编者按：近年来，随着二代测序（NGS）等技术的发展，基于液体活检的前列腺癌检测成为现实。通过液体活检进行早期筛查和检测，不仅有望对前列腺癌患者进行早期干预，而且能够及时发现相关突变靶点，从而进行精准治疗。在近期举行的欧洲肿瘤内科学会亚洲年会（ESMO Asia 2025）上，中国香港养和医院潘明骏（Darren Poon）教授团队相关研究入选，为晚期前列腺癌患者带来了精准诊疗新策略。肿瘤瞭望-泌尿时讯特邀潘明骏教授现场分享液体活检对于中国雄激素受体配体结合域突变前列腺癌患者的临床价值及未来前景。

 

潘明骏（Darren Poon）教授：对于转移性前列腺癌的检测而言，液体活检技术是其中非常重要的检测手段之一。其在为患者带来便利的同时，也面临着一些挑战。

 

首先，假阴性问题是液体活检或液体NGS监测面临的一个主要挑战。我们知道，组织活检能够直接获取组织样本进行NGS检测。而液体活检，比如通过血液进行的NGS检测，结果会受到多种因素的影响。其中，患者的肿瘤负荷以及采集的血液样本中DNA含量是否足够，会直接影响检测结果。简单来说，如果血液中来自肿瘤的DNA含量较少，就可能导致检测不出来，出现假阴性的情况，这无疑会给后续的诊断和治疗带来困扰。

 

其次，如何区分特定突变是源于基因突变还是克隆性造血。有时候，在液体NGS检测中会发现一些基因突变，但这些突变可能并非真正来源于肿瘤本身，而是源于克隆性造血，特别是那些与DNA修复通路相关的突变。目前大多数的NGS检测手段很难准确区分这两种情况。这一点非常重要，因为如果错误地认为某个突变是肿瘤特有的，从而针对该突变进行靶向治疗，而实际上这个突变是由克隆性造血引起的，那么治疗效果可能就会大打折扣。

 

不过，液体NGS也有它独特的优势。它的操作简便，只需要采集少量血液样本就能进行检测。而且，液体NGS还可以监测特定前列腺癌患者突变谱的动态变化。因为我们的一些研究发现，癌细胞的突变会随着时间不断演变。例如，雄激素受体配体结合域突变（AR LBD）这类新的靶向突变，可能会在后续的治疗过程中出现。而这些新出现的突变往往与系统治疗相关。通过液体NGS，我们就能够及时捕捉到这些突变谱的变化，为制定更精准的治疗方案提供有力依据。

 

Oncology Frontier-UroStream:Compared to traditional tumor tissue biopsies，what are the main technical challenges overcome by liquid biopsy-based analysis?What are its advantages in analyzing tumor heterogeneity and dynamically monitoring gene evolution?

 

Dr.Darren M.Poon:The first challenges for the liquid biopsy or the liquid NGS for the metastatic prostate cancer would be the false negative possibilities.Because if you compare the tissue biopsy，you can really get a tissue and send for the NGS testing，whereas for the blood or the liquid NGS，it really depends on the patient’s tumor load as well as the blood that drawn for the NGS，whether that consists of sufficient DNA contents for the analysis.So the possibilities of false negative is one of the challenges for liquid biopsy.

 

The second challenges will be the differentiation between the mutations versus clonal hematopoiesis for that particular mutations，because sometimes the genetic mutations that detected in the liquid NGS may be arising from the clonal hematopoiesis，especially for the mutations that are related to the DNA repair pathway.So far most of the NGS testing is difficult to differentiate such differences，so that may also affect the therapeutic implications，because if it is really a clonal hematopoiesis mutation，the targeted therapy that add on that mutation may not be very effective compared to the mutations that really arising from that particular tumor.

 

But the liquid NGS has a very important and advantages that is much easier，and it can take the blood very easily for the liquid NGS，and also you can monitor the dynamic changes for the mutational profile for that particular prostate cancer patients.Because we have some data suggested that the mutations may be evolving with time，and also some of the new targeted such as the androgen receptor ligand binding domain mutations may be happen with a later lines of therapies，because these mutations may be happen with a more systemic therapies they are keep evolving.So liquid NGS could help for the monitoring of these dynamic mutational profiling changes.

