The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC).
Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < 0.05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival.
ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = 0.0043). Thirty-one prostate cancer-related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = 0.0039) and shorter TTTC (P = 0.0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = 0.026 and P = 0.017, respectively), shorter TTTC (P = 0.0008 and P = 0.0016, respectively), and poor survival (P = 0.0025 and P = 0.0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = 0.0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = 0.002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < 0.05).
Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.
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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
Sridhar SS, Freedland SJ, Gleave ME, Higano C, Mulders P, Parker C, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur Urol. 2014;65:289–99.
Gartrell BA, Saad F. Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy. Ther Adv Urol. 2015;7:194–202.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.
Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.
Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22:369–78.
Ren S, Wei GH, Liu D, Wang L, Hou Y, Zhu S, et al. Whole-genome and transcriptome sequencing of prostate cancer identify new genetic alterations driving disease progression. Eur Urol. 2017;73:322–39.
Wang L, Dehm SM, Hillman DW, Sicotte H, Tan W, Gormley M, et al. A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone. Ann Oncol. 2018;29:352–60.
Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.
Jimenez RE, Atwell TD, Sicotte H, Eckloff B, Wang L, Barman P, et al. A prospective correlation of tissue histopathology with nucleic acid yield in metastatic castration-resistant prostate cancer biopsy specimens. Mayo Clin Proc Innov Qual Outcomes. 2019;3:14–22.
Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13:7053–8.
Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1598–606.
Ulz P, Belic J, Graf R, Auer M, Lafer I, Fischereder K, et al. Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun. 2016;7:12008.
Hovelson DH, Liu CJ, Wang Y, Kang Q, Henderson J, Gursky A, et al. Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy. Oncotarget. 2017;8:89848–66.
Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315–24.
Kohli M, Li J, Du M, Hillman DW, Dehm SM, Tan W, et al. Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients. Prostate Cancer Prostatic Dis. 2018;21:411–8.
Romanel A, Gasi Tandefelt D, Conteduca V, Jayaram A, Casiraghi N, Wetterskog D, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7:312re310.
Choudhury AD, Werner L, Francini E, Wei XX, Ha G, Freeman SS, et al. Tumor fraction in cell-free DNA as a biomarker in prostate cancer. JCI Insight. 2018;3:1–14. https://www.ncbi.nlm.nih.gov/pubmed/30385733.
Mayrhofer M, De Laere B, Whitington T, Van Oyen P, Ghysel C, Ampe J, et al. Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. Genome Med. 2018;10:85.
Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.
De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam PJ, Van Oyen P, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:1766–73.
Torquato S, Pallavajjala A, Goldstein A, Toro PV, Silberstein JL, Lee J, et al. Genetic alterations detected in cell-free DNA are associated with enzalutamide and abiraterone resistance in castration-resistant prostate cancer. JCO Precis Oncol. 2019;3. https://www.ncbi.nlm.nih.gov/pubmed/31131348.
Xia S, Kohli M, Du M, Dittmar RL, Lee A, Nandy D, et al. Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer. Oncotarget. 2015;6:16411–21.
Li J, Dittmar RL, Xia S, Zhang H, Du M, Huang CC, et al. Cell-free DNA copy number variations in plasma from colorectal cancer patients. Mol Oncol. 2017;11:1099–111.
Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017;8:1324.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148–59.
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174:758–69.e9.
Luijten MNH, Lee JXT, Crasta KC. Mutational game changer: chromothripsis and its emerging relevance to cancer. Mutat Res. 2018;777:29–51.
Wyatt AW, Annala M, Aggarwal R, Beja K, Feng F, Youngren J, et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst. 2017;109. https://www.ncbi.nlm.nih.gov/pubmed/29206995.
Newcombe PJ, Connolly S, Seaman S, Richardson S, Sharp SJ. A two-step method for variable selection in the analysis of a case-cohort study. Int J Epidemiol. 2018;47:597–604.
Wang F, Koul HK. Androgen receptor (AR) cistrome in prostate differentiation and cancer progression. Am J Clin Exp Urol. 2017;5:18–24.
AR enhancer amplification drives castration-resistant prostate cancer. Cancer Discov. 2018;8:OF17. https://doi.org/10.1158/2159-8290.CD-RW2018-105.
Takeda DY, Spisak S, Seo JH, Bell C, O’Connor E, Korthauer K, et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate. Cancer Cell. 2018;174:422–32.e13.
Viswanathan SR, Ha G, Hoff AM, Wala JA, Carrot-Zhang J, Whelan CW, et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell. 2018;174:433–47.e19.
Goto K, Oue N, Hayashi T, Shinmei S, Sakamoto N, Sentani K, et al. Oligophrenin-1 is associated with cell adhesion and migration in prostate cancer. Pathobiology. 2014;81:190–8.
Zhao D, Ma G, Zhang X, He Y, Li M, Han X, et al. Zinc finger homeodomain factor Zfhx3 is essential for mammary lactogenic differentiation by maintaining prolactin signaling activity. J Biol Chem. 2016;291:12809–20.
Gupta S, Li J, Kemeny G, Bitting RL, Beaver J, Somarelli JA, et al. Whole genomic copy number alterations in circulating tumor cells from men with abiraterone or enzalutamide-resistant metastatic castration-resistant prostate cancer. Clin Cancer Res. 2017;23:1346–57.
Soave A, Chun FK, Hillebrand T, Rink M, Weisbach L, Steinbach B, et al. Copy number variations of circulating, cell-free DNA in urothelial carcinoma of the bladder patients treated with radical cystectomy: a prospective study. Oncotarget. 2017;8:56398–407.
Arafeh R, Samuels Y. PIK3CA in cancer: the past 30 years. Semin Cancer Biol. 2019;59:36–49. https://doi.org/10.1016/j.semcancer.2019.02.002.
Pearson HB, Li J, Meniel VS, Fennell CM, Waring P, Montgomery KG, et al. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with pten loss to accelerate progression and castration-resistant growth. Cancer Discov. 2018;8:764–79.
Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.
Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77.
Nava Rodrigues D, Casiraghi N, Romanel A, Crespo M, Miranda S, Rescigno P, et al. RB1 heterogeneity in advanced metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:687–97.
We thank the HMGC Sequencing Core at Medical College of Wisconsin for providing DNA sequencing service. We thank Paul Fletcher and Daley Drucker (H. Lee Moffitt Cancer Center and Research Center) for editorial assistance. They were not compensated beyond their regular salaries.
This study was supported by the National Institute of Health (CA212097; to LW and MK)
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Du, M., Tian, Y., Tan, W. et al. Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 23, 705–713 (2020). https://doi.org/10.1038/s41391-020-0224-4
Multiplex Digital PCR to Detect Amplifications of Specific Androgen Receptor Loci in Cell-Free DNA for Prognosis of Metastatic Castration-Resistant Prostate Cancer
Société Internationale d’Urologie Journal (2020)