Male breast cancer is not congruent with the female disease

Abstract

It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC.

Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females.

MBC is almost always estrogen receptor positive (ER + ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs and an increase in risk of mortality compared to tamoxifen. The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. These important biological differences point the way to the development of new therapies for MBC based on differences rather than similarities with FBC.

Introduction

Because of the relative rarity of male breast cancer (MBC), which comprises <1% of western cases, for men with the disease it has been accepted that trial results derived from its big sister should form the basis for treatment. In the absence of national and international randomised trials for male breast cancer this appears superficially to be an appropriate response. Closer examination of available data suggests that aspects of aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women.

At a microscopic level the major difference between FBC and MBC is the almost total lack of invasive lobular cancers in the latter group since lobular differentiation is an unusual event in males. These very rare cases of invasive lobular cancer may have Klinefelter’s syndrome (Sanchez et al., 1986), be taking estrogens as transsexuals (Burcombe et al., 2003) or prostate cancer sufferers (Dore et al., 1982) but predominantly have no known endocrine risk factor (Spencer and Shutter, 2009). One major obstacle to the molecular investigation of MBC is the absence of any human MBC cell line. Such a resource would greatly improve our understanding of this disease.