BACKGROUND Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients. OBJECTIVE To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide. DESIGN, SETTING, AND PARTICIPANTS Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints. RESULTS AND LIMITATIONS Of 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression. CONCLUSIONS Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients. PATIENT SUMMARY In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

中文翻译：

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Wnt通路激活突变与去势抵抗性前列腺癌对一线阿比特龙和恩杂鲁胺的耐药性相关。

背景技术Wnt信号传导是涉及胚胎发生，发育和瘤形成的细胞途径。Wnt途径激活可能会加速前列腺癌雄激素非依赖性生长并介导抗雄激素耐药性。由于10-20％的晚期前列腺癌具有Wnt激活突变，因此我们旨在表征此类患者的临床特征和对新型抗雄激素的反应。目的确定具有Wnt途径突变的转移性去势抵抗性前列腺癌（mCRPC）男性对一线新型激素疗法（阿比特龙/ enzalutamide）的反应是否较差。设计，地点和参与者回顾性评估接受一线阿比特龙或恩杂鲁胺治疗的mCRPC患者。使用肿瘤DNA分析，我们查询了CTNNB1中的激活突变或APC或RNF43中的失活突变，所有这些都预计会刺激Wnt信号传导。是否存在至少一种Wnt激活改变与临床病理特征和治疗结果相关。结果测量和统计分析测量到前列腺特异性抗原（PSA）进展，总生存（OS）和PSA反应的时间。使用Cox回归模型测试Wnt状态与临床病理结果之间的关联。Kaplan-Meier和对数秩分析用于比较事件发生时间的终点。结果与局限性在所评估的137例患者中，有11％（n = 15）的肿瘤DNA分析显示出至少一种Wnt刺激性改变。具有Wnt激活突变的患者在数字上比Wnt野生型患者的T3 / T4肿瘤更少（分别为31％和51％），但总体而言是平衡的。在Wnt激活的患者中，一线阿比特龙/ enzalutamide接受PSA进展的中位时间较短（6.5 vs 9.6mo，危险比[HR] 2.34，p = 0.003），OS则更短（23.6 vs 27.7mo，HR 2.28，p） = 0.01）。Wnt激活患者的PSA反应在数值上更差（53％比75％，p = 0.12）。Wnt激活改变的存在（调整后的HR [aHR] 2.33，p = 0.007）和使用先前的化疗（aHR 1.83，p = 0.004）均与进展风险增加独立相关。结论体细胞Wnt途径激活突变的患者对一线阿比特龙/恩杂鲁胺的治疗效果比Wnt野生型患者差。我们的数据表明，对于mCRPC患者的这一相关亚组，需要更多的基因组学信息疗法。病人总结在本报告中，我们回顾性检查了首次接受阿比特龙或恩杂鲁胺的有或无Wnt途径突变的转移性前列腺癌患者的结局，以检查这些突变是否影响预后。我们的研究表明，与没有这些突变的患者相比，具有Wnt途径激活突变的患者从阿比特龙和恩杂鲁胺中获得的收益较少。我们得出的结论是Wnt途径突变可能会降低阿比特龙和enzalutamide的有效性，并且我们认为Wnt途径可能是这些患者的良好治疗靶点，