Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Clinical Research
  • Published:

Immunohistochemistry-based assessment of androgen receptor status and the AR-null phenotype in metastatic castrate resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 23, pages 507–516 (2020)Cite this article

Subjects

Abstract

Background

Molecular and immunohistochemistry-based profiling of prostatic adenocarcinoma has revealed frequent Androgen Receptor (AR) gene and protein alterations in metastatic disease. This includes an AR-null non-neuroendocrine phenotype of metastatic castrate resistant prostate cancer which may be less sensitive to androgen receptor signaling inhibitors. This AR-null non-neuroendocrine phenotype is thought to be associated with TP53 and RB1 alterations. Herein, we have correlated molecular profiling of metastatic castrate resistant prostate cancer with AR/P53/RB immunohistochemistry and relevant clinical correlates.

Design

Twenty-seven cases of metastatic castrate resistant prostate cancer were evaluated using histopathologic examination to rule out neuroendocrine differentiation. A combination of a hybridization exon-capture next-generation sequencing-based assay (n = 26), fluorescence in situ hybridization for AR copy number status (n = 16), and immunohistochemistry for AR (n = 27), P53 (n = 24) and RB (n = 25) was used to profile these cases.

Results

Of 27 metastatic castrate resistant prostate cancer cases, 17 had AR amplification and showed positive nuclear expression of AR by immunohistochemistry. Nine cases lacked AR copy number alterations using next-generation sequencing/fluorescence in situ hybridization. A subset of these metastatic castrate resistant prostate cancer cases demonstrated the AR-null phenotype by immunohistochemistry (five cases and one additional case where next-generation sequencing failed). Common co-alterations in these cases involved the TP53, RB1, and PTEN genes and all these patients received prior therapy with androgen receptor signaling inhibitors (abiraterone and/or enzalutamide).

Conclusions

Our study suggests that AR immunohistochemistry may distinguish AR-null from AR-expressing cases in the metastatic setting. AR-null status informs clinical decision-making regarding continuation of therapy with androgen receptor signaling inhibitors and consideration of other treatment options. This might be a relevant and cost-effective diagnostic strategy when there is limited access and/or limited tumor material for molecular testing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Copy number assessment and immunohistochemistry for AR.
Fig. 2: Histopathology and immunohistochemistry: clonal evolution/selection.
Fig. 3: Molecular profiling and immunohistochemistry.
Fig. 4: Schematic representation of hypothesized prostate cancer evolution.

Similar content being viewed by others

References

  1. Crawford ED, Higano CS, Shore ND, Hussain M, Petrylak DP. Treating patients with metastatic castration resistant prostate cancer: a comprehensive review of available therapies. J Urol. 2015;194:1537–47.

    Article  Google Scholar 

  2. Wale DJ, Viglianti BL, Gross MD, Ferretti A, Rubello D, Wong KK. Nuclear medicine therapy with 223radium-dichloride for osseous metastases in prostate carcinoma. Am J Clin Oncol. 2019;42:99–106.

    Article  CAS  Google Scholar 

  3. 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;363:411–22.

    Article  CAS  Google Scholar 

  4. Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 2017;32:474–89. e476.

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;1:1–26.

  7. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  CAS  Google Scholar 

  8. Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36:2492–503.

    Article  CAS  Google Scholar 

  9. Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15:271–86.

    Article  CAS  Google Scholar 

  10. Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.

    Article  CAS  Google Scholar 

  11. Hyman DM, Solit DB, Arcila ME, Cheng DT, Sabbatini P, Baselga J, et al. Precision medicine at Memorial Sloan Kettering Cancer Center: clinical next-generation sequencing enabling next-generation targeted therapy trials. Drug Discov Today. 2015;20:1422–8.

    Article  CAS  Google Scholar 

  12. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13.

    Article  CAS  Google Scholar 

  13. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:pl1–pl1.

    Article  Google Scholar 

  14. Epstein JI, Amin MB, Beltran H, Lotan TL, Mosquera JM, Reuter VE, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756–67.

    Article  Google Scholar 

  15. Gupta S, Cheville JC, Jungbluth AA, Zhang Y, Zhang L, Chen YB et al. JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management. Mod Pathol. 2019;32:1344–58.

  16. Gupta S, Vanderbilt CM, Cotzia P, Arias-Stella JA 3rd, Chang JC, Zehir A, et al. Next-generation sequencing-based assessment of JAK2, PD-L1, and PD-L2 copy number alterations at 9p24.1 in breast cancer: potential implications for clinical management. J Mol Diagn. 2019;21:307–17.

