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dc.contributor.authorDe Laere, Ben_US
dc.contributor.authorOeyen, Sen_US
dc.contributor.authorMayrhofer, Men_US
dc.contributor.authorWhitington, Ten_US
dc.contributor.authorvan Dam, P-Jen_US
dc.contributor.authorVan Oyen, Pen_US
dc.contributor.authorGhysel, Cen_US
dc.contributor.authorAmpe, Jen_US
dc.contributor.authorOst, Pen_US
dc.contributor.authorDemey, Wen_US
dc.contributor.authorHoekx, Len_US
dc.contributor.authorSchrijvers, Den_US
dc.contributor.authorBrouwers, Ben_US
dc.contributor.authorLybaert, Wen_US
dc.contributor.authorEveraert, EGen_US
dc.contributor.authorDe Maeseneer, Den_US
dc.contributor.authorStrijbos, Men_US
dc.contributor.authorBols, Aen_US
dc.contributor.authorFransis, Ken_US
dc.contributor.authorBeije, Nen_US
dc.contributor.authorde Kruijff, IEen_US
dc.contributor.authorvan Dam, Ven_US
dc.contributor.authorBrouwer, Aen_US
dc.contributor.authorGoossens, Den_US
dc.contributor.authorHeyrman, Len_US
dc.contributor.authorVan den Eynden, GGen_US
dc.contributor.authorRutten, Aen_US
dc.contributor.authorDel Favero, Jen_US
dc.contributor.authorRantalainen, Men_US
dc.contributor.authorRajan, Pen_US
dc.contributor.authorSleijfer, Sen_US
dc.contributor.authorUllén, Aen_US
dc.contributor.authorYachnin, Jen_US
dc.contributor.authorGrönberg, Hen_US
dc.contributor.authorVan Laere, SJen_US
dc.contributor.authorLindberg, Jen_US
dc.contributor.authorDirix, LYen_US
dc.date.accessioned2018-10-08T14:36:24Z
dc.date.available2018-09-11en_US
dc.date.issued2018-09-12en_US
dc.date.submitted2018-09-24T15:28:39.994Z
dc.identifier.issn1078-0432en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/45963
dc.description.abstractPURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). EXPERIMENTAL DESIGN: Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). CONCLUSIONS: In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis.en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofClin Cancer Resen_US
dc.titleTP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer.en_US
dc.typeArticle
dc.identifier.doi10.1158/1078-0432.CCR-18-1943en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/30209161en_US
pubs.notes12 monthsen_US
pubs.publication-statusPublished onlineen_US
dcterms.dateAccepted2018-09-11en_US


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