Skip to main content

Advertisement

SpringerLink
Log in

Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study

  • Short Communication
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Introduction

Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).

Objective

To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.

Patients and Methods

Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.

Results

The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0–7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti-HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8–5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6–6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy).

Conclusion

In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  2. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43(2):209–23. https://doi.org/10.1001/archsurg.1941.01210140043004.

    Article  CAS  Google Scholar 

  3. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–12. https://doi.org/10.1056/NEJMoa040720.

    Article  PubMed  CAS  Google Scholar 

  4. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. https://doi.org/10.1056/NEJMoa1001294.

    Article  PubMed  CAS  Google Scholar 

  5. 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(2):138–48. https://doi.org/10.1056/NEJMoa1209096.

    Article  PubMed  CAS  Google Scholar 

  6. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23. https://doi.org/10.1056/NEJMoa1213755.

    Article  PubMed  CAS  Google Scholar 

  7. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33. https://doi.org/10.1056/NEJMoa1405095.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25. https://doi.org/10.1016/j.cell.2015.10.025.

    Article  CAS  Google Scholar 

  9. 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(7406):239–43. https://doi.org/10.1038/nature11125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One. 2015;10(10):e0140712. https://doi.org/10.1371/journal.pone.0140712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Chung JH, Pavlick D, Hartmaier R, Schrock AB, Young L, Forcier B, et al. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer. Ann Oncol. 2017;28(11):2866–73. https://doi.org/10.1093/annonc/mdx490.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023–31. https://doi.org/10.1038/nbt.2696.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–608. https://doi.org/10.1158/1535-7163.Mct-17-0386.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28(33):4877–83. https://doi.org/10.1200/jco.2009.26.5983.

    Article  Google Scholar 

  15. 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(5):1215–28. https://doi.org/10.1016/j.cell.2015.05.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ritch E, Wyatt AW. Predicting therapy response and resistance in metastatic prostate cancer with circulating tumor DNA. Urol Oncol. 2017. https://doi.org/10.1016/j.urolonc.2017.11.017.

  17. Barata PC, Koshkin VS, Funchain P, Sohal D, Pritchard A, Klek S, et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann Oncol. 2017;28(10):2458–63. https://doi.org/10.1093/annonc/mdx405.

    Article  PubMed  CAS  Google Scholar 

  18. Torga G, Pienta KJ. Patient-paired sample congruence between 2 commercial liquid biopsy tests. JAMA Oncol. 2018;4(6):868–70. https://doi.org/10.1001/jamaoncol.2017.4027.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Pedro C. Barata, Prateek Mendiratta, Stefan Klek, Petros Grivas, Davendra P. S. Sohal & Jorge A. Garcia

  2. Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    Brandie Heald

  3. Case Comprehensive Cancer Center, Cleveland Clinic—Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA

    Jorge A. Garcia

Authors
  1. Pedro C. Barata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prateek Mendiratta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brandie Heald
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Klek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Petros Grivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Davendra P. S. Sohal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jorge A. Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jorge A. Garcia.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of Interest

Brandie Heald has disclosed to be on an advisory board for Invitae and the speakers’ bureau for Myriad Genetics Laboratory. Dr. Petros Grivas has disclosed to be a consultant or advisor for Foundation Medicine, Genentech, Dendreon, Bayer, Driver Inc., Exelixis, Merck & Co., Bristol-Myers Squibb, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, and Seattle Genetics; has received research funding from Mirati Therapeutics, Genentech/Roche, Merck, Oncogenex, Bayer, Pfizer, and AstraZeneca. Dr. Davendra Sohal has disclosed to be a consultant or advisor for Perthera and Foundation Medicine, and received research funding from Novartis, Celgene, OncoMed, Bayer, and Genentech/Roche. Dr. Jorge Garcia has disclosed to be a consultant or advisor for Sanofi, Pfizer, Bayer, Eisai, Exelexis, Medivation/Astellas, and Genentech/Roche; has received research funding from Pfizer, Astellas Pharma, Orion Pharma GmbH, Bayer, Janssen Oncology, Genentech/Roche, and Lilly. Pedro C. Barata, Prateek Mendiratta, and Stefan Klek declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barata, P.C., Mendiratta, P., Heald, B. et al. Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study. Targ Oncol 13, 495–500 (2018). https://doi.org/10.1007/s11523-018-0576-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-018-0576-z

Search

Navigation