 

潘明骏（Darren Poon）教授：检测AR LBD突变具有重要意义。因为一些数据显示，携带这些突变的患者预后可能较差；而且当这些突变出现时，患者对雄激素受体通路抑制剂的反应也会受到影响。所以，对于携带AR LBD突变的患者来说，我们迫切需要找到更有效的治疗方法。

 

其中，一种很有潜力的靶向疗法就是Opifovestat，这是一种CYP11A1抑制剂，能够降低睾酮水平以及后续雄激素生成。去年欧洲肿瘤内科学会（ESMO）大会公布了Opifovestat针对携带AR LBD突变患者的II期临床试验结果。结果显示，这些患者对这种新型靶向疗法反应良好，给很多患者带来了希望。

 

目前正在进行Opifovestat相关的3期临床试验，以评估Opifovestat这种新型药物在那些既往接受过系统治疗、但疗效不佳、并且携带AR LBD突变的转移性去势抵抗性前列腺癌（mCRPC）患者中的疗效。我们都在密切关注着这些试验的数据，而液体NGS监测有助于监测这些AR LBD突变。因为这些突变可能在首次治疗时就存在，也可能在疾病进展的后续治疗过程中才出现。所以，通过连续监测，我们就能更好地监测这些突变的发生，为患者的治疗提供更准确的信息。

 

Oncology Frontier-UroStream:For patients with detected AR LBD mutations，what factors should clinicians focus on when developing treatment strategies?

 

Dr.Darren M.Poon:The importance of detecting the androgen receptor ligand binding domain mutations is because we have some data to suggest with the presence of these mutations，the patients may have a poor prognosis，and the response to the androgen receptor pathway inhibitors may be affected when these mutation occur.And nowadays we looking forward for new targeted therapy focusing on these patients with AR LBD mutations.One of the potential targeted therapy is the Opifovestat，which is a CYP11A1 inhibitor，and then it will cut down the testosterone and also the subsequent all the androgen productions.And from the phase 2 trials that has been presented in ESMO last year for patients with these AR LBD mutations，they are quite responding to these new targeted therapies.

 

So there are some ongoing phase 3 clinical trials to evaluate this new compound in patients with androgen receptor ligand binding domain mutations with mCRPC disease that have failed prior systemic therapies.And we look for that data and the liquid NGS could help to detect these AR LBD mutations.And we can also check these mutations whether they had present in serial testing，because they may be happen not only in the first setting，they may develop in the subsequent setting when they have a progression of disease.So we can monitor these mutations to be happen in a serial measurement.

 

潘明骏（Darren Poon）教授：对于大多数前列腺癌患者而言，前列腺癌转移通常发生在骨骼。这就带来了一个问题，骨活检在获取组织样本进行NGS时面临诸多困难：一方面，骨活检很难提供足够数量的组织用于检测；另一方面，它是一种侵入性的检查方式，会给患者带来疼痛。不过，液体NGS技术的出现为解决这些问题提供了新的思路。相较于骨活检，通过液体NGS获取足够的DNA样本来进行NGS分析要容易得多。

 

除此之外，很多患者的组织活检样本可能是在首次确诊前列腺癌时采集的，随着时间的推移，这些样本可能已经“过时”。比如，这些组织样本的质量可能不佳，而且大多是留存组织。在进行组织NGS检测时，需要提取切片；在这个过程中，组织质量很可能已经受到影响，导致无法顺利进行NGS检测。但液体NGS则不存在这样的问题，它不受组织质量的限制，只需要采集血液样本来检测液体DNA即可；而且还可以监测突变随时间的变化。

 

正是由于液体NGS具有这些优势，在中国香港，我们已经积累了更多使用液体NGS技术的数据和经验，能够为转移性前列腺癌患者提供基因组分析信息。我们希望通过推广和应用液体NGS技术，能够为患者和医生提供更便捷、更个性化的治疗方案，让更多的患者受益。

 

Oncology Frontier-UroStream:Overall，what do you think is the most important implication of this liquid biopsy study targeting the Chinese population for advancing precision medicine in prostate cancer?

 

Dr.Darren M.Poon:Now for prostate cancer patients most of the time the metastasis will be happen in the bone.And you know with a bone biopsy it is challenging to provide sufficient tissue for the NGS，and a bone biopsy is invasive and painful.But for liquid NGS it is much more easier to provide sufficient DNA amount or content for the NGS analysis.

 

Secondly，most of the patients if they have a tissue biopsy that may be quite outdated，it may be happen during the first diagnosis for the prostate cancer from the prostate biopsy，but those tissue may not be in good quality and they are some archival tissues，and during the time of the tissue NGS retrieving those slides the quality of the tissue may be already affected and may not feasible to have the formal NGS.But for liquid NGS it implies that the quality of the tissue will not affect because we just take a blood to monitor the liquid DNA.And it is much easier and also we can monitor the serial changes of the mutations with time.

 

So I think nowadays in Hong Kong we have more data on using liquid NGS in providing more informations about the genomic profiling for the metastatic prostate cancer patients.And we hope that by using liquid NGS it is easier and more convenient to the patients and the physician to provide a more personalized medicines approach.

 

潘明骏（Darren Poon）教授

养和医院综合肿瘤科中心副主任、临床肿瘤科名誉顾问医生

香港大学临床肿瘤学系名誉临床副教授香港中文大学肿瘤学系名誉临床副教授临床肿瘤科专科医生