生成患者特异性的全基因组肿瘤特征谱（Veracyte）。将这些特征应用于治疗前、治疗中及治疗后采集的271份尿液和329份血浆样本的cfDNA WGS数据，以检测尿液肿瘤（ut）DNA和循环肿瘤（ct）DNA。同时，采用Olink免疫肿瘤学panel对344份尿液上清进行分析，并对55例肿瘤进行了总RNA测序。更新的随访数据将在会上呈现。5例（6%）患者在BCG治疗前检出血浆ctDNA；其中3例后来发生高级别（HG）复发或进展。治疗前ctDNA阳性与更高的复发风险相关（HR = 6.88），但与肿瘤分期（p > 0.42）或分级（p = 0.91）无关。BCG治疗前、治疗中及治疗后分别有58%、51%和27%的患者检出尿液utDNA。BCG治疗中或治疗后utDNA阳性与更短的无复发生存期相关。在BCG治疗后可检出utDNA的患者中10/22（45%）发生复发，而在无可测得utDNA的患者中11/49（22%）发生复发（p=0.022）。平均而言，utDNA较临床检出提前133天（范围：4-405天）。UPEL DNA能够在肿瘤材料有限（仅CIS）的病例中生成患者特异性模型并检测ctDNA/utDNA。BCG治疗诱导尿液免疫肿瘤学蛋白升高。肿瘤相关蛋白（MMP-12、IL6、IL8）在BCG治疗前升高，而八种免疫调节蛋白——包括HO-1、GZMA、GZMB、LAP TGF-beta-1和TRAIL——在治疗早期于HG复发病例中相较非HG复发病例上调。治疗前ctDNA识别出HG复发或进展高风险患者，支持其作为潜在再分期工具的作用。UPEL DNA是可靠的肿瘤替代物，在组织有限（如CIS）时颇为有用。utDNA检测识别出高复发风险患者，且早于膀胱镜检查。尿液蛋白质组学反映了BCG诱导的免疫反应，复发与非复发患者在治疗早期呈现出不同的特征谱。综上，ctDNA/utDNA与蛋白质组监测可实现治疗失败的早期检测并指导及时的治疗干预。

查看英文原文 English abstract

Only about 40% of patients with non-muscle invasive bladder cancer (NMIBC) respond to Bacillus Calmette-Guérin (BCG) therapy. While immune cell exhaustion has been linked to BCG resistance, early disease dissemination (i.e., occult muscle-invasive disease) may also contribute to BCG failure. We assessed whether serial analysis of urine and plasma samples could reveal signs of immune exhaustion, residual disease, and early dissemination, predictive of BCG outcome. In a prospective cohort of 102 BCG-treated NMIBC patients (median follow-up 28 months; inclusion ended April 2024), whole-genome DNA sequencing (WGS) was used to generate patient-specific genomic-wide tumor-based signatures (Veracyte) from paired buffy coat and tumor or urine pellet (UPEL) DNA. These were applied to cfDNA WGS data from 271 urine and 329 plasma samples collected before, during, and after treatment to detect urinary tumor (ut)DNA and circulating tumor (ct)DNA. In parallel,344 urine supernatants were profiled using Olink immuno-oncology panels, and total RNA sequencing was performed on 55 tumors. Updated follow-up will be presented at the meeting. Plasma ctDNA was detected pre-BCG in 5 (6%) patients; three later developed high grade (HG) recurrence or progressed. Pre-treatment ctDNA positivity was associated with higher recurrencerisk (HR = 6.88) but not with tumor stage (p > 0.42) or grade (p =0.91). Urine utDNA was detected in 58%, 51% and 27% of patients before, during, and after BCG, respectively. utDNA-positivity during or after BCG correlated with shorter recurrence-free survival. Recurrence was observed in 10/22 (45%) patients with detectable post-BCG utDNA and in 11/49 (22%) patients without measurable utDNA (p=0.022). On average, utDNA preceeded clinical detection with 133 days (range: 4-405). UPEL DNA enabled patient-specific model generation and ctDNA/utDNA detection in cases with limited tumor material (CIS only). BCG therapy induced increased urinary immuno-oncology proteins. Tumor-associated proteins (MMP-12, IL6, IL8) were elevated pre-BCG, while eight immunemodulatory proteins - including HO-1, GZMA, GZMB, LAP TGF-beta-1 and TRAIL were upregulated early during treatment in HG-recurrent versus non-HG-recurrent cases. Pre-treatment ctDNA identified patients at high risk of HG recurrence or progression, supporting a role as a potential restaging tool. UPEL DNA was a reliable tumor proxy and useful when tissue was limited (e.g., CIS). utDNA detection identified patients at high risk of recurrence and earlier than cystoscopy. Urine proteomics mirrored BCG-induced immune responses, with distinct early on-treatment profiles in recurrent versus non-recurrent patients. Together, ctDNA/utDNA and proteomic monitoring may enable early detection of treatment failure and guide timely therapeutic interventions.

利益披露 Disclosure

T. Strandgaard, None.. T. G. Andreasen, None.. I. Nordentoft, None.. N. Fryd, None.. P. Lamy, None.. J. Harrits, None. B. Oklander, Veracyte, Inc, Employment. D. Afterman, Veracyte, Inc Employment. T. Katz-Ezov, Veracyte, Inc, Employment. I. Bourzgui, Veracyte, Inc Employment. J. Jakobsen, Ferring Pharmaceuticals, A/S Employment. K. Juul, Ferring Pharmaceuticals, A/S Employment. J. Jensen, medac, Photocure ASA ). Roche ), advisory. Ferring ), advisory. Olympus ), advisory. Astellas ). Cepheid ), advisory. Nucleix ). Urotech ). Pfizer ). AstraZenica ). VingMed ). Laborie ). AMBU ), advisory role. Cystotech ). Janssen advisory role. Polyceutix advisory role. Johnsson & Johnsson Travel. L. Dyrskjøt, with C2i Genomics ). Natera ). AstraZeneca ), speaker honoraria. Photocure ). Ferring ), advisory/consulting role. MSD Travel, advisory/consulting role. Cystotech advisory/consulting role. UroGen advisory/consulting role. Roche speaker honoraria. Pfize speaker honoraria.

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