Shedding Light on the Mystery of Male Breast Cancer


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Fatima Cardoso, MD

Jorge S. Reis-Filho, MD, PhD, FRCPath

Lajos Pusztai, MD

The Challenge of Male Breast Cancer

Male breast cancer is a rare disease, and there are no prospective or randomized data on management. Mortality lags behind that in female breast cancer, reflecting the need for further studies to improve outcomes.

—Fatima Cardoso, MD
Triple-negative breast cancer is very rare in men, and we do not know why.

—Lajos Pusztai, MD

Male breast cancer represents less than 1% of  all breast cancers, which partially explains why so little is known about the disease. Two presentations at the 2014 San Antonio Breast Cancer Symposium focused on the characteristics of male breast cancer drawn from a large international registry and genomic analysis of 59 male breast cancer cases.1,2 The wealth of data are currently being parsed and analyzed. At present, understanding of male breast cancer is a work in progress.

The first report—a joint effort by the European Organisation for Research and Treatment of Cancer (EORTC), Translational Breast Cancer Research Consortium, Breast International Group, and North American Breast Cancer Group—found similarities between male breast cancer and female breast cancer and some differences. More than 90% of male breast cancers were estrogen receptor–positive, whereas around 65% to 70% of female breast cancers are estrogen receptor–positive.

Characteristics of Male Breast Cancer

Positivity of both estrogen receptor and progesterone receptor was associated with outcome in male breast cancers, similar to female breast cancers. Androgen receptor positivity was also associated with outcome, but to a lesser extent than estrogen receptor and progesterone receptor expression. Metastatic disease and node positivity are associated with worse survival.

“Male breast cancer is a rare disease, and there are no prospective or randomized data on management. Treatments are extrapolated from female breast cancer. Mortality lags behind that in female breast cancer, reflecting the need for further studies to improve outcomes. The International Male Breast Cancer Program was created to better understand this disease and improve its management. It has three parts: a retrospective joint analysis of 1,800 cases, a prospective international registry, and international clinical trials,” explained Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, who presented data on the characteristics of males with early-stage breast cancer. Dr. Cardoso is Secretary General of the EORTC.

The first part of this program included 1,800 eligible patients enrolled from 1990 to 2010. About 90% were between the ages of 51 and 79 years or older (median age at diagnosis, 65 years), and more than 90% patients were evenly divided between the age groups of 51 to 65, 66 to 75, and 75 or older. Central laboratory assessments were available for 1,483 (82.4%): 1,394 from the European Union and 89 from the United States. The vast majority of cancers identified were invasive ductal carcinoma grade. 2

Male breast cancer is most commonly estrogen receptor–positive, progesterone receptor–positive, and androgen receptor–positive and of luminal A-like subtype; 9% were HER2-positive, and less than 1% were triple-negative breast cancer. A total of 56% were node-negative, 31% were staged as N1, 5% had N2 disease, 3% had N3 disease, and 6% had an unknown nodal status.

Although for the most part adjuvant radiation was given according to guidelines, 36% of N1 patients and 15% of N2 patients did not receive adjuvant radiation. Data on adjuvant radiotherapy were available for 819 of 1,054 patients who were nonmetastatic at diagnosis; in node-negative patients, 32% had adjuvant radiation therapy after mastectomy, whereas 69% of node-positive patients had radiation post mastectomy.

Even though 56% of patients had tumors suitable for breast-conserving surgery, only 29 patients (4%) took advantage of the less-extensive surgery; among the breast-conserving surgery cohort, 7 node-positive patients (100%) had adjuvant radiation, whereas 46% of 22 node-negative patients had radiation. Thirty percent of patients received adjuvant chemotherapy, mostly with anthracyclines or anthracyclines and taxanes.

In M0 patients, 93% had strong estrogen receptor expression, but only 77% received adjuvant endocrine therapy, mainly with tamoxifen; 35% were strongly progesterone receptor–positive. Eighty-eight percent were androgen receptor–positive, 9% were HER2-positive, and 25% were Ki67-positive.

The median overall survival was 10.41 years for nonmetastatic node-negative patients, 8.36 years for nonmetastatic node-positive patients, and 2.63 years for metastatic patients. Grade, Ki67 expression, and immunohistochemistry subtypes were not prognostic. This cohort will continue to be studied, and clinical trials will be designed and initiated, she said.

Genomic Landscape

Jorge S. Reis-Filho, MD, PhD, ­FRCPath, gave a presentation on genome sequencing of 241 genes in samples from 59 patients with male breast cancer diagnosed and treated at Memorial Sloan Kettering Cancer Center in New York. The median age was 66 years, and the median tumor size was 2 cm. The vast majority were grades 2 and 3; all tumors were estrogen receptor–positive, and only two cases were HER2-amplified. In 10 patients where germline mutations were assessed clinically, 3 harbored BRCA2 germline ­mutations.

Genomic analysis showed that estrogen receptor–positive male breast cancers are characterized by somatic mutations in PIK3CA, GATA3, TP53, and MAP3K1. Copy number changes include 1q+, 16q–, 16p+, and 8q+. Recurrent amplifications affect genes also amplified in luminal female breast cancer, including MYC and PPM1D.

In males, luminal B-like tumors display the following alterations more frequently than luminal A-like tumors: GATA3 somatic mutations, mutations affecting DNA repair-related genes, and 11q losses.

Male luminal breast cancers have similar mutation rates as female luminal breast cancers but have less frequent PIK3CA and TP53 mutations. As compared to luminal female breast cancers, luminal male breast cancers exhibit similar patterns of gene copy number alterations, and are more frequently 12q+. Luminal breast cancers in males, but not in females, are more frequently enriched for mutations affecting DNA repair-related genes.

What to Make of All This?

Lajos Pusztai, MD, of Yale University School of Medicine, New Haven, congratulated the authors on tackling this rare disease entity.

“Both of these studies are important in that they focus on an understudied, rare subset of male breast cancer. The first report from a very large consortium does not reveal any unexpected findings. The stage distribution and survival results are difficult to compare with female breast cancer results due to the heterogeneous dataset and the vastly different sample sizes for male and female breast cancer databases,” he wrote in an e-mail.

Dr. Pusztai noted that the differences in estrogen receptor positivity between males and females suggest possible differences in etiology and origins of male breast cancer. “Triple-negative breast cancer is very rare in men, and we do not know why,” he wrote.

“The second abstract is an independent molecular confirmation of the unusual molecular class distribution of male breast cancers. The authors pretty much confirm that male breast cancers are of the luminal subtype. They tested a number of preselected molecular abnormalities and found that the distribution of them is largely similar to what we already know and would expect from luminal cancers in women,” Dr. Pusztai continued.

He said that the investigators were able to draw some testable hypotheses about altered pathways in male cancers that are less frequently observed in female breast cancers. “These hypotheses will need to be tested on independent samples, and hopefully the international consortium will take on this challenge. The consortium will also conduct clinical trials in male breast cancer, like FGFR signaling perturbations in male breast cancer, which are directly testable in the clinical setting,” he said. n

Disclosure: Drs. Cardoso, Reis-Filho, and Pusztai reported no potential conflicts of interest.

References

1. Cardoso F, Bartlett J, Slaets L, et al: Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. 2014 San Antonio Breast Cancer Symposium. Abstract S6-05. Presented December 12, 2014.

2. Piscuoglio S, Murray M, Ng CKY, et al: The genomic landscape of male breast cancers. 2014 San Antonio Breast Cancer Symposium. Abstract S6-06. Presented December 12, 2014.



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