Is anti-androgen therapy for male breast cancer feasible?
Male breast cancer (MBC) is a very rare disease with a paucity of treatment options. In an article in CancerLetters, Dr. Lauro from Italy describes the molecular and endocrine concepts related to the androgen receptor (AR) and androgens in MBC, describing the evidence for anti-androgen therapy in clinical practice.
Current status of MBC incidence
MBC accounts for 0.5%C1% of all breast cancers (BC) and predominates in older men, with incidence increasing with age, unlike the bimodal incidence pattern of female breast cancer (FBC). Men are prone to MBC when they have a high estrogen/androgen ratio, such as Klinefelter’s syndrome, testicular disease, obesity or liver disease.
Genetically, MBC shares risk factors with FBC, such as BRCA1 and BRCA2 germline mutations, in addition to genetic alterations associated with MBC including PALB2, AR, CYP17, CHEK2, and RAD51B.
The available evidence for MBC therapies comes from small, retrospective studies, and prospective studies are difficult to conduct because of the rarity of the disease and recruitment difficulties.
Hormone therapy for MBC
In the 1940s, treatment was achieved mainly through surgical adjustment of hormone levels, with procedures including orchiectomy, adrenalectomy and pituitary resection. Nowadays, surgical adjustment of hormone levels has been replaced by medication to regulate hormone levels.
The tremendous advances in the pharmacological treatment of hormone receptor-positive FBC have had a profound impact on MBC treatment. Because most MBCs are estrogen receptor (ER)-positive, ER expression is even higher than in FBC; some studies have shown that ER-guided therapy is effective in MBC patients. Anti-estrogen therapy for MBC has been highly valued over the past decades, but its success has also overshadowed other treatments.
In the mid-1980s, Lopez proposed a theory of similarity between MBC and prostate cancer, namely androgen dependence, and evidence that anti-androgen therapy could lead to tumor regression. Previous evidence of the potential of anti-androgen therapy was only derived from extrapolation of treatment outcomes in small samples of metastatic MBC. The importance of androgens in MBC has been raised again in recent years with the advancement of AIs, as patients treated with AIs gain therapeutic benefit due to decreased 17b-estradiol and increased androgen levels due to hypothalamic-pituitary feedback activation.
Androgen receptor (AR) gene mutations
AR mutations in MBCs were first reported in 1992, when two brothers suffering from MBC developed androgen resistance at the same time. Examination of 13 MBC patients 1 year later revealed a mutation in exon 3, and patients carrying this AR mutation showed androgen insensitivity.
Given that MBC cases with AR mutations were found in the context of androgen treatment insensitivity, it has been speculated that AR has a protective effect and that the mutation may induce a decrease in AR activity, thus counteracting the protective effect of androgens on MBC patients. However, it has also been speculated that AR mutations result in altered interactions with normal proteins or that AR mutations acquire altered sequence-specific DNA binding capacity, allowing AR to bind to estrogen response elements (EREs) and promote estrogen-regulated gene transcription.
Genetic evidence is scarce or even ambiguous, but it is still proposed that androgen hypersensitivity caused by AR mutations or long CAG repeats is the etiology of MBC. If AR has a protective role in MBC, how can this explain tumor regression after anti-androgen therapy?
Subclassification of MBC
Attempts to further subclassify MBC have recently begun. Initial genomic studies suggested the existence of two subclasses of MBC, the male complex and the male simplex, with the latter considered to be a male-only disease. Based on gene expression status, MBC was further identified as two subclasses, luminalM1 (70%) and luminalM2 (30%), with completely different survival and biological processes in the two groups of patients.
Another study reviewed the differences between MBC and FBC, with approximately 1.000 genes differentially expressed and a significantly higher number of genes associated with AR in MBC, suggesting AR activation. Using FBC as a foresight, clarifying the molecular mechanisms of AR activation in MBC may help to derive therapeutic strategies as well as the therapeutic potential of AR pharmacological inhibition.
In FBC cells, the clinical outcome of AR activation correlates with ER status, with androgen treatment inhibiting ERα-driven proliferation in ERα-positive cells and androgen treatment promoting proliferation in ER-negative BC (molecular subtypes of sweat glands or intraluminal androgen receptors).
Earlier studies have shown the effectiveness of bilirubamide in treating ER-negative/AR-positive FBC, a result supported by the effectiveness of enzalutamide in treating AR-positive triple-negative BC in a phase 2 study in which androgen-driven genetic alterations were characterized and associated with better clinical outcomes. Enzalutamide also inhibited the growth of ER-positive/AR-positive tumors in vivo, correlating with a high nuclear AR:ER ratio.
With the increasing understanding of the molecular features of FBC (e.g., triple-negative BC has six different molecular subtypes) and the results of available cellular and animal models, AR-guided drug therapy is likely to be active and genetic studies offer hope for MBC subclassification, but multiple efforts are still needed to promote the development of AR-targeted drug therapy in MBC.