A correlative biomarker study and integrative prognostic model in chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide

被引：4

作者：

Fernandez-Perez, Maria P. ^{[1
]}

Perez-Navarro, Enrique ^{[2
]}

Alonso-Gordoa, Teresa ^{[3
]}

Conteduca, Vicenza ^{[4
]}

Font, Albert ^{[5
]}

Vazquez-Estevez, Sergio ^{[6
]}

Gonzalez-del-Alba, Aranzazu ^{[7
]}

Wetterskog, Daniel ^{[8
]}

Antonarakis, Emmanuel S. ^{[9
]}

Mellado, Begona ^{[10
]}

Fernandez-Calvo, Ovidio ^{[11
]}

Mendez-Vidal, Maria J. ^{[12
]}

Climent, Miguel A. ^{[13
]}

Duran, Ignacio ^{[14
]}

Gallardo, Enrique ^{[15
]}

Rodriguez Sanchez, Angel ^{[16
]}

Santander, Carmen ^{[17
]}

Saez, Maria, I ^{[18
]}

Puente, Javier ^{[19
]}

Tudela, Julian ^{[20
]}

Martinez, Alberto ^{[21
]}

Lopez-Andreo, Maria J. ^{[22
]}

Padilla, Jose ^{[1
]}

Lozano, Rebeca ^{[23
,24
]}

Hervas, David ^{[25
]}

Luo, Jun ^{[26
]}

de Giorgi, Ugo ^{[4
]}

Castellano, Daniel ^{[2
]}

Attard, Gerhardt ^{[8
]}

Grande, Enrique ^{[27
]}

Gonzalez-Billalabeitia, Enrique ^{[1
,2
,28
]}

机构：

[1] Hosp Univ Morales Meseg, IMIB, Dept Haematol & Med Oncol, Murcia, Spain

[2] Hosp Univ 12 Octubre, Inst Invest, Dept Med Oncol, Madrid, Spain

[3] Hosp Ramon & Cajal, Dept Med Oncol, Madrid, Spain

[4] Ist Sci Romagnolo Studio & Cura Tumori IRST Di, Dept Med Oncol, Meldola, Italy

[5] Catalan Inst Oncol, Badalona Appl Res Grp Oncol BARGO, Dept Med Oncol, Badalona, Spain

[6] Hosp Univ Lucus Augusti, Dept Med Oncol, Lugo, Spain

[7] Hosp Univ Son Espases, Dept Med Oncol, Palma De Mallorca, Spain

[8] UCL, Canc Inst, Paul OGorman Bldg, London, England

[9] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[10] Hosp Clin Univ Barcelona, IDIBAPS, Dept Med Oncol, Barcelona, Spain

[11] Complejo Hosp Univ Ourense, Dept Med Oncol, Orense, Spain

[12] Hosp Univ Reina Sofia HURS, Maimonides Inst Biomed Res Cordoba IMIBIC, Dept Med Oncol, Cordoba, Spain

[13] Inst Valenciano Oncol, Serv Oncol Med, Valencia, Spain

[14] Univ Seville, Hosp Univ Virgen del Rocio, CSIC, IBiS,Inst Biomed Sevilla, Seville, Spain

[15] Univ Autonoma Barcelona, Parc Tauli Hosp Univ, Inst Invest & Innovacio Parc Tauli I3PT, Dept Med Oncol,Serv Oncol Med, Sabadell, Spain

[16] Hosp Univ Leon, Dept Med Oncol, Leon, Spain

[17] Hosp Univ Miguel Servet, Dept Med Oncol, Zaragoza, Spain

[18] Reg & Virgen de la Victoria Univ Hosp, IBIMA, Med Oncol Interctr Unit, Malaga, Spain

[19] Hosp Clin San Carlos, CIBERONC, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Dept Med Oncol, Madrid, Spain

