Novel Approaches in Male Breast Cancer

Patrick I. Borgen, MD

Male breast cancer (MBC) is a rare and poorly understood disease, but recent molecular studies have revealed fundamental differences from female breast cancer that could help guide treatment strategies toward a more tailored approach, according to Patrick I. Borgen, MD, chairman of the department of surgery at Maimonides Medical Center and chair of the 2017 Miami Breast Cancer Conference. Borgen discussed those findings in a presentation at the meeting.

MBC comprises less than 1% of all cancers in men and less than 1% of all breast cancers, according to a 2016 Histopathology review that Borgen discussed.¹ For every 100 to 200 female patients with breast cancer, 1 man is diagnosed. MBC tends to present in older patients and often with estrogen receptor (ER)-positive disease.²

In general, men lack knowledge about MBC and may be uncomfortable seeking care for breast complaints that are more commonly associated with women. This leads to more late diagnoses of advanced cancer in men. The differences in screening and delayed diagnoses contribute to a 25% higher mortality rate in men than women, although with standard treatment, survival rates are similar.³ Researchers note that the incidence of MBC is increasing.

Proportionally, significantly more male cases arise with an underlying germline cancer disposition, and they display a “vastly different” phenotypic expression compared with females, according to the Histopathology review. BRCA2 is the strongest risk factor for MBC, with a relative risk of 80 times the general population. MBCs in BRCA2 mutation carriers appear to harbor a more aggressive phenotype. Meanwhile, BRCA1 mutations are not associated with basallike cancer in men with breast cancer as they are in women. One study of BRCAx mutations in female patients showed a higher incidence of MBC in families with PALB2 heterozygous mutations, but direct screening of unselected MBC populations has been inconclusive on whether there is an increased risk.

Different somatic changes have also been reported, although only just over 200 MBC patients have been studied and findings are mixed. Changes in the PIK3CA gene are the most common mutations in male patients, occurring more frequently than in females and in different parts of the gene. Recent studies have not detected KRAS mutations in men, and the TP53 mutation—the most common genetic change in females—was seen in only about 1% of MBCs. Chromosomalbased changes are seen more often in MBC, with some major studies showing more genetic regions with gains and fewer with losses. Methylation, the most common mechanism of tumor suppressor gene silencing, is seen less frequently.

Researchers have identified several molecular subtypes that could aid in prognosis, including tumors displaying more complex chromosomal rearrangement and high levels of methylation. In addition to the typical estrogen-responsive MBC, a much less common phenotype has been suggested by findings of gene expression profiles related to epithelial mesenchymal transition and hormonal therapy insensitivity.

Gene expression profile observations related to signaling pathway differences have implications in monitoring disease activity through positron emission tomography or other techniques and for novel therapeutics that target cancer metabolism in early-phase trials, the Histopathology article notes. Divergence of genes associated with cell motility in MBC compared with female breast cancer suggests potential targets for vinca alkaloids, taxanes, or newly developed drugs such as epothilones or eribulin.

Borgen noted in his presentation abstract for the Miami meeting that male-specific multicenter trials based on individual disease characteristics are needed, but such trials are impractical given the rarity of MBC. He recommends establishing national tumor repositories and prospective registries, coupled with prospective/retrospective studies of the type that produced the 21-gene genomic assay in ER-positive, HER2-negative breast cancer. “Continued emphasis on the development of reliable preclinical models to elucidate more clearly the pathogenesis of MBC should provide attractive targets for study and hold out hope of improving the prognosis seen in this disease,” Borgen wrote.

References:

1. Deb S, Lakhani SR, Ottini L, Fox SB. The cancer genetics and pathology of male breast cancer. Histopathology. 2016;68:110-118.
2. Dixon J. Dr. Dixon on prevalence and risk factors of male breast cancer. OncLive; August 10, 2016. https://www.onclive.com/onclive-tv/dr-dixon-on-prevalence-and-riskfactors- of-male-breast-cancer.
3. Male breast cancer: a rare, increasing trend. Johns Hopkins Medicine. http://www.hopkinsmedicine.org/health/ articles-and-answers/prevention/male-breast-cancer-rareyet- increasing-trend. Accessed February 22, 2017.