Shah Kalpit, Secrest Matthew H, Zhou Wei, Wang Shu, Canter Dan, Zhang Yuxiang, Jin Dexter, Sokol Ethan, Nowicka Malgorzata, Ang Houle Armande, Metcalfe Ciara, Gendreau Steven, Schröder Carsten, Wongchenko Matthew, Attard Gerhardt
Translational Medicine - Oncology, Genentech, Inc., South San Francisco, California.
Data and Statistical Sciences, Product Development, Genentech, Inc., South San Francisco, California.
Clin Cancer Res. 2025 Jul 1;31(13):2824-2838. doi: 10.1158/1078-0432.CCR-24-1812.
Many preclinical hypotheses, including reciprocal feedback activation between the androgen receptor (AR)-PI3K pathway in PTEN loss and AR signaling inhibitor-induced "BRCAness" regardless of BRCA1/2 status, have struggled to translate into clinical benefit for patients with metastatic prostate cancer. This gap in translatability, particularly in metastatic castration-resistant prostate cancer (mCRPC), may stem from a limited understanding of prostate cancer evolution. A key challenge is the correlation between early-stage tumor genetics and mCRPC. By examining clinical, genomic, and molecular changes over time, we aimed to refine clinical trial design.
Using a comprehensive dataset from electronic health records with genomic profiling, a shift in the prognostic value of biomarkers from metastatic hormone-sensitive prostate cancer (mHSPC) to mCRPC was observed. Additionally, genomic and transcriptomic analyses of primary tumors from the IPATential150 trial and mCRPC samples from the Stand Up To Cancer cohort examined the changing AR-PI3K signaling correlation.
PI3K-AKT pathway alterations lost their prognostic significance in later stages. Although AR and PI3K-AKT signaling were inversely correlated in primary tumors, this relationship was disrupted in mCRPC, independent of PIK3CA/AKT1/PTEN status. We identified broad transcriptional rewiring associated with AR signaling, increasing tumor heterogeneity. Improving the understanding of early-stage disease, we identified a high-risk mHSPC subset enriched for AR alterations. Additionally, in a subset of patients, AR ligand-binding domain mutations preceded amplification, potentially leading to preferential amplification of the mutant AR form.
Our findings underscore the dynamic nature of prostate tumor biology and emphasize the need for translational research to validate preclinical hypotheses in clinically relevant settings, ultimately improving trial design and therapeutic strategies.
许多临床前假说，包括在PTEN缺失情况下雄激素受体（AR）-PI3K通路之间的相互反馈激活以及AR信号抑制剂诱导的“BRCA样状态”（无论BRCA1/2状态如何），都难以转化为转移性前列腺癌患者的临床获益。这种可转化性的差距，尤其是在转移性去势抵抗性前列腺癌（mCRPC）中，可能源于对前列腺癌演变的了解有限。一个关键挑战是早期肿瘤遗传学与mCRPC之间的相关性。通过研究随时间变化的临床、基因组和分子变化，我们旨在优化临床试验设计。
利用来自电子健康记录并带有基因组分析的综合数据集，观察到生物标志物的预后价值从转移性激素敏感性前列腺癌（mHSPC）向mCRPC发生了转变。此外，对IPATential150试验的原发性肿瘤和“勇敢抗癌”队列中的mCRPC样本进行基因组和转录组分析，研究了不断变化的AR-PI3K信号相关性。
PI3K-AKT通路改变在后期失去了其预后意义。虽然AR和PI3K-AKT信号在原发性肿瘤中呈负相关，但这种关系在mCRPC中被破坏，与PIK3CA/AKT1/PTEN状态无关。我们发现了与AR信号相关的广泛转录重排，增加了肿瘤异质性。为了更好地理解早期疾病，我们确定了一个富含AR改变的高危mHSPC亚组。此外，在一部分患者中，AR配体结合域突变先于扩增出现，这可能导致突变型AR形式的优先扩增。
我们的研究结果强调了前列腺肿瘤生物学的动态性质，并强调需要进行转化研究以在临床相关环境中验证临床前假说，最终改善试验设计和治疗策略。
