Clinical and genomic characterization of Low PSA Secretors: a unique subset of metastatic castration resistant prostate cancer



Metastatic disease burden out of proportion to serum PSA has been used as a marker of aggressive phenotype prostate cancer but is not well defined as a distinct subgroup. We sought to prospectively characterize the molecular features and clinical outcomes of Low PSA Secretors.


Eligible metastatic castration resistant prostate cancer (mCRPC) patients without prior small cell histology underwent metastatic tumor biopsy with molecular characterization. Low PSA secretion was defined as serum PSA < 2, 5, or 10 ng/mL plus >5 metastases with radiographic progression at study entry. Clinical and molecular features were compared between low PSA vs. normal secretors in a post-hoc fashion.


183 patients were enrolled, including 15 (8%) identified as Low PSA Secretors using optimal PSA cut point of 5 ng/mL. Biopsies from Low PSA Secretors demonstrated higher t-SCNC and RB1 loss and lower AR transcriptional signature scores compared with normal secretors. Genomic loss of RB1 and/or TP53 was more common in Low PSA Secretors (80% vs. 41%). Overall survival (OS) was shorter in Low PSA Secretors (median OS = 26.7 vs. 46.0 months, hazard ratio = 2.465 (95% CI: 0.982–6.183). Progression-free survival (PFS) on post-biopsy treatment with AR-targeted therapy was shorter than with chemotherapy (median PFS 6.2 vs. 4.1 months).


Low PSA secretion in relation to metastatic tumor burden may be a readily available clinical selection tool for de-differentiated mCRPC with molecular features consistent with t-SCNC. Prospective validation is warranted.

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Fig. 1: Genomic variants in patient cohort from targeted next-generation DNA sequencing.
Fig. 2: Treatment-emergent small cell NEPC signature scores in Low PSA Secretor and normal PSA secretor mCRPC samples.
Fig. 3: Survival outcomes by PSA secretor status.


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  2. 2.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    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;371:424–33.

    Article  Google Scholar 

  5. 5.

    Parimi V, Goyal R, Poropatich K, Yang XJ. Neuroendocrine differentiation of prostate cancer: a review. Am J Clin Exp Urol. 2014;2:273–85.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bonkhoff H, Stein U, Remberger K. Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol. 1994;25:42–6.

    CAS  Article  Google Scholar 

  7. 7.

    Yuan TC, Veeramani S, Lin MF. Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr Relat Cancer. 2007;14:531–47.

    CAS  Article  Google Scholar 

  8. 8.

    Priemer DS, Montironi R, Wang L, Williamson SR, Lopez-Beltran A, Cheng L. Neuroendocrine tumors of the prostate: emerging insights from molecular data and updates to the 2016 world health organization classification. Endocr Pathol. 2016;27:123–35.

    CAS  Article  Google Scholar 

  9. 9.

    Aparicio A, Logothetis CJ, Maity SN. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Disco. 2011;1:466–8.

    Article  Google Scholar 

  10. 10.

    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 

  11. 11.

    Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.

    CAS  Article  Google Scholar 

  12. 12.

    Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    CAS  Article  Google Scholar 

  14. 14.

    Aparicio AM, Harzstark AL, Corn PG, Wen S, Araujo JC, Tu SM, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19:3621–30.

    CAS  Article  Google Scholar 

  15. 15.

    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. 2015;22:1520–30.

    Article  Google Scholar 

  16. 16.

    Taplin ME, Armstrong AJ, Lin P, Krivoshik A, Phung, Parli T, et al. Clinical outcomes of chemotherapy naïve men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen treated with enzalutamide vs placebo. J Urol. 2017;198:1324–32.

    CAS  Article  Google Scholar 

  17. 17.

    Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, et al. Prostate cancer clinical trials working group 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.

    Article  Google Scholar 

  18. 18.

    Holmes MG, Foss E, Joseph G, Foye A, Beckett B, Motamedi D, et al. CT-guided bone biopsies in metastatic castration-resistant prostate cancer: factors predictive of maximum tumor yield. J Vasc Interventional Radiol. 2017;28:1073–81.

    Article  Google Scholar 

  19. 19.

    Hovelson DH, McDaniel AS, Cani AK, Johnson B, Rhodes K, Williams PD, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756–67.

    Article  Google Scholar 

  20. 20.

    Hovelson DH, McDaniel AS, Cani AK, Johnson B, Rhodes K, Williams PD, et al. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015;17:385–99.

    CAS  Article  Google Scholar 

  21. 21.

    Lih CJ, Harrington RD, Sims DJ, Harper KN, Bouk CH, Datta V, et al. Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial: molecular analysis for therapy choice clinical trial. J Mol Diagn. 2017;19:313–27.

    Article  Google Scholar 

  22. 22.

    McNair C, Xu K, Mandigo AC, Benelli M, Leiby B, Rodrigues D, et al. Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Investig. 2018;128:341–58.

    Article  Google Scholar 

  23. 23.

    Mahal BA, Yang DD, Wang NQ, Alshalalfa M, Davicioni E, Choeurng V, et al. Clinical and genomic characterization of low-prostate-specific antigen, high-grade prostate cancer. Eur Urol. 2018;74:146–54.

    CAS  Article  Google Scholar 

  24. 24.

    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.

    CAS  Article  Google Scholar 

  25. 25.

    Su W, Han HH, Wang Y, Zhang B, Zhou B, Cheng Y, et al. The polycomb repressor complex 1 drives double-negative prostate cancer metastasis by coordinating stemness and immune suppression. Cancer Cell. 2019;36:139–55.

    CAS  Article  Google Scholar 

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This research was supported in part by a Stand Up To Cancer Dream Team award, funded by the Prostate Cancer Foundation, Movember, and Stand up to Cancer, grant number SU2C-AACR-DT0812 (PI: EJS). The authors thank Karen Knudsen and Christopher McNair for providing a RB1 loss signature [21] for application to the transcriptome.

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Correspondence to Rahul Aggarwal.

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Aggarwal, R., Romero, G.R., Friedl, V. et al. Clinical and genomic characterization of Low PSA Secretors: a unique subset of metastatic castration resistant prostate cancer. Prostate Cancer Prostatic Dis (2020).

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