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The impact of genetic polymorphism on CYP19A1 in androgen-deprivation therapy among Japanese men

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Abstract

Purpose

Inadequate suppression of testosterone during androgen-deprivation therapy impairs its efficacy. This study investigated the significance of genetic polymorphism in CYP19A1, which encodes aromatase that catalyzes androgens into estrogens, among men treated with primary ADT for metastatic prostate cancer.

Methods

This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of CYP19A1 gene polymorphism (rs1870050) with clinicopathological parameters including serum testosterone levels during ADT as well as progression-free survival and overall survival was examined.

Results

Serum testosterone levels during ADT of men carrying homozygous wild-type (AA) in the CYP19A1 gene [median (interquartile range); 11.6 (8.3–20.3) ng/dl] were higher than those in men carrying the heterozygous/homozygous variant (AC/CC) [median (interquartile range); 10.0 (6.4–12.8) ng/dl]. When adjusted by Gleason score, initial PSA, M-stage and serum testosterone level during ADT, heterozygous/homozygous variant (AC/CC) in the CYP19A1 gene was associated with a lower risk of progression to castration resistance [hazard ratio (95% confidence interval), 0.53 [0.29–0.92], p = 0.025], but not to any-cause death [hazard ratio (95% confidence interval), 0.74 [0.36–1.49], p = 0.40].

Conclusions

These findings suggest that genetic variation in CYP19A1 (rs1870050) might affect the prognosis of patients with metastatic prostate cancer when treated with ADT by regulating serum testosterone levels.

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References

  1. Shiota M, Eto M (2016) Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer. Int J Urol 23:360–369

    Article  PubMed  Google Scholar 

  2. Klotz L, O’Callaghan C, Ding K, Toren P, Dearnaley D, Higano CS, Horwitz E, Malone S, Goldenberg L, Gospodarowicz M, Crook JM (2015) Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 33:1151–1156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shiota M, Fujimoto N, Yokomizo A, Takeuchi A, Kashiwagi E, Dejima T, Kiyoshima K, Inokuchi J, Tatsugami K, Eto M (2016) The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism. Prostate Cancer Prostatic Dis 19:191–196

    Article  CAS  PubMed  Google Scholar 

  4. Pickles T, Hamm J, Morris WJ, Schreiber WE, Tyldesley S (2012) Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: does it happen and does it matter? BJU Int 110:E500–E507

    Article  CAS  PubMed  Google Scholar 

  5. Shiota M, Fujimoto N, Takeuchi A, Kashiwagi E, Dejima T, Inokuchi J, Tatsugami K, Yokomizo A, Kajioka S, Uchiumi T, Eto M (2018) The association of polymorphisms in the gene encoding gonadotropin-releasing hormone with serum testosterone level during androgen deprivation therapy and prognosis of metastatic prostate cancer. J Urol 199:734–740

    Article  CAS  PubMed  Google Scholar 

  6. Cai C, Balk SP (2011) Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer 18:R175–R182

    Article  CAS  PubMed  Google Scholar 

  7. Lévesque É, Huang SP, Audet-Walsh É, Lacombe L, Bao BY, Fradet Y, Laverdière I, Rouleau M, Huang CY, Yu CC, Caron P, Guillemette C (2013) Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression. Clin Cancer Res 19:699–709

    Article  CAS  PubMed  Google Scholar 

  8. Hiramatsu M, Maehara I, Ozaki M, Harada N, Orikasa S, Sasano H (1997) Aromatase in hyperplasia and carcinoma of the human prostate. Prostate 31:118–124

    Article  CAS  PubMed  Google Scholar 

  9. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A (2009) History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 30:343–375

    Article  CAS  PubMed  Google Scholar 

  10. Travis RC, Schumacher F, Hirschhorn JN, Kraft P, Allen NE, Albanes D, Berglund G, Berndt SI, Boeing H, Bueno-de-Mesquita HB, Calle EE, Chanock S, Dunning AM, Hayes R, Feigelson HS, Gaziano JM, Giovannucci E, Haiman CA, Henderson BE, Kaaks R, Kolonel LN, Ma J, Rodriguez L, Riboli E, Stampfer M, Stram DO, Thun MJ, Tjønneland A, Trichopoulos D, Vineis P, Virtamo J, Le Marchand L, Hunter DJ (2009) CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 18:2734–2744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanda S, Tsuchiya N, Narita S, Inoue T, Huang M, Chiba S, Akihama S, Saito M, Numakura K, Tsuruta H, Satoh S, Saito S, Ohyama C, Arai Y, Ogawa O, Habuchi T (2015) Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival. Int J Cancer 136:74–82

    Article  CAS  PubMed  Google Scholar 

  12. Tsuchiya N, Wang L, Suzuki H, Segawa T, Fukuda H, Narita S, Shimbo M, Kamoto T, Mitsumori K, Ichikawa T, Ogawa O, Nakamura A, Habuchi T (2006) Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer. J Clin Oncol 24:1982–1989

