A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences
Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ERα, ERβ1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26–0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46–1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07–0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12–0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR–PRA–PRB and ERβ1/2 clusters. A striking feature was the occurrence of ERα on distinct clusters between genders. In female breast cancer, ERα clustered with PR and its isoforms; in male breast cancer, ERα clustered with ERβ isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.
KeywordsMale breast cancer Hormone receptors Androgen receptor Hierarchical clustering
Thanks to the Tayside Tissue Bank for kindly providing some of the MBC cases. This study was supported by the Breast Cancer Campaign (UK Charity no. 05074725).
Conflict of interest
- 1.Breast cancer-survival statistics. Cancer Research UK Web Site. http://info.cancerresearchuk.org/cancerstats/. Accessed 26 Jan 2011
- 12.Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, Ellis IO, Robertson JF, Paish EC, Saunders PT, Groome NP, Speirs V (2008) Nuclear and cytoplasmic expression of ERβ1, ERβ2, and ERβ5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 14:5228–5235PubMedCrossRefGoogle Scholar
- 13.Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R (2000) Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. UK Receptor Group, UK NEQAS, The Scottish Breast Cancer Pathology Group, and The Receptor and Biomarker Study Group of the EORTC. J Clin Pathol 53:634–635PubMedCrossRefGoogle Scholar
- 14.Castellano I, Allia E, Accortanzo V, Vandone AM, Chiusa L, Arisio R, Durando A, Donadio M, Bussolati G, Coates AS, Viale G, Sapino A (2010) Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat 124:607–617PubMedCrossRefGoogle Scholar
- 16.Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116:340–350PubMedCrossRefGoogle Scholar
- 17.Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkilä P, Heikkinen T, Nevanlinna H, Akslen LA, Bégin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, García-Closas M, Caldas C, Pharoah PD, Huntsman D (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 Studies. PLoS Med 7:e1000279PubMedCrossRefGoogle Scholar
- 36.Xia LP, Zhou FF, Guo GF, Wang F, Wang X, Yuan ZY, Zhang B (2010) Chinese female breast cancer patients show a better overall survival than their male counterparts. Chin Med J (Engl) 123:2347–2352Google Scholar
- 47.Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, Jindal S, Segara D, Jia L, Moore NL, Henshall SM, Birrell SN, Coetzee GA, Sutherland RL, Butler LM, Tilley WD (2009) Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 69:6131–6140PubMedCrossRefGoogle Scholar
- 58.Korde LA, Zujewski JA, Kamin L, Giordano S, Domchek S, Anderson WF, Bartlett JM, Gelmon K, Nahleh Z, Bergh J, Cutuli B, Pruneri G, McCaskill-Stevens W, Gralow J, Hortobagyi G, Cardoso F (2010) Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 28:2114–2122PubMedCrossRefGoogle Scholar
- 62.Orr N, Cooke R, Jones M, Fletcher O, Dudbridge F, Chilcott-Burns S, Tomczyk K, Broderick P, Houlston R, Ashworth A, Swerdlow A (2011) Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men. Plos Genet 7:e1002290PubMedCrossRefGoogle Scholar