TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer

被引：147

作者：

De Laere, Bram ^{[1
]}

Oeyen, Steffi ^{[1
]}

Mayrhofer, Markus ^{[2
]}

Whitington, Tom ^{[2
]}

van Dam, Pieter-Jan ^{[1
,3
]}

Van Oyen, Peter ^{[4
]}

Ghysel, Christophe ^{[4
]}

Ampe, Jozef ^{[4
]}

Ost, Piet ^{[5
]}

Demey, Wim ^{[6
]}

Hoekx, Lucien ^{[7
]}

Schrijvers, Dirk ^{[8
]}

Brouwers, Barbara ^{[9
]}

Lybaert, Willem ^{[10
]}

Everaert, Els G. ^{[10
]}

De Maeseneer, Daan ^{[11
]}

Strijbos, Michiel ^{[6
]}

Bols, Alain ^{[9
]}

Fransis, Karen ^{[7
]}

Beije, Nick ^{[12
]}

de Kruijff, Inge E. ^{[12
]}

van Dam, Valerie ^{[1
]}

Brouwer, Anja ^{[1
]}

Goossens, Dirk ^{[13
]}

Heyrman, Lien ^{[13
]}

Van den Eynden, Gert G. ^{[14
]}

Rutten, Annemie ^{[15
]}

Del Favero, Jurgen ^{[13
]}

Rantalainen, Mattias ^{[2
]}

Rajan, Prabhakar ^{[16
]}

Sleijfer, Stefan ^{[12
]}

Ullen, Anders ^{[17
,18
]}

Yachnin, Jeffrey ^{[17
,18
]}

Gronberg, Henrik ^{[2
]}

Van Laere, Steven J. ^{[1
]}

Lindberg, Johan ^{[19
]}

Dirix, Luc Y. ^{[1
,15
]}

机构：

[1] Univ Antwerp, Ctr Oncol Res CORE, Antwerp, Belgium

[2] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[3] HistoGeneX NV, Antwerp, Belgium

[4] Acad Hosp St Jan, Dept Urol, Brugge, Belgium

[5] Ghent Univ Hosp, Dept Radiat Oncol, Ghent, Belgium

[6] AZ KLINA, Dept Oncol, Brasschaat, Belgium

[7] Antwerp Univ Hosp, Dept Urol, Antwerp, Belgium

[8] ZNA Middelheim, Dept Oncol, Antwerp, Belgium

[9] Acad Hosp St Jan, Dept Oncol, Brugge, Belgium

[10] AZ Nikolaas, Dept Oncol, St Niklaas, Belgium

[11] AZ Sint Lucas, Dept Oncol, Brugge, Belgium

[12] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst, Med Oncol & Canc Genom Netherlands, Rotterdam, Netherlands

[13] Agilent Technol, Niel, Belgium

[14] GZA Hosp Sint Augustinus, Dept Pathol, Antwerp, Belgium

[15] GZA Hosp Sint Augustinus, Dept Oncol, Antwerp, Belgium

[16] Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England

[17] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[18] Univ Hosp, Stockholm, Sweden

[19] Karolinska Inst, Dept Med Epidemiol & Biostat, Sci Life Lab, Stockholm, Sweden

来源：

CLINICAL CANCER RESEARCH | 2019年 / 25卷 / 06期

基金：

瑞典研究理事会;

关键词：

CIRCULATING TUMOR-CELLS; MESSENGER-RNA DETECTION; CLINICAL-SIGNIFICANCE; 2ND-LINE ABIRATERONE; RECOMMENDATIONS; EXPRESSION; SURVIVAL; THERAPY; DESIGN; TRIALS;

D O I：

10.1158/1078-0432.CCR-18-1943

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). 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 radiologic 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, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (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, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 1699

引用

页码：1766 / 1773

页数：8

共 30 条

[1] Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer [J].

Annala, Matti ;

Vandekerkhove, Gillian ;

Khalaf, Daniel ;

Taavitsainen, Sinja ;

Beja, Kevin ;

Warner, Evan W. ;

Sunderland, Katherine ;

Kollmannsberger, Christian ;

Eigl, Bernhard J. ;

Finch, Daygen ;

Oja, Conrad D. ;

Vergidis, Joanna ;

Zulfiqar, Muhammad ;

Azad, Arun A. ;

Nykter, Matti ;

Gleave, Martin E. ;

Wyatt, Alexander W. ;

Chi, Kim N. .

CANCER DISCOVERY, 2018, 8 (04) :444-457

[2] Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration- Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide [J].

Antonarakis, Emmanuel S. ;

Lu, Changxue ;

Luber, Brandon ;

Wang, Hao ;

Chen, Yan ;

Zhu, Yezi ;

Silberstein, John L. ;

Taylor, Maritza N. ;

Maughan, Benjamin L. ;

Denmeade, Samuel R. ;

Pienta, Kenneth J. ;

Paller, Channing J. ;

Carducci, Michael A. ;

Eisenberger, Mario A. ;

Luo, Jun .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (19) :2149-+

[3] AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer [J].

