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HSD3B1, prostate cancer mortality and modifiable outcomes

Nature Reviews Urology (2024)Cite this article

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Abstract

Androgen receptor stimulation by testosterone and dihydrotestosterone is crucial for prostate cancer progression. Despite the initial effectiveness of androgen deprivation therapy (ADT), castration-resistant prostate cancer eventually develops in most men. A common germline missense-encoding polymorphism in HSD3B1 increases extra-gonadal androgen biosynthesis from adrenal precursors owing to increased availability of the encoded enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) — hence, it is called the adrenal-permissive enzyme. This mechanism explains the more rapid progression to castration-resistant prostate cancer in men who inherit this allele than in men without it via sustained androgen receptor activation despite ADT. Multiple clinical studies, including data derived from prospective phase III studies, have linked adrenal-permissive allele inheritance to inferior clinical responses to ADT and increased mortality, but reversal is possible with upfront adrenal androgen blockade. The adrenal-permissive allele exhibits divergent frequencies across various groups worldwide, which could contribute to differences in clinical outcomes among these populations. Large-scale data from the Million Veteran Program have shown homozygous HSD3B1 adrenal-permissive allele inheritance to be an independent biomarker of prostate cancer-specific mortality. Together, these observations support the integration of HSD3B1 into germline testing and clinical trials as it might help to identify groups at increased likelihood of benefiting from early, intensified, AR-_targeting interventions. Lastly, 3βHSD1 is a promising _target for pharmacological inhibition, which enables new strategies for systemic prostate cancer therapy.

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Fig. 1: The genetics, androgen biosynthesis and clinical outcomes associated with adrenal-permissive and adrenal-restrictive HSD3B1 inheritance.

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References

  1. Dai, C., Dehm, S. M. & Sharifi, N. _targeting the androgen signaling axis in prostate cancer. J. Clin. Oncol. 41, 4267–4278 (2023).

    Article  CAS  Google Scholar 

  2. Sharifi, N. Minireview: androgen metabolism in castration-resistant prostate cancer. Mol. Endocrinol. 27, 708–714 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Dai, C. et al. Direct metabolic interrogation of dihydrotestosterone biosynthesis from adrenal precursors in primary prostatectomy tissues. Clin. Cancer Res. 23, 6351–6362 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Chang, K.-H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 108, 13728–13733 (2011).

    Article  CAS  Google Scholar 

  5. Montgomery, R. B. et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Geller, J. et al. DHT concentrations in human prostate cancer tissue. J. Clin. Endocrinol. Metab. 46, 440–444 (1978).

    Article  CAS  Google Scholar 

  7. Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B. & Mohler, J. L. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11, 4653–4657 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Auchus, R. J. & Sharifi, N. Sex hormones and prostate cancer. Annu. Rev. Med. 71, 33–45 (2020).

    Article  CAS  Google Scholar 

  9. Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Hettel, D. & Sharifi, N. HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer. Nat. Rev. Urol. 15, 191–196 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Hussain, M. et al. Metastatic hormone-sensitive prostate cancer and combination treatment outcomes: a review. JAMA Oncol. 10, 807–820 (2024).

    Article  PubMed  Google Scholar 

  12. Sabharwal, N. & Sharifi, N. HSD3B1 genotypes conferring adrenal-restrictive and adrenal-permissive phenotypes in prostate cancer and beyond. Endocrinology 160, 2180–2188 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Simard, J. et al. Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase gene family. Endocr. Rev. 26, 525–582 (2005).

    Article  CAS  Google Scholar 

  15. Evaul, K., Li, R., Papari-Zareei, M., Auchus, R. J. & Sharifi, N. 3β-Hydroxysteroid dehydrogenase is a possible pharmacological _target in the treatment of castration-resistant prostate cancer. Endocrinology 151, 3514–3520 (2010).

    Article  CAS  Google Scholar 

  16. Chang, K. H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hearn, J. W. D. et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 17, 1435–1444 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Locke, J. A. et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 68, 6407–6415 (2008).

    Article  CAS  Google Scholar 

  19. Thomas, L. & Sharifi, N. Germline HSD3B1 genetics and prostate cancer outcomes. Urology 145, 13–21 (2020).

    Article  PubMed  Google Scholar 

  20. Chang, K., Ercole, C. & Sharifi, N. Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences. Br. J. Cancer 111, 1249–1254 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hahn, A. W. et al. Germline variant in HSD3B1 (1245 A > C) and response to abiraterone acetate plus prednisone in men with new-onset metastatic castration-resistant prostate cancer. Clin. Genitourin. Cancer 16, 288–292 (2018).

