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Breast Cancer Research and Treatment

, Volume 147, Issue 2, pp 227–235 | Cite as

Aromatase inhibitors for metastatic male breast cancer: molecular, endocrine, and clinical considerations

  • Marcello Maugeri-SaccàEmail author
  • Maddalena Barba
  • Patrizia Vici
  • Laura Pizzuti
  • Domenico Sergi
  • Ruggero De Maria
  • Luigi Di Lauro
Review

Abstract

Male breast cancer is a rare condition. Aromatase inhibitors are widely used for treating metastatic male breast cancer patients. In this setting, their use is not substantiated by prospective clinical trials, but is rather driven by similarities supposedly existing with breast cancer in postmenopausal women. This oversimplified approach was questioned by studies addressing the molecular and endocrine roots of the disease. In this manuscript, we discuss relevant aspects of the current use of aromatase inhibitors in metastatic male breast cancer in light of the most updated evidence on the molecular landscape of the disease and the specific changes in the hormonal background occurring with aging. We further point to strategies for blocking multiple hormonal pathway nodes with the goal of improving their therapeutic potential. We searched PubMed from its inception until March 2014 for relevant literature on the use of aromatase inhibitors in metastatic male breast cancer. Selected terms were combined and used both as medical headings and text words. The reference list of the suitable manuscripts was inspected for further publications. Aromatase inhibitors represent the mainstay of treatment in the metastatic setting. Yet, efforts aimed at sharpening the therapeutic potential of aromatase inhibitors still pose a challenge due to the paucity of data. The choice of dual hormonal (or sequential) therapy combining aromatase inhibitors with a GnRH analogue may represent a valid alterative, particularly if informed by cancer- and patient-related features including molecular, endocrine, and clinic characteristics.

Keywords

Male breast cancer Aromatase inhibitors GnRH analogue Hormone receptor pathways 

Notes

Acknowledgments

We thank Tania Merlino and Ana Maria Edlisca for technical assistance.

Conflict of interest

The authors have declared no conflicts of interest.

