Peter H J Slootbeek, María Victoria Luna-Velez, Bastiaan M Privé, Maarten J van der Doelen, Iris S H Kloots, Samhita Pamidimarri Naga, Hilde E Onstenk, James Nagarajah, Harm Westdorp, Inge M van Oort, Leonie I Kroeze, Jack A Schalken, Haiko J Bloemendal, Niven Mehra
{"title":"Impact of <i>TP53</i> loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.","authors":"Peter H J Slootbeek, María Victoria Luna-Velez, Bastiaan M Privé, Maarten J van der Doelen, Iris S H Kloots, Samhita Pamidimarri Naga, Hilde E Onstenk, James Nagarajah, Harm Westdorp, Inge M van Oort, Leonie I Kroeze, Jack A Schalken, Haiko J Bloemendal, Niven Mehra","doi":"10.7150/thno.96322","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. <b>Methods:</b> The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including <i>TP53</i>-mutational status. <b>Results:</b> Patients with <i>TP53</i> loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, <i>P</i><0.001), a lower median PSA change (-55% vs. -75%, <i>P</i>=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, <i>P</i>=0.003) compared to <i>TP53</i>-wildtype patients. Pathogenic alterations in <i>AR</i>, <i>MYC</i>, <i>BRCA1</i>, or <i>BRCA2</i> as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside <i>TP53</i>-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (<i>P</i><0.05). <b>Conclusion:</b> <i>TP53</i> loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373632/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.96322","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion:TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.