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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 and Prostatic Diseases volume 21, pages 411–418 (2018)Cite this article

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Abstract

Background

The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known.

Methods

As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan–Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors.

Results

ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535–966). ARamp was associated with poor OS (2-year OS of 35% in ARamp vs. 71% in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74%; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002).

Conclusions

CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491–8.

    Article  Google Scholar 

  3. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. Beer TM, Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:1755–6.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Beltran H, Eng K, Mosquera JM, Sigaras A, Romanel A, Rennert H, et al. Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol. 2015;1:466–74.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Halabi S, Lin CY, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671–7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. van der Toom EE, Verdone JE, Gorin MA, Pienta KJ. Technical challenges in the isolation and analysis of circulating tumor cells. Oncotarget. 2016;7:62754–62766.

    PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61:112–23.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    PubMed  PubMed Central  Google Scholar 

  15. Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6:254ra125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10:6897–904.

    Article  PubMed  Google Scholar 

  19. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402–18.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med. 2009;15:559–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Heitzer E, Ulz P, Geigl JB, Speicher MR. Non-invasive detection of genome-wide somatic copy number alterations by liquid biopsies. Mol Oncol. 2016;10:494–502.

    Article  PubMed  CAS  Google Scholar 

  22. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Zhu Y, et al. 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 Clin Oncol. 2017;35:2149–56.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful for the administrative assistance provided by Bobbi-Ann Jebens for this submission. We also would like to thank all patients who participated in this study for their selfless contribution in bringing precision medicine to future advanced prostate cancer patients. We highly appreciate the support of family members as well.

Funding:

This study is funded in part by the Mayo Clinic Center for Individualized Medicine; National Institutes of Health—National Cancer Institute (R01CA21209) to MK and LW; Department of Defense (W81XWH-15-1-0634) to MK and SMD; and Mayo Clinic Schulze Center for Novel Therapeutics in Cancer Research to MK and LW; Joseph and Gail Gassner to MK; and Advancing a Healthier Wisconsin Fund (#5520227) and National Institutes of Health (R01CA157881) to LW; National Institutes of Health—National Cancer Institute (R01CA174777) to SMD.

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Author notes

  1. These authors contributed equally: Manish Kohli, Jian Li.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, USA

    Manish Kohli

  2. Department of Internal Medicine, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    Jian Li

  3. Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Jian Li, Meijun Du, Huijuan Zhang, Peng Zhang & Liang Wang

  4. Division of Biomedical Statistics and Informatics, Department of Health Sciences, Mayo Clinic, Rochester, MN, USA

    David W Hillman, Rachel Carlson & Liguo Wang

  5. Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Scott M. Dehm

  6. Department of Urology, University of Minnesota, Minneapolis, MN, USA

    Scott M. Dehm

  7. Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL, USA

    Winston Tan

  8. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Michael B. Campion

  9. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Liewei Wang

  10. Physical Examination Center, Zhengzhou Seventh People Hospital, Zhengzhou, Henan, China

    Huijuan Zhang

  11. Department of Medicine, Medical College of Wisconsin and Milwaukee VA Medical Center, Milwaukee, WI, USA

    Deepak Kilari

  12. Joseph J Zilber School of Public Health, University of Wisconsin, Milwaukee, WI, USA

    Chiang-Ching Huang

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Correspondence to Manish Kohli or Liang Wang.

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Co-First authors: Manish Kohli, Jian Li.

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Kohli, M., Li, J., Du, M. 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 21, 411–418 (2018). https://doi.org/10.1038/s41391-018-0043-z

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