References

  1. 1.
    Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN (2004) Breast carcinoma in men: a population-based study. Cancer 101:51–57PubMedCrossRefGoogle Scholar
  2. 2.
    Ruddy KJ, Winer EP (2013) Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 24:1434–1443PubMedCrossRefGoogle Scholar
  3. 3.
    Brinton LA, Cook MB, McCormack V, Johnson KC, Olsson H, Casagrande JT, et al (2014) Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results. J Natl Cancer Inst 106:doi:  10.1093/jnci/djt465
  4. 4.
    Anderson WF, Jatoi I, Tse J, Rosenberg PS (2010) Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 28:232–239PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Cardoso F, Bischoff J, Brain E, Zotano ÁG, Lück HJ, Tjan-Heijnen VC et al (2013) A review of the treatment of endocrine responsive metastatic breast cancer in postmenopausal women. Cancer Treat Rev 39:457–465PubMedCrossRefGoogle Scholar
  6. 6.
    Johansson I, Nilsson C, Berglund P, Lauss M, Ringnér M, Olsson H et al (2012) Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies Nacetyltransferase-1 (NAT1) as a novel prognostic biomarker. Breast Cancer Res 14:R31PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Callari M, Cappelletti V, De Cecco L, Musella V, Miodini P, Veneroni S et al (2011) Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer. Breast Cancer Res Treat 127:601–610PubMedCrossRefGoogle Scholar
  8. 8.
    Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I (2002) Estradiol in elderly men. Aging Male 5:98–102PubMedCrossRefGoogle Scholar
  9. 9.
    Eggemann H, Ignatov A, Smith BJ, Altmann U, von Minckwitz G, Röhl FW et al (2013) Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat 137:465–470PubMedCrossRefGoogle Scholar
  10. 10.
    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Huo D, Ikpatt F, Khramtsov A, Dangou JM, Nanda R, Dignam J et al (2009) Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol 27:4515–4521PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70CrossRefGoogle Scholar
  13. 13.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346–352PubMedCentralPubMedGoogle Scholar
  14. 14.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Rudlowski C, Schulten HJ, Golas MM, Sander B, Barwing R, Palandt JE et al (2006) Comparative genomic hybridization analysis on male breast cancer. Int J Cancer 118:2455–2460PubMedCrossRefGoogle Scholar
  16. 16.
    Kornegoor R, Moelans CB, Verschuur-Maes AH, Hogenes MC, de Bruin PC, Oudejans JJ et al (2012) Promoter hypermethylation in male breast cancer: analysis by multiplex ligation-dependent probe amplification. Breast Cancer Res 14:R101PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kornegoor R, Moelans CB, Verschuur-Maes AH, Hogenes MC, de Bruin PC, Oudejans JJ et al (2012) Oncogene amplification in male breast cancer: analysis by multiplex ligation-dependent probe amplification. Breast Cancer Res Treat 135:49–58PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Johansson I, Nilsson C, Berglund P, Strand C, Jönsson G, Staaf J et al (2011) High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer. Breast Cancer Res Treat 129:747–760PubMedCrossRefGoogle Scholar
  19. 19.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570PubMedCrossRefGoogle Scholar
  20. 20.
    Shaaban AM, Ball GR, Brannan RA, Cserni G, Di Benedetto A, Dent J et al (2012) A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences. Breast Cancer Res Treat 133:949–958PubMedCrossRefGoogle Scholar
  21. 21.
    Fassan M, Baffa R, Palazzo JP, Lloyd J, Crosariol M, Liu CG et al (2009) MicroRNA expression profiling of male breast cancer. Breast Cancer Res 11:R58PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Johansson I, Ringnér M, Hedenfalk I (2013) The landscape of candidate driver genes differs between male and female breast cancer. PLoS ONE 8:e78299PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Patani N, Martin LA (2014) Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer. Mol Cell Endocrinol 382:683–694PubMedCrossRefGoogle Scholar
  24. 24.
    Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45:1446–1451PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Toy W, Shen Y, Won H, Green B, Sakr RA, Will M et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45:1439–1445PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Li S, Shen D, Shao J, Crowder R, Liu W, Prat A et al (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4:1116–1130PubMedCrossRefGoogle Scholar
  27. 27.
    Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R et al (2013) D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73:6856–6864PubMedCrossRefGoogle Scholar
  28. 28.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529PubMedCrossRefGoogle Scholar
  29. 29.
    Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM (2000) Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. J Endocrinol 164:225–238PubMedCrossRefGoogle Scholar
  30. 30.
    Mauras N, O’Brien KO, Klein KO, Hayes V (2000) Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab 85:2370–2377PubMedGoogle Scholar
  31. 31.
