PO.CL01.09 · 临床研究

通过ctDNA测序识别的PI3K-AKT通路改变在转移性去势抵抗性前列腺癌中的预后意义

Prognostic significance of PI3K-AKT pathway alterations identified by ctDNA sequencing in metastatic castration-resistant prostate cancer

编号 3841 展板 2 时间 4/20 02:00–05:00 区域 Section 45 主讲 Dong-Soo Kyung

分会场 Liquid Biopsies: Circulating Nucleic Acids 3

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作者与单位 Authors & Affiliations

DongSoo Kyung¹, Yongjun Cha¹, Chang Wook Jeong², Seung-hwan Jeong², Chel Lee³, Won Yeong Ko¹, Jee-Soo Lee⁴, Moon-Woo Seong⁴, Cheol Kwak², Tae-You Kim⁵

¹IMBdx, Seoul, Korea, Republic of,²Urology, Seoul National University Hospital, Seoul, Korea, Republic of,³Pathology, Seoul National University Hospital, Seoul, Korea, Republic of,⁴Laboratory Medicine, Seoul National University Hospital, Seoul, Korea, Republic of,⁵Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景：PI3K-AKT通路的异常是去势抵抗性前列腺癌（CRPC）的关键驱动因素，可促进治疗耐药和不良预后。随着这些改变对靶向治疗的相关性日益增强，通过无创基因组分析界定其患病率和预后价值至关重要。因此，我们使用高深度循环肿瘤DNA（ctDNA）测序评估了转移性CRPC中的PI3K-AKT通路改变。方法：共127例mCRPC患者使用AlphaLiquid®100检测进行了高深度ctDNA测序，涵盖PI3K-AKT通路基因和同源重组修复基因。87例患者可获得配对PBMC，而40例仅进行血浆分析，并应用我们基于机器学习的模型去除CHIP相关变异。为进行正交比较，使用小鼠单克隆抗体（克隆6H2.1，M3627，Dako）进行PTEN免疫组化（IHC）。ctDNA指标结合基线临床数据和总生存期（OS）进行评估，并在PI3K-AKT改变型与野生型疾病之间比较结局。结果：在127例患者中（中位年龄66岁），高级别肿瘤常见（Gleason≥8者占71.7%），临床T3-T4晚期疾病占78.7%，淋巴结受累占59.8%，同时性转移占58.3%。诊断时中位PSA为53.7 ng/mL，33.1%曾接受手术。体细胞ctDNA改变在91.3%中被检出（中位3；范围0–47），变异类型和肿瘤分数存在显著异质性（中位0.98%；范围0.05–79.6%）。PTEN致病性突变见于9.4%，活化性PIK3CA和AKT1改变分别见于7.9%和0.8%。IHC检测的PTEN缺失见于46.9%（30/64），与cfDNA中PTEN致病性突变的总体一致率为54.7%。除更高的T3-T4疾病（p<0.001）外，PI3K-AKT改变型与野生型肿瘤的基线临床特征相似。PTEN IHC缺失在全队列（HR 1.47，95% CI 0.36–6.06）或同时性转移（HR 2.41，95% CI 0.37–15.55）中均与总生存期（OS）无关。相比之下，通过ctDNA检测到的PTEN致病性突变在整体队列中与较差OS相关（HR 3.19，95% CI 0.90–11.37；p=0.073），并在同时性转移中显示出显著影响（HR 4.91，95% CI 1.29–18.67；p=0.019）。PIK3CA和/或AKT1突变也呈现类似趋势（HR 3.25，95% CI 0.95–11.16；p=0.061）。结论：通过ctDNA测序识别的PTEN致病性突变与mCRPC中较差的总生存期强烈相关，且在预后价值上优于PTEN IHC。这些结果凸显了ctDNA分析在检测PI3K-AKT通路改变方面的效用及其为mCRPC靶向治疗策略提供信息的潜力。

查看英文原文 English abstract

Background: Aberrations in the PI3K-AKT pathway are key drivers of castration-resistant prostate cancer (CRPC), promoting therapeutic resistance and poor outcomes. As these alterations become increasingly relevant for targeted therapy, defining their prevalence and prognostic value through noninvasive genomic profiling is essential. We therefore assessed PI3K-AKT pathway alterations in metastatic CRPC using high-depth circulating tumor DNA (ctDNA) sequencing. Methods: A total of 127 patients with mCRPC underwent high-depth ctDNA sequencing using the AlphaLiquid®100 assay, covering PI3K-AKT pathway genes and homologous recombination repair genes. Paired PBMCs were available for 87 patients, while 40 underwent plasma-only profiling with our machine learning-based model applied to remove CHIP-related variants. For orthogonal comparison, PTEN immunohistochemistry (IHC) was performed using a mouse monoclonal antibody (clone 6H2.1, M3627, Dako). ctDNA metrics were evaluated with baseline clinical data and overall survival (OS), and outcomes were compared between PI3K-AKT-altered and wild-type disease. Results: Among 127 patients (median age, 66 years), high-grade tumors were common (Gleason ≥8 in 71.7%), with advanced clinical T3-T4 disease in 78.7%, nodal involvement in 59.8%, and synchronous metastasis in 58.3%. The median PSA at diagnosis was 53.7 ng/mL, and 33.1% had undergone prior surgery. Somatic ctDNA alterations were detected in 91.3% (median 3; range 0-47), with substantial heterogeneity in variant types and tumor fractions (median 0.98%; range 0.05-79.6%). PTEN pathogenic mutations were found in 9.4% and activating PIK3CA and AKT1 alterations in 7.9% and 0.8%. PTEN loss by IHC was present in 46.9% (30/64), with the overall 54.7% concordance with PTEN pathogenic mutations in cfDNA. Baseline clinical features were similar between PI3K-AKT-altered and wild-type tumors, except for higher T3-T4 disease (p<0.001). PTEN IHC loss was not associated with overall survival (OS) in the full cohort (HR 1.47, 95% CI 0.36-6.06) or in synchronous metastasis (HR 2.41, 95% CI 0.37-15.55). In contrast, PTEN pathogenic mutations detected via ctDNA were associated with inferior OS in the overall cohort (HR 3.19, 95% CI 0.90-11.37; p=0.073) and showed significant impact in synchronous metastasis (HR 4.91, 95% CI 1.29-18.67; p=0.019). A similar trend was seen for PIK3CA and/or AKT1 mutations (HR 3.25, 95% CI 0.95-11.16; p=0.061). Conclusion: PTEN pathogenic mutations identified through ctDNA sequencing were strongly associated with worse overall survival in mCRPC and outperformed PTEN IHC in prognostic value. These results underscore the utility of ctDNA profiling for detecting PI3K-AKT pathway alterations and its potential to inform targeted treatment strategies in mCRPC.

利益披露 Disclosure

D. Kyung, IMBdx Employment. Y. Cha, IMBdx g., Board of Directors, non-salaried role). C. Jeong, None.. S. Jeong, None.. C. Lee, None. W. Ko, IMBdx Employment. J. Lee, None.. M. Seong, None.. C. Kwak, None. T. Kim, IMBdx Employment, g., Board of Directors, non-salaried role).

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