Tumor fraction in cell-free DNA as a biomarker in prostate cancer

被引：102

作者：

Choudhury, Atish D. ^{[1
,2
,3
]}

Werner, Lillian ^{[1
,2
]}

Francini, Edoardo ^{[1
,4
]}

Wei, Xiao X. ^{[1
,2
]}

Ha, Gavin ^{[1
,3
]}

Freeman, Samuel S. ^{[3
]}

Rhoades, Justin ^{[3
]}

Reed, Sarah C. ^{[3
]}

Gydush, Gregory ^{[3
]}

Rotem, Denisse ^{[3
]}

Lo, Christopher ^{[3
]}

Taplin, Mary-Ellen ^{[1
,2
]}

Harshman, Lauren C. ^{[1
,2
]}

Zhang, Zhenwei ^{[1
]}

O'Connor, Edward P. ^{[1
]}

Stover, Daniel G. ^{[5
]}

Parsons, Heather A. ^{[1
,2
,3
]}

Getz, Gad ^{[3
,6
]}

Meyerson, Matthew ^{[1
,2
,3
]}

Love, J. Christopher ^{[3
,7
]}

Hahn, William C. ^{[1
,2
,3
]}

Adalsteinsson, Viktor A. ^{[3
,7
]}

机构：

[1] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA USA

[3] Eli & Edythe Brd Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA

[4] Sapienza Univ Rome, Rome, Italy

[5] Ohio State Univ, Columbus, OH 43210 USA

[6] Massachusetts Gen Hosp, Boston, MA 02114 USA

[7] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

JCI INSIGHT | 2018年 / 3卷 / 21期

关键词：

INCREASED SURVIVAL; CHEMOTHERAPY; MUTATIONS; ENZALUTAMIDE; ABIRATERONE;

D O I：

10.1172/jci.insight.122109

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

BACKGROUND. Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described. METHODS. CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy. RESULTS. TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to = 30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was > 7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic. CONCLUSION. TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response.

引用

页数：13

共 33 条

[1] Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors [J].

Adalsteinsson, Viktor A. ;

Ha, Gavin ;

Freeman, Samuel S. ;

Choudhury, Atish D. ;

Stover, Daniel G. ;

Parsons, Heather A. ;

Gydush, Gregory ;

Reed, Sarah C. ;

Rotem, Denisse ;

Rhoades, Justin ;

Loginov, Denis ;

Livitz, Dimitri ;

Rosebrock, Daniel ;

Leshchiner, Ignaty ;

Kim, Jaegil ;

Stewart, Chip ;

Rosenberg, Mara ;

Francis, Joshua M. ;

Zhang, Cheng-Zhong ;

Cohen, Ofir ;

Oh, Coyin ;

Ding, Huiming ;

Polak, Paz ;

Lloyd, Max ;

Mahmud, Sairah ;

Helvie, Karla ;

Merrill, Margaret S. ;

Santiago, Rebecca A. ;

O'Connor, Edward P. ;

Jeong, Seong H. ;

Leeson, Rachel ;

Barry, Rachel M. ;

Kramkowski, Joseph F. ;

Zhang, Zhenwei ;

Polacek, Laura ;

Lohr, Jens G. ;

Schleicher, Molly ;

Lipscomb, Emily ;

Saltzman, Andrea ;

Oliver, Nelly M. ;

Marini, Lori ;

Waks, Adrienne G. ;

Harshman, Lauren C. ;

Tolaney, Sara M. ;

Van Allen, Eliezer M. ;

Winer, Eric P. ;

Lin, Nancy U. ;

Nakabayashi, Mari ;

Taplin, Mary-Ellen ;

Johannessen, Cory M. .

NATURE COMMUNICATIONS, 2017, 8

[2] 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

[3]

[Anonymous], [No title captured]

[4] Whole exome sequencing (WES) of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate cancer (NEPC) informs tumor heterogeneity. [J].

Beltran, Himisha ;

Romanel, Alessandro ;

Casiraghi, Nicola ;

Sigouros, Michael ;

Benelli, Matteo ;

Xiang, Jenny ;

Demichelis, Francesca .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35

[5] Aggressive Variants of Castration-Resistant Prostate Cancer [J].

Beltran, Himisha ;

Tomlins, Scott ;

Aparicio, Ana ;

Arora, Vivek ;

Rickman, David ;

Ayala, Gustavo ;

Huang, Jiaoti ;

True, Lawrence ;

Gleave, Martin E. ;

Soule, Howard ;

Logothetis, Christopher ;

Rubin, Mark A. .

CLINICAL CANCER RESEARCH, 2014, 20 (11) :2846-2850

[6] 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-+

[7] Absolute quantification of somatic DNA alterations in human cancer [J].

Carter, Scott L. ;

Cibulskis, Kristian ;

Helman, Elena ;

McKenna, Aaron ;

Shen, Hui ;

Zack, Travis ;

Laird, Peter W. ;

Onofrio, Robert C. ;

Winckler, Wendy ;

Weir, Barbara A. ;

Beroukhim, Rameen ;

Pellman, David ;

Levine, Douglas A. ;

Lander, Eric S. ;

Meyerson, Matthew ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2012, 30 (05) :413-+

[8] 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

[9] Abiraterone and Increased Survival in Metastatic Prostate Cancer [J].

De Bono, Johann S. ;

Logothetis, Christopher J. ;

Molina, Arturo ;

Fizazi, Karim ;

North, Scott ;

Chu, Luis ;

Chi, Kim N. ;

Jones, Robert J. ;

Goodman, Oscar B., Jr. ;

Saad, Fred ;

Staffurth, John N. ;

Mainwaring, Paul ;

Harland, Stephen ;

Flaig, Thomas W. ;

Hutson, Thomas E. ;

Cheng, Tina ;

Patterson, Helen ;

Hainsworth, John D. ;

Ryan, Charles J. ;

Sternberg, Cora N. ;

Ellard, Susan L. ;

Flechon, Aude ;

Saleh, Mansoor ;

Scholz, Mark ;

Efstathiou, Eleni ;

Zivi, Andrea ;

Bianchini, Diletta ;

Loriot, Yohann ;

Chieffo, Nicole ;

Thian Kheoh ;

Haqq, Christopher M. ;

Scher, Howard I. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (21) :1995-2005

[10] The Clinical Utilization of Circulating Cell Free DNA (CCFDNA) in Blood of Cancer Patients [J].

Elshimali, Yahya I. ;

Khaddour, Husseina ;

Sarkissyan, Marianna ;

Wu, Yanyuan ;

Vadgama, Jaydutt V. .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2013, 14 (09) :18925-18958

← 1 2 3 4 →