    Article  PubMed  Google Scholar 

  22. Shiota, M. et al. Association of missense polymorphism in HSD3B1 with outcomes among men with prostate cancer treated with androgen-deprivation therapy or abiraterone. JAMA Netw. Open 2, e190115 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Khalaf, D. J. et al. HSD3B1 (1245A>C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies. Ann. Oncol. 31, 1186–1197 (2020).

    Article  CAS  Google Scholar 

  24. Sharifi, N. Homozygous HSD3B1(1245C) inheritance and poor outcomes in metastatic castration-resistant prostate cancer with abiraterone or enzalutamide: what does it mean? Ann. Oncol. 31, 1103–1105 (2020).

    Article  PubMed  Google Scholar 

  25. Varenhorst, E. et al. Predictors of early androgen deprivation treatment failure in prostate cancer with bone metastases. Cancer Med. 5, 407–414 (2016).

    Article  CAS  Google Scholar 

  26. Agarwal, N. et al. Independent validation of effect of HSD3B1 genotype on response to androgen-deprivation therapy in prostate cancer. JAMA Oncol. 3, 856–857 (2017).

    Article  PubMed Central  Google Scholar 

  27. Wu, G. et al. Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer. Prostate 75, 777–782 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Borrell, L. N. et al. Race and genetic ancestry in medicine — a time for reckoning with racism. N. Engl. J. Med. 384, 474–480 (2021).

    Article  Google Scholar 

  29. Hougen, H. Y. et al. Disparities in diagnosis, treatment access, and time to treatment among Hispanic men with metastatic prostate cancer. JCO Oncol. Pract. 19, 645–653 (2023).

    Article  PubMed  Google Scholar 

  30. Moul, J. W. Real-world analyses of mortality risk after androgen deprivation therapy initiation in Black vs. White patients with prostate cancer. J. Clin. Oncol. 42, 84–84 (2024).

    Article  Google Scholar 

  31. Morgan, K. M. et al. Androgen deprivation therapy and outcomes after radiation therapy in black patients with prostate cancer. JAMA Netw. Open 7, e2415911 (2024).

    Article  PubMed  Google Scholar 

  32. Hearn, J. W. D. et al. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol. 4, 558–562 (2018).

    Article  PubMed  Google Scholar 

  33. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

    Article  PubMed  Google Scholar 

  34. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2012).

    Article  PubMed Central  Google Scholar 

  35. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

    Article  CAS  Google Scholar 

  36. Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sharifi, N., McPhaul, M. J. & Auchus, R. J. “Getting from here to there”-mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer. J. Investig. Med. 58, 938–944 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Naelitz, B. D. & Sharifi, N. Through the looking-glass: reevaluating DHEA metabolism through HSD3B1 genetics. Trends Endocrinol. Metab. 31, 680–690 (2020).

    Article  CAS  Google Scholar 

  39. Almassi, N. et al. HSD3B1 and response to a nonsteroidal CYP17A1 inhibitor in castration-resistant prostate cancer. JAMA Oncol. 4, 554–557 (2018).

    Article  Google Scholar 

  40. Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015).

    Article  CAS  Google Scholar 

  41. Li, Z. et al. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer anti-androgen therapy. Nature 533, 547–551 (2016).

    Article  CAS  Google Scholar 

  42. Alyamani, M. et al. HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J. Clin. Invest. 128, 3333–3340 (2018).

    Article  Google Scholar 

  43. Mei, Z. et al. Management of prostate cancer by _targeting 3βHSD1 after enzalutamide and abiraterone treatment. Cell Rep. Med. 3, 100608 (2022).

    Article  CAS  Google Scholar 

  44. Lu, C. et al. Treatment with abiraterone and enzalutamide does not overcome poor outcome from metastatic castration-resistant prostate cancer in men with the germline homozygous HSD3B1 c.1245C genotype. Ann. Oncol. 31, 1178–1185 (2020).

    Article  CAS  Google Scholar 

  45. Khalaf, D. J. et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 20, 1730–1739 (2019).

    Article  CAS  Google Scholar 

  46. Castro, E. et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 37, 490–503 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Hearn, J. W. D. et al. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncol. 6, e196496 (2020).

    Article  PubMed  Google Scholar 

  48. Sharifi, N. et al. HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy (ADT) and enzalutamide: (ARCHES). Cell Rep. Med. 5, 101644 (2024).