Antonarakis, Emmanuel S. ;

Lu, Changxue ;

Wang, Hao ;

Luber, Brandon ;

Nakazawa, Mary ;

Roeser, Jeffrey C. ;

Chen, Yan ;

Mohammad, Tabrez A. ;

Chen, Yidong ;

Fedor, Helen L. ;

Lotan, Tamara L. ;

Zheng, Qizhi ;

De Marzo, Angelo M. ;

Isaacs, John T. ;

Isaacs, William B. ;

Nadal, Rosa ;

Paller, Channing J. ;

Denmeade, Samuel R. ;

Carducci, Michael A. ;

Eisenberger, Mario A. ;

Luo, Jun .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (11) :1028-1038

[4] Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer [J].

Bernemann, Christof ;

Schnoeller, Thomas J. ;

Luedeke, Manuel ;

Steinestel, Konrad ;

Boegemann, Martin ;

Schrader, Andres J. ;

Steinestel, Julie .

EUROPEAN UROLOGY, 2017, 71 (01) :1-3

[5] Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling [J].

Bluemn, Eric G. ;

Coleman, Ilsa M. ;

Lucas, Jared M. ;

Coleman, Roger T. ;

Hernandez-Lopez, Susana ;

Tharakan, Robin ;

Bianchi-Frias, Daniella ;

Dumpit, Ruth F. ;

Kaipainen, Arja ;

Corella, Alexandra N. ;

Yang, Yu Chi ;

Nyquist, Michael D. ;

Mostaghel, Elahe ;

Hsieh, Andrew C. ;

Zhang, Xiaotun ;

Corey, Eva ;

Brown, Lisha G. ;

Nguyen, Holly M. ;

Pienta, Kenneth ;

Ittmann, Michael ;

Schweizer, Michael ;

True, Lawrence D. ;

Wise, David ;

Rennie, Paul S. ;

Vessella, Robert L. ;

Morrissey, Colm ;

Nelson, Peter S. .

CANCER CELL, 2017, 32 (04) :474-+

[6] Evolutionary dynamics of cancer in response to targeted combination therapy [J].

Bozic, Ivana ;

Reiter, Johannes G. ;

Allen, Benjamin ;

Antal, Tibor ;

Chatterjee, Krishnendu ;

Shah, Preya ;

Moon, Yo Sup ;

Yaqubie, Amin ;

Kelly, Nicole ;

Le, Dung T. ;

Lipson, Evan J. ;

Chapman, Paul B. ;

Diaz, Luis A., Jr. ;

Vogelstein, Bert ;

Nowak, Martin A. .

ELIFE, 2013, 2

[7] Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study [J].

Conteduca, V. ;

Wetterskog, D. ;

Sharabiani, M. T. A. ;

Grande, E. ;

Fernandez-Perez, M. P. ;

Jayaram, A. ;

Salvi, S. ;

Castellano, D. ;

Romanel, A. ;

Lolli, C. ;

Casadio, V. ;

Gurioli, G. ;

Amadori, D. ;

Font, A. ;

Vazquez-Estevez, S. ;

Gonzalez del Alba, A. ;

Mellado, B. ;

Fernandez-Calvo, O. ;

Mendez-Vidal, M. J. ;

Climent, M. A. ;

Duran, I. ;

Gallardo, E. ;

Rodriguez, A. ;

Santander, C. ;

Saez, M. I. ;

Puente, J. ;

Tandefelt, D. Gasi ;

Wingate, A. ;

Dearnaley, D. ;

Demichelis, F. ;

De Giorgi, U. ;

Gonzalez-Billalabeitia, E. ;

Attard, G. .

ANNALS OF ONCOLOGY, 2017, 28 (07) :1508-1516

[8] EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer [J].

Cornford, Philip ;

Bellmunt, Joaquim ;

Bolla, Michel ;

Briers, Erik ;

De Santis, Maria ;

Gross, Tobias ;

Henry, Ann M. ;

Joniau, Steven ;

Lam, Thomas B. ;

Mason, Malcolm D. ;

van der Poel, Henk G. ;

van der Kwast, Theo H. ;

Rouviere, Olivier ;

Wiegel, Thomas ;

Mottet, Nicolas .

EUROPEAN UROLOGY, 2017, 71 (04) :630-642

[9] Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns [J].

De laere, Bram ;

van Dam, Pieter-Jan ;

Whitington, Tom ;

Mayrhofer, Markus ;

Diaz, Emanuela Henao ;

Van den Eynden, Gert ;

Vandebroek, Jean ;

Del-Favero, Jurgen ;

Van Laere, Steven ;

Dirix, Luc ;

Gronberg, Henrik ;

Lindberg, Johan .

EUROPEAN UROLOGY, 2017, 72 (02) :192-200

[10] PTEN Protein Loss and Clinical Outcome from Castration-resistant Prostate Cancer Treated with Abiraterone Acetate [J].

Ferraldeschi, Roberta ;

Rodrigues, Daniel Nava ;

Riisnaes, Ruth ;

Miranda, Susana ;

Figueiredo, Ines ;

Rescigno, Pasquale ;

Ravi, Praful ;

Pezaro, Carmel ;

Omlin, Aurelius ;

Lorente, David ;

Zafeiriou, Zafeiris ;

Mateo, Joaquin ;

Altavilla, Amelia ;

Sideris, Spyridon ;

Bianchini, Diletta ;

Grist, Emily ;

Thway, Khin ;

Lopez, Raquel Perez ;

Tunariu, Nina ;

Parker, Chris ;

Dearnaley, David ;

Reid, Alison ;

Attard, Gerhardt ;

de Bono, Johann .

EUROPEAN UROLOGY, 2015, 67 (04) :795-802

← 1 2 3 →