Breast Cancer in Men Requires Different Approach Than in Women

Neil Osterweil

December 22, 2014

SAN ANTONIO — News flash: men are different from women.

That much is obvious, but far less evident, until now, is the fact that breast cancer in men differs in important and potentially targetable ways from breast cancer in women, as shown by a major international study and a separate genomic analysis presented here at the San Antonio Breast Cancer Symposium 2014.

Male breast cancers are relatively rare, accounting for less than 1% of all cancers in men and about 1% of all invasive breast cancers.

"Unfortunately, our knowledge of how to treat male breast cancer is pretty much just extrapolated from our knowledge of treating female breast cancer," said Shannon L. Puhalla, MD, assistant professor of medicine at the University of Pittsburgh Medical Center Cancer Center, who was not involved in either study.

Breast cancer in men is largely estrogen receptor (ER)-, progesterone receptor (PR)-, and androgen receptor (AR)-positive and of the luminal B-like subtype, potentially offering multiple therapeutic targets, said Fatima Cardoso, MD, director of the breast cancer unit at Champalimaud Cancer Center in Lisbon, Portugal, who was involved in the international study.

But although the majority of male breast cancers are hormone-receptor-positive, "not all men received endocrine therapy, possibly given the theoretical concern about risk of prostate cancer with the use of aromatase inhibitors in males, said Aditya Bardia, MD, MPH, a breast cancer specialist at the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study. Given that, this merits further evaluation and research, he told Medscape Medical News.

In their retrospective review, Dr Cardoso and her colleagues determined that although early disease was found in more than half the men with breast cancer, only 4% got breast-conserving surgery. Furthermore, 36% of patients with involvement of a single lymph node (N1 disease) did not receive adjuvant radiotherapy, nor did 15% of N2 patients. In addition, even though more than 90% of the breast tumors were ER-positive, only 77% of the men received endocrine therapy.

These findings suggest that there is still significant room for improvement, Dr Cardoso said.

"The incidence seems to have come down since 2000, and the mortality has come down, but [it is still] lagging significantly behind female breast cancer," she said.

Multinational Trial Group

Dr Cardoso presented first results from the EORTC10085/TBCRC/BIG/NABCG International Male Breast Cancer Program, a joint production of the European Organization for Research and Treatment of Cancer, the Translational Breast Cancer Research Consortium, the Breast Intergroup, and the North American Breast Cancer Group.

The retrospective analysis involved all male breast cancer patients diagnosed and treated at participating centers in the previous 20 years.

Tumor blocks were collected and centrally analyzed for tumor biology. Of the 1822 men identified, a good quality tumor sample was available for 1483 men. The 1054 men with no metastases (M0) were included in the analysis.

Median age at diagnosis was 68.4 years. For women, median age at diagnosis is 61.0 years, according to 2011 Surveillance, Epidemiology, and End Results (SEER) data.

Slightly more than half the men (56.2%) had node-negative disease (N0), which is higher than the rate seen in women with breast cancer. In addition, 30.5% of the men had N1 disease, 5.0% had N2 disease, 2.8% had N3 disease, and nodes were not evaluable in 5.5% of the men.

Of the 828 men with M0 disease scheduled for surgery, 827 underwent surgery, 96% of which was modified radical mastectomy and 4% of which was breast-conserving surgery.

Data on lymph node management was available for 822 men; 76% underwent axillary lymph node dissection, 18% underwent sentinel node dissection, and 6% had no nodal dissection. There was a significant trend over time toward greater use of sentinel node biopsy (P < .001), Dr Cardoso reported.

After mastectomy, 69% of men with node-positive disease received adjuvant radiotherapy, as did 32% of men with node-negative disease. For men with N1 disease, 35.9% received adjuvant radiotherapy, as did 15.1% of men with N2 disease and 6.9% of men with N3 disease.

All patients with node-positive disease who underwent breast-conserving surgery received adjuvant radiotherapy. However, "for reasons that are a bit difficult to understand, 46% of patients who were node-negative but who had breast-conserving surgery did not receive adjuvant radiation therapy," Dr. Cardoso said.