[20] Hosp Morales Meseguer, Dept Pathol, Murcia, Spain

[21] IMIB, Nodo 3, Biobanco Reg Murcia, Murcia, Spain

[22] Univ Murcia, IMIB, SAI, Dept Mol Biol, Murcia, Spain

[23] Spanish Natl Canc Res Ctr, Prostate Canc Clin Res Unit, Madrid, Spain

[24] Inst Invest Biomed Malaga, Genitourinary Translat Res Grp, Malaga, Spain

[25] Inst Invest Sanitaria La Fe, Data Sci Unit, Valencia, Spain

[26] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA

[27] MD Anderson Canc Ctr Madrid, Madrid, Spain

[28] Univ Catolica San Antonio Murcia UCAM, Murcia, Spain

来源：

PROSTATE | 2023年 / 83卷 / 04期

关键词：

AR gain; AR-V7; CTCs; enzalutamide; prostate cancer; TMPRSS2-ERG; CIRCULATING TUMOR-CELLS; GENE STATUS; ANDROGEN RECEPTOR; CLINICAL-TRIALS; ABIRATERONE; SURVIVAL; SURROGATE; TMPRSS2; FUSION; MEN;

D O I：

10.1002/pros.24469

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundThere is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). MethodsWe conducted a phase II trial of enzalutamide in first-line chemo-naive asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. ResultsNinety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. ConclusionsTMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