    Article  CAS  Google Scholar 

  17. Ross DS, Zehir A, Cheng DT, Benayed R, Nafa K, Hechtman JF, et al. Next-generation assessment of human epidermal growth factor receptor 2 (ERBB2) amplification status: clinical validation in the context of a hybrid capture-based, comprehensive solid tumor genomic profiling assay. J Mol Diagn. 2017;19:244–54.

    Article  CAS  Google Scholar 

  18. Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih Ie M, et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol. 2011;24:1248–53.

    Article  CAS  Google Scholar 

  19. Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 2014;20:890–903.

    Article  CAS  Google Scholar 

  20. Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013;63:920–6.

    Article  CAS  Google Scholar 

  21. Aparicio AM, Shen L, Tapia EL, Lu JF, Chen HC, Zhang J, et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin Cancer Res. 2016;22:1520–30.

    Article  CAS  Google Scholar 

  22. Tao DL, Bailey S, Beer TM, Foss E, Beckett B, Fung A, et al. Molecular testing in patients with castration-resistant prostate cancer and its impact on clinical decision making. JCO Precis Oncol. 2017;1:1–11.

  23. Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. Eur Urol. 2019;76:89–97.

    Article  CAS  Google Scholar 

  24. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  Google Scholar 

  25. 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. e413.

    Article  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol. 2017;71:874–82.

    Article  CAS  Google Scholar 

  28. Conteduca V, Wetterskog D, Sharabiani MTA, Grande E, Fernandez-Perez MP, Jayaram A, et al. 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. Ann Oncol. 2017;28:1508–16.

    Article  CAS  Google Scholar 

  29. 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.

    Article  CAS  Google Scholar 

  30. Roudier MP, True LD, Higano CS, Vesselle H, Ellis W, Lange P, et al. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum Pathol. 2003;34:646–53.

    Article  Google Scholar 

  31. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004;64:9209–16.

    Article  CAS  Google Scholar 

  32. Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol. 2008;32:65–71.

    Article  Google Scholar 

  33. Scher HI, Graf RP, Schreiber NA, McLaughlin B, Jendrisak A, Wang Y, et al. Phenotypic heterogeneity of circulating tumor cells informs clinical decisions between AR signaling inhibitors and taxanes in metastatic prostate cancer. Cancer Res. 2017;77:5687–98.

    Article  CAS  Google Scholar 

  34. Fox JJ, Gavane SC, Blanc-Autran E, Nehmeh S, Gonen M, Beattie B, et al. Positron emission tomography/computed tomography-based assessments of androgen receptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer. JAMA Oncol. 2018;4:217–24.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Irina Ostrovnaya and Marina Asher from the Precision Pathology Biobanking Center (PPBC) at Memorial Sloan Kettering Cancer Center, New York, NY for technical assistance as well as Jennifer Posada and Christine Moon for administrative assistance.

Funding

This study was supported in part through NIH/NCI Prostate Cancer SPORE Award P50CA092629 (MSKCC), NIH/NCI Cancer Center Support grant P30CA008748, CDMRP Prostate Cancer Research Program Award W81XWH-12-PCRP-TIA (to AG, VER, and HS), CDMRP W81XWH-14-2-0186 and Prostate Cancer Biorepository Network-PCRP Pathology Resource Network Award (to AG).

Author information

Authors and Affiliations

  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sounak Gupta, Chad Vanderbilt, Samson W. Fine, Satish K. Tickoo, Hikmat A. Al-Ahmadie, Ying-Bei Chen, Sahussapont J. Sirintrapun, Ann Bialik, Marc Ladanyi, Victor E. Reuter & Anuradha Gopalan

  2. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Wassim Abida, Michael J. Morris & Howard I. Scher

  3. Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kalyani Chadalavada & Gouri J. Nanjangud

Authors
  1. Sounak Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chad Vanderbilt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wassim Abida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samson W. Fine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satish K. Tickoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hikmat A. Al-Ahmadie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying-Bei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sahussapont J. Sirintrapun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kalyani Chadalavada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gouri J. Nanjangud
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ann Bialik
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael J. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Howard I. Scher
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Marc Ladanyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Victor E. Reuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anuradha Gopalan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anuradha Gopalan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gupta, S., Vanderbilt, C., Abida, W. et al. Immunohistochemistry-based assessment of androgen receptor status and the AR-null phenotype in metastatic castrate resistant prostate cancer. Prostate Cancer Prostatic Dis 23, 507–516 (2020). https://doi.org/10.1038/s41391-020-0214-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-020-0214-6

This article is cited by

Search

Advanced search

Quick links