    T’Sjoen GG, Giagulli VA, Delva H, Crabbe P, De Bacquer D, Kaufman JM (2005) Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab 90:5717–5722PubMedCrossRefGoogle Scholar
  32. 32.
    Bighin C, Lunardi G, Del Mastro L, Marroni P, Taveggia P, Levaggi A et al (2010) Estrone sulphate, FSH, and testosterone levels in two male breast cancer patients treated with aromatase inhibitors. Oncologist 15:1270–1272PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C (2004) Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab 89:1174–1180PubMedCrossRefGoogle Scholar
  34. 34.
    Burnett-Bowie SA, Roupenian KC, Dere ME, Lee H, Leder BZ (2009) Effects of aromatase inhibition in hypogonadal older men: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol 70:116–123CrossRefGoogle Scholar
  35. 35.
    Lopez M, Di Lauro L, Lazzaro B, Papaldo P (1985) Hormonal treatment of disseminated male breast cancer. Oncology 42:345–349PubMedCrossRefGoogle Scholar
  36. 36.
    Lopez M (1985) Cyproterone acetate in the treatment of metastatic cancer of the male breast. Cancer 55:2334–2336PubMedCrossRefGoogle Scholar
  37. 37.
    Lopez M, Natali M, Di Lauro L, Vici P, Pignatti F, Carpano S (1993) Combined treatment with buserelin and cyproterone acetate in metastatic male breast cancer. Cancer 72:502–505PubMedCrossRefGoogle Scholar
  38. 38.
    Dakin Haché K, Gray S, Barnes PJ, Dewar R, Younis T, Rayson D et al (2007) Clinical and pathological correlations in male breast cancer: intratumoral aromatase expression via tissue microarray. Breast Cancer Res Treat 105:169–175PubMedCrossRefGoogle Scholar
  39. 39.
    Takagi K, Moriya T, Kurosumi M, Oka K, Miki Y, Ebata A et al (2013) Intratumoral estrogen concentration and expression of estrogen-induced genes in male breast carcinoma: comparison with female breast carcinoma. Horm Cancer 4:1–11PubMedCrossRefGoogle Scholar
  40. 40.
    White J, Kearins O, Dodwell D, Horgan K, Hanby AM, Speirs V (2011) Male breast carcinoma: increased awareness needed. Breast Cancer Res 13:219PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Anelli TF, Anelli A, Tran KN, Lebwohl DE, Borgen PI (1994) Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients. Cancer 74:74–77PubMedCrossRefGoogle Scholar
  42. 42.
    Visram H, Kanji F, Dent SF (2010) Endocrine therapy for male breast cancer: rates of toxicity and adherence. Curr Oncol 17:17–21PubMedCentralPubMedGoogle Scholar
  43. 43.
    Pemmaraju N, Munsell MF, Hortobagyi GN, Giordano SH (2012) Retrospective review of male breast cancer patients: analysis of tamoxifen-related side-effects. Ann Oncol 23:1471–1474PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Giordano SH, Valero V, Buzdar AU, Hortobagyi GN (2002) Efficacy of anastrozole in male breast cancer. Am J Clin Oncol 25:235–237PubMedCrossRefGoogle Scholar
  45. 45.
    Zabolotny BP, Zalai CV, Meterissian SH (2005) Successful use of letrozole in male breast cancer: a case report and review of hormonal therapy for male breast cancer. J Surg Oncol 90:26–30PubMedCrossRefGoogle Scholar
  46. 46.
    Arriola E, Hui E, Dowsett M, Smith IE (2007) Aromatase inhibitors and male breast cancer. Clin Transl Oncol 9:192–194PubMedCrossRefGoogle Scholar
  47. 47.
    Doyen J, Italiano A, Largillier R, Ferrero JM, Fontana X, Thyss A (2010) Aromatase inhibition in male breast cancer patients: biological and clinical implications. Ann Oncol 21:1243–1245PubMedCrossRefGoogle Scholar
  48. 48.
    Giordano SH, Hortobagyi GN (2006) Leuprolide acetate plus aromatase inhibition for male breast cancer. J Clin Oncol 24:e42–e43PubMedCrossRefGoogle Scholar
  49. 49.
    Zagouri F, Sergentanis TN, Koutoulidis V, Sparber C, Steger GG, Dubsky P et al (2013) Aromatase inhibitors with or without gonadotropin-releasing hormone analogue in metastatic male breast cancer: a case series. Br J Cancer 108:2259–2263PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Di Lauro L, Vici P, Del Medico P, Laudadio L, Tomao S, Giannarelli D et al (2013) Letrozole combined with gonadotropin-releasing hormone analog for metastatic male breast cancer. Breast Cancer Res Treat 141:119–123PubMedCrossRefGoogle Scholar
  51. 51.
    Korde LA, Zujewski JA, Kamin L, Giordano S, Domchek S, Anderson WF et al (2010) Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 28:2114–2122PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Lopez M, Di Lauro L, Papaldo P, Lazzaro B (1985) Chemotherapy in metastatic male breast cancer. Oncology 42:205–209PubMedCrossRefGoogle Scholar
  53. 53.
    Zagouri F, Sergentanis TN, Chrysikos D, Zografos E, Rudas M, Steger G et al (2013) Fulvestrant and male breast cancer: a case series. Ann Oncol 24:265–266PubMedCrossRefGoogle Scholar
  54. 54.
    de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Marcello Maugeri-Saccà
    • 1
    • 2
    Email author
  • Maddalena Barba
    • 1
  • Patrizia Vici
    • 1
  • Laura Pizzuti
    • 1
  • Domenico Sergi
    • 1
  • Ruggero De Maria
    • 2
  • Luigi Di Lauro
    • 1
  1. 1.Division of Medical Oncology B“Regina Elena” National Cancer InstituteRomeItaly
  2. 2.Scientific Direction“Regina Elena” National Cancer InstituteRomeItaly

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