Amanda Broderick, Elizabeth Pan, Jinju Li, Alec Chu, Clara Hwang, Pedro C Barata, Frank Cameron Cackowski, Matthew Labriola, Alyssa Ghose, Mehmet Asim Bilen, Deepak Kilari, Bicky Thapa, Michael Piero, Laura Graham, Abhishek Tripathi, Rohan Garje, Vadim S Koshkin, Erik Hernandez, Tanya B Dorff, Michael Thomas Schweizer, Ajjai Shivaram Alva, Rana R McKay, Andrew J Armstrong
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Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status.</p><p><strong>Results: </strong>Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). 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引用次数: 0
摘要
背景:在临床前模型中,Wnt 信号转导异常与前列腺癌的肿瘤发生和转移有关,但 Wnt 信号转导基因的遗传改变对晚期前列腺癌男性患者的影响尚不清楚:我们利用前列腺癌精准医学多机构协作努力(PROMISE)临床基因组数据库进行了这项回顾性分析。CTNNB1或RSPO2发生激活突变或APC、RNF43或ZNRF3发生灭活突变的患者被定义为Wnt改变患者,而没有发生此类改变的患者被定义为Wnt非改变患者。我们根据 Wnt 改变状态比较了患者特征、临床结果以及并发遗传改变:在纳入的 1498 名患者中,有 193 人(12.9%)发生了 Wnt 改变。与未发生 Wnt 改变的患者相比,这些男性患者在初次诊断(4.66% 对 2.15%;6.22% 对 3.07%)、首次转移性疾病诊断(10.88% 对 5.29%;13.99% 对 6.21%)和 CRPC 发展(11.40% 对 6.36%;12.95% 对 5.29%)时的肝脏和肺部转移发生率在统计学上显著增加了 2 倍。Wnt改变与更多的RB1(10.4% vs 6.2%)、AR(38.9% vs 25.7%)、SPOP(13.5% vs 4.1%)、FOXA1(6.7% vs 2.8%)和PIK3CA(10.9% vs 5.1%)共存改变相关。我们发现,从最初诊断、首次转移性疾病、诊断为CRPC或使用AR抑制剂治疗mCRPC开始,Wnt组之间的总生存期或其他临床结果没有明显差异:结论:Wnt改变的前列腺癌患者内脏转移率较高,且富含RB1、AR、SPOP、FOXA1和PIK3CA改变。尽管存在这些关联,但Wnt改变与晚期前列腺癌男性患者更差的生存期或治疗效果无关。
Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.
Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown.
Methods: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status.
Results: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups.
Conclusions: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.
期刊介绍:
Prostate Cancer and Prostatic Diseases covers all aspects of prostatic diseases, in particular prostate cancer, the subject of intensive basic and clinical research world-wide. The journal also reports on exciting new developments being made in diagnosis, surgery, radiotherapy, drug discovery and medical management.
Prostate Cancer and Prostatic Diseases is of interest to surgeons, oncologists and clinicians treating patients and to those involved in research into diseases of the prostate. The journal covers the three main areas - prostate cancer, male LUTS and prostatitis.
Prostate Cancer and Prostatic Diseases publishes original research articles, reviews, topical comment and critical appraisals of scientific meetings and the latest books. The journal also contains a calendar of forthcoming scientific meetings. The Editors and a distinguished Editorial Board ensure that submitted articles receive fast and efficient attention and are refereed to the highest possible scientific standard. A fast track system is available for topical articles of particular significance.