    Article  CAS  PubMed  Google Scholar 

  49. Sharifi, N. et al. Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance. J. Clin. Invest. 134, e183583 (2024).

    Article  CAS  Google Scholar 

  50. Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Van der Eecken, K. et al. Tissue- and blood-derived genomic biomarkers for metastatic hormone-sensitive prostate cancer: a systematic review. Eur. Urol. Oncol. 4, 914–923 (2021).

    Article  Google Scholar 

  52. Armstrong, A. J. et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 37, 2974–2986 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sweeney, C. J. et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 24, 323–334 (2023).

    Article  CAS  Google Scholar 

  54. McKay, R. R. et al. Adrenal-permissive germline HSD3B1 allele and prostate cancer outcomes. JAMA Netw. Open 7, e242976 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Schiffer, L. & Sharifi, N. Adrenal-permissive HSD3B1 genotype-an invisible stimulator of prostate cancer mortality. JAMA Netw. Open 7, e243402 (2024).

    Article  PubMed  Google Scholar 

  56. Castro, E. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 31, 1748–1757 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Marar, M. et al. Outcomes among African American and non-hispanic white men with metastatic castration-resistant prostate cancer with first-line abiraterone. JAMA Netw. Open 5, e2142093 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  58. George, D. J. et al. Survival by race in men with chemotherapy-naive enzalutamide- or abiraterone-treated metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 25, 524–530 (2022).

    Article  CAS  Google Scholar 

  59. Dess, R. T. et al. Association of black race with prostate cancer-specific and other-cause mortality. JAMA Oncol. 5, 975–983 (2019).

    Article  PubMed Central  Google Scholar 

  60. Dorff, T. et al. Prostate cancer characteristics and outcomes after prostatectomy in Asian-American men. Clin. Genitourin. Cancer 20, 92–92.e96 (2022).

    Article  Google Scholar 

  61. Bernard, B. et al. Impact of ethnicity on the outcome of men with metastatic, hormone-sensitive prostate cancer. Cancer 123, 1536–1544 (2017).

    Article  CAS  Google Scholar 

  62. Ganguly, S. et al. Intratumoral androgen biosynthesis associated with 3β-hydroxysteroid dehydrogenase 1 promotes resistance to radiotherapy in prostate cancer. J. Clin. Invest. 133, e165718 (2023).

    Article  CAS  PubMed  Google Scholar 

  63. Sharifi, N. et al. Survival of men with metastatic hormone sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance. J. Clin. Invest. 134, e183583 (2024).

    Article  CAS  PubMed Central  Google Scholar 

  64. Li, X. et al. BMX controls 3βHSD1 and sex steroid biosynthesis in cancer. J. Clin. Invest. 133, e163498 (2023).

    Article  CAS  Google Scholar 

  65. Dai, B. et al. Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells. Cancer Res. 70, 5587–5596 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  66. Chen, S. et al. BMX-mediated regulation of multiple tyrosine kinases contributes to castration resistance in prostate cancer. Cancer Res. 78, 5203–5215 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  67. Qiu, Y. A phosphorylation switch controls androgen biosynthesis in prostate cancer. J. Clin. Invest. 133, e166499 (2023).

    Article  CAS  Google Scholar 

  68. Alu, A., Lei, H., Han, X., Wei, Y. & Wei, X. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J. Hematol. Oncol. 15, 138 (2022).

    Article  CAS  Google Scholar 

  69. Montoya, S. et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science 383, eadi5798 (2024).

    Article  CAS  PubMed Central  Google Scholar 

  70. McKay, R. R. et al. The Maverick trial: a phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 41, TPS5106 (2023).

    Article  Google Scholar 

  71. Shiota, M. et al. Importance of 3β-hydroxysteroid dehydrogenases and their clinical use in prostate cancer. Endocr. Relat. Cancer 31, e240023 (2024).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by grants from NCI, NIH (R01CA172382, R01CA236780, R01CA261995 and R01CA249279). N.S. is a co-inventor on a Cleveland Clinic patent on HSD3B1.

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  1. Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Pedro F. S. Freitas, Alireza Abdshah & Nima Sharifi

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Alireza Abdshah & Nima Sharifi

  3. Division of Hematology-Oncology, Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Rana R. McKay

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P.F.S.F., A.A., R.R.M. and N.S. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and/or edited the manuscript before submission.

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Correspondence to Nima Sharifi.

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N.S. is a co-inventor on patents related to HSD3B1 filed by his former employer, Cleveland Clinic. The other authors declare no competing interests.

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Freitas, P.F.S., Abdshah, A., McKay, R.R. et al. HSD3B1, prostate cancer mortality and modifiable outcomes. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00953-0

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