引用

页码：376 / 384

页数：9

共 33 条

[1] Genomic correlates of clinical outcome in advanced prostate cancer
Abida, Wassim
Cyrta, Joanna
Heller, Glenn
Prandi, Davide
Armenia, Joshua
Coleman, Ilsa
Cieslik, Marcin
Benelli, Matteo
Robinson, Dan
Van Allen, Eliezer M.
Sboner, Andrea
Fedrizzi, Tarcisio
Mosquera, Juan Miguel
Robinson, Brian D.
De Sarkar, Navonil
Kunju, Lakshmi P.
Tomlins, Scott
Wu, Yi Mi
Rodrigues, Daniel Nava
Loda, Massimo
Gopalan, Anuradha
Reuter, Victor E.
Pritchard, Colin C.
Mateo, Joaquin
Bianchini, Diletta
Miranda, Susana
Carreira, Suzanne
Rescigno, Pasquale
Filipenko, Julie
Vinson, Jacob
Montgomery, Robert B.
Beltran, Himisha
Heath, Elisabeth I.
Scher, Howard I.
Kantoff, Philip W.
Taplin, Mary-Ellen
Schultz, Nikolaus
deBono, Johann S.
Demichelis, Francesca
Nelson, Peter S.
Rubin, Mark A.
Chinnaiyan, Arul M.
Sawyers, Charles L.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (23) : 11428 - 11436
[2] AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer
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
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (11) : 1028 - 1038
[3] The long tail of oncogenic drivers in prostate cancer
Armenia, Joshua
Wankowicz, Stephanie A. M.
Liu, David
Gao, Jianjiong
Kundra, Ritika
Reznik, Ed
Chatila, Walid K.
Chakravarty, Debyani
Han, G. Celine
Coleman, Ilsa
Montgomery, Bruce
Pritchard, Colin
Morrissey, Colm
Barbieri, Christopher E.
Beltran, Himisha
Sboner, Andrea
Zafeiriou, Zafeiris
Miranda, Susana
Bielski, Craig M.
Penson, Alexander V.
Tolonen, Charlotte
Huang, Franklin W.
Robinson, Dan
Wu, Yi Mi
Lonigro, Robert
Garraway, Levi A.
Demichelis, Francesca
Kantoff, Philip W.
Taplin, Mary-Ellen
Abida, Wassim
Taylor, Barry S.
Scher, Howard I.
Nelson, Peter S.
de Bono, Johann S.
Rubin, Mark A.
Sawyers, Charles L.
Chinnaiyan, Arul M.
Schultz, Nikolaus
Van Allen, Eliezer M.
[J]. NATURE GENETICS, 2018, 50 (05) : 645 - +
[4] Development and validation of a prognostic model for overall survival in chemotherapy-na⟨ve men with metastatic castration-resistant prostate cancer
Armstrong, A. J.
Lin, P.
Higano, C. S.
Sternberg, C. N.
Sonpavde, G.
Tombal, B.
Templeton, A. J.
Fizazi, K.
Phung, D.
Wong, E. K.
Krivoshik, A.
Beer, T. M.
[J]. ANNALS OF ONCOLOGY, 2018, 29 (11) : 2200 - 2207
[5] Prostate cancer
Attard, Gerhardt
Parker, Chris
Eeles, Ros A.
Schroder, Fritz
Tomlins, Scott A.
Tannock, Ian
Drake, Charles G.
de Bono, Johann S.
[J]. LANCET, 2016, 387 (10013) : 70 - 82
[6] Improvements in Radiographic Progression-Free Survival Stratified by ERG Gene Status in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Abiraterone Acetate
Attard, Gerhardt
de Bono, Johann S.
Logothetis, Christopher J.
Fizazi, Karim
Mukherjee, Som D.
Joshuas, Anthony M.
Schrijvers, Dirk
van den Eertwegh, Alfons J. M.
Li, Weimin
Molina, Arturo
Griffin, Thomas W.
Kheoh, Thian
Ricci, Deborah S.
Zelinsky, Kathy
Rathkopf, Dana E.
Scher, Howard I.
Ryan, Charles J.
[J]. CLINICAL CANCER RESEARCH, 2015, 21 (07) : 1621 - 1627
[7] Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer
Attard, Gerhardt
Swermenhuis, Joost F.
Olmos, David
Reid, Alison H. M.
Vickers, Elaine
A'Hern, Roger
Levink, Rianne
Coumans, Frank
Moreira, Joana
Riisnaes, Ruth
Oommen, Nikhil Babu
Hawche, George
Jameson, Charles
Thompson, Emilda
Sipkema, Ronald
Carden, Craig P.
Parker, Christopher
Dearnaley, David
Kaye, Stan B.
Cooper, Colin S.
Molina, Arturo
Cox, Michael E.
Terstappen, Leon W. M. M.
de Bono, Johann S.
[J]. CANCER RESEARCH, 2009, 69 (07) : 2912 - 2918
[8] Beer TM, 2014, NEW ENGL J MED, V371, P424, DOI 10.1056/NEJMoa1405095
[9] Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study
Beer, Tomasz M.
Armstrong, Andrew J.
Rathkopf, Dana
Loriot, Yohann
Sternberg, Cora N.
Higano, Celestia S.
Iversen, Peter
Evans, Christopher P.
Kim, Choung-Soo
Kimura, Go
Miller, Kurt
Saad, Fred
Bjartell, Anders S.
Borre, Michael
Mulders, Peter
Tammela, Teuvo L.
Parli, Teresa
Sari, Suha
van Os, Steve
Theeuwes, Ad
Tombal, Bertrand
[J]. EUROPEAN UROLOGY, 2017, 71 (02) : 151 - 154
[10] The Molecular Taxonomy of Primary Prostate Cancer
Abeshouse, Adam
Ahn, Jaeil
Akbani, Rehan
Ally, Adrian
Amin, Samirkumar
Andry, Christopher D.
Annala, Matti
Aprikian, Armen
Armenia, Joshua
Arora, Arshi
Auman, J. Todd
Balasundaram, Miruna
Balu, Saianand
Barbieri, Christopher E.
Bauer, Thomas
Benz, Christopher C.
Bergeron, Alain
Beroukhim, Rameen
Berrios, Mario
Bivol, Adrian
Bodenheimer, Tom
Boice, Lori
Bootwalla, Moiz S.
dos Reis, Rodolfo Borges
Boutros, Paul C.
Bowen, Jay
Bowlby, Reanne
Boyd, Jeffrey
Bradley, Robert K.
Breggia, Anne
Brimo, Fadi
Bristow, Christopher A.
Brooks, Denise
Broom, Bradley M.
Bryce, Alan H.
Bubley, Glenn
Burks, Eric
Butterfield, Yaron S. N.
Button, Michael
Canes, David
Carlotti, Carlos G.
Carlsen, Rebecca
Carmel, Michel
Carroll, Peter R.
Carter, Scott L.
Cartun, Richard
Carver, Brett S.
Chan, June M.
Chang, Matthew T.
Chen, Yu
[J]. CELL, 2015, 163 (04) : 1011 - 1025

← 1 2 3 4 →