Of 821 M0 patients for whom chemotherapy data were available, 30% received chemotherapy. The regimen involved anthracycline in 43% of cases; anthracycline plus taxane in 32%; cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in 15%; and something else in 8%. There was a significant trend over time toward giving more adjuvant chemotherapy (P < .001).

Although 93% of tumors had high levels of ER expression and 35% had high levels of PR expression, only 77% of the men received adjuvant endocrine therapy, primarily with tamoxifen alone. Of the men who did receive endocrine therapy, 4% received an aromatase inhibitor and 4% received a combination of tamoxifen and aromatase inhibitor. The remaining men received tamoxifen plus a luteinizing hormone-releasing hormone agonist (1%), another unspecified agent (1%), or a combination (1%).

A pathology review of 395 samples, mostly from patients in the Netherlands, showed invasive ductal cancers in more than 80%, and a sprinkling of invasive lobular, mixed, or other histologies. Slightly more than half the tumors were of grade 2; grade 1 and grade 3 tumors occurred in roughly equal proportions.

An analysis of biomarkers other than ER and PR showed that 88% of the tumors strongly expressed AR, whereas only 9% were positive for HER2, and just 25% strongly expressed the Ki-67 protein. Less than 1% of tumors were triple-negative cancers, lacking ER, PR, and HER2.

Median overall survival was 10.41 years for men with M0/N0 tumors, 8.36 years for those with M0 node-positive disease, and 2.63 years for men with at least one distant metastatic site.

High ER and PR expression levels were associated with favorable outcomes, Dr Cardoso and colleagues report. AR expression was also prognostic, but was less robust; there was no detectable prognostic value for tumor grade, Ki-67, or St. Gallen molecular subtype.

Results from subsequent phases of this trial will be presented at future meetings, Dr Cardoso said.

Genomic Landscape

A separate study of the genomic landscape of male breast cancers was also presented at the meeting.

Male breast cancers are predominantly of the luminal A subtype, and are characterized by recurrent mutations in the PIK3CA, GATA3, FLG, and PLEC genes, according to Salvatore Piscuoglio, PhD, a research fellow at Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

The genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth-factor pathways, but the pathways that are known to drive luminal cancers when mutated are seen less often in women than in men, the researchers report.

Practice Implications

These findings will help us determine, down the road, whether "there are significant differences in how targeted therapy might apply," said Stephen P. Naber, MD, PhD, chief of anatomic pathology at Tufts University School of Medicine in Boston, who was not involved in either study.

The genomic information, in particular, offers insights into tumor pathology and staging.

"It's very important that we understand as much as we can about male breast cancer, making certain that, for anything that we're testing for in the way of biomarkers — the hormonal receptors, HER2, and any others — we are able to work out the parameters of that testing and be very confident that we're making measures that our accurate," Dr Naber explained.

Given the rarity of male breast cancer, the size of the sample and the wealth of information provided were impressive, said John V. Kiluk, MD, FACS, associate member of the comprehensive breast program at the Moffitt Cancer Center in Tampa, Florida.

"It confirms our suspicions that these tumors are almost always ER-positive, which is what we have found in our experience as well," he told Medscape Medical News.

Dr Kiluk noted that although the use of endocrine therapy in men was lower than might be expected, given the prevalence of ER-positive tumors, the older age at diagnosis of many patients might explain the less-aggressive management.

"If the patient is 85 and has a mastectomy for a T1c tumor, do you really have to give him tamoxifen?" he asked.

Dr Kiluk noted that the prevalence of the luminal B-like subtype in men, rather than the luminal A-like subtype found more commonly in women, underscores the idea that male breast cancer might require a different therapeutic approach from female breast cancer.

The international consortium study was supported by the Breast Cancer Research Foundation, the European Breast Cancer Council, the EORTC Breast Cancer Group, Dutch Pink Ribbon, the Swedish Breast Cancer Association, Susan G. Komen for the Cure, and the Ontario Institute for Cancer Research. Dr Puhalla, Dr Cardoso, Dr Bardia, Dr Piscuoglio, Dr Naber, and Dr Kiluk have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2014: Abstracts S6-05 and S6-06. Presented December 12, 2014.

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