    Article  CAS  PubMed  Google Scholar 

  13. Ross RW, Oh WK, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin ME, Regan MM, Kantoff PW, Freedman M (2008) Inherited variation in the androgen pathway is associated with the efficacy of androgen-deprivation therapy in men with prostate cancer. J Clin Oncol 26:842–847

    Article  PubMed  Google Scholar 

  14. Tao MH, Cai Q, Zhang ZF, Xu WH, Kataoka N, Wen W, Wen W, Xiang YB, Zheng W, Shu XO (2007) Polymorphisms in the CYP19A1 (aromatase) gene and endometrial cancer risk in Chinese women. Cancer Epidemiol Biomarkers Prev 16:943–949

    Article  CAS  PubMed  Google Scholar 

  15. Shiota M, Fujimoto N, Imada K, Yokomizo A, Itsumi M, Takeuchi A, Kuruma H, Inokuchi J, Tatsugami K, Uchiumi T, Oda Y, Naito S (2016) Potential role for YB-1 in castration-resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7. J Natl Cancer Inst 108:djw005

    Article  CAS  Google Scholar 

  16. Shiota M, Fujimoto N, Itsumi M, Takeuchi A, Inokuchi J, Tatsugami K, Yokomizo A, Kajioka S, Uchiumi T, Eto M (2017) Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress. Ann Oncol 28:569–575

    CAS  PubMed  Google Scholar 

  17. International Union Against Cancer (1997) Urologic tumors. Prostate. In: Sobin LH, Wittekind CH (eds) TNM classification of malignant tumors, 5th edn. Wiley, New York, pp 170–173

    Google Scholar 

  18. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Prostate Cancer Clinical Trials Working Group (2008) 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 26:1148–1159

    Article  PubMed  Google Scholar 

  19. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN, LATITUDE Investigators (2017) Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352–360

    Article  CAS  PubMed  Google Scholar 

  20. James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O’Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR, STAMPEDE Investigators (2017) Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377:338–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shiota M, Fujimoto N, Yokomizo A, Takeuchi A, Itsumi M, Inokuchi J, Tatsugami K, Uchiumi T, Naito S (2015) SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy. Eur J Cancer 51:1962–1969

    Article  CAS  PubMed  Google Scholar 

  22. Grindstad T, Skjefstad K, Andersen S, Ness N, Nordby Y, Al-Saad S, Fismen S, Donnem T, Khanehkenari MR, Busund LT, Bremnes RM, Richardsen E (2016) Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome. Sci Rep 6:33114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Davies JH, Dowsett M, Jacobs S, Coombes RC, Hedley A, Shearer RJ (1992) Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer. Br J Cancer 66:139–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Santen RJ, Petroni GR, Fisch MJ, Myers CE, Theodorescu D, Cohen RB (2001) Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma. Cancer 92:2095–2101

    Article  CAS  PubMed  Google Scholar 

  25. Smith MR, Kaufman D, George D, Oh WK, Kazanis M, Manola J, Kantoff PW (2002) Selective aromatase inhibition for patients with androgen-independent prostate carcinoma. Cancer 95:1864–1868

    Article  CAS  PubMed  Google Scholar 

  26. Block JL, Block NL, Lokeshwar BL (1996) Inhibition of aromatase activity and growth suppression by 4-methoxy-4-androstene-3,17-dione in an androgen sensitive human prostatic carcinoma cell line. Cancer Lett 101:143–148

    Article  CAS  PubMed  Google Scholar 

  27. Rahman HP, Hofland J, Foster PA (2016) In touch with your feminine side: how oestrogen metabolism impacts prostate cancer. Endocr Relat Cancer 23:R249–R266

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Ms. Noriko Hakoda and Ms. Eriko Gunshima for technical assistance, and Edanz Group Japan for editorial assistance. We particularly thank Dr. Hiroyuki Masaoka (Kyushu University, Fukuoka, Japan) for excellent advices for statistical analyses.

Funding

This work was supported by JSPS KAKENHI grant (17K11145) and Research Promotion Grant from Shin-Nihon Foundation of Advanced Medical Research.

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Author notes

  1. Masaki Shiota and Naohiro Fujimoto are contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masaki Shiota, Shigehiro Tsukahara, Miho Ushijima, Ario Takeuchi, Eiji Kashiwagi, Junichi Inokuchi, Katsunori Tatsugami & Masatoshi Eto

  2. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8556, Japan

    Naohiro Fujimoto

  3. Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Shigehiro Tsukahara & Takeshi Uchiumi

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  1. Masaki Shiota
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  2. Naohiro Fujimoto
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Correspondence to Masaki Shiota.

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Shiota, M., Fujimoto, N., Tsukahara, S. et al. The impact of genetic polymorphism on CYP19A1 in androgen-deprivation therapy among Japanese men. Cancer Chemother Pharmacol 83, 933–938 (2019). https://doi.org/10.1007/s00280-019-03811-8

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