Male Breast Cancer: Current Clinical Practice 'Justified'

Liam Davenport

October 31, 2018

MUNICH — Despite the fact that male breast cancer patients are, on average, older than their female counterparts and that the disease profiles of male breast cancer and female breast cancer differ at diagnosis, male breast cancer patients appear to respond just as well to the same treatments as those given to women, suggest data from several new studies.

The new analyses were presented as posters here at the European Society of Medical Oncology (ESMO) 2018 Congress. They were welcomed by experts, who pointed out that male breast cancer is a rare disease for which there is a paucity of data both on incidence and treatment outcomes.

In the first study, Mohamed A. Gouda, MD, Department of Clinical Oncology, Menoufia University, Shebin El Kom, Egypt, examined data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program on all cases of breast cancer reported in the United States during 15-year period (2000-2015).

His team identified 6790 men who were diagnosed during the study period, at an incidence rate of 10.2 per 100,000,000 men.

The incidence rate increased significantly during the study period, at an annual percentage change of 1.9% (P < .05).

The majority (81.3%) of cases occurred in white men (median age, 68 years). The cancer was more likely to occur on the left side, at a rate of 52.3%. Most cases were either regional (43.8%) or localized (46.4%) at the time of diagnosis.

Of note, breast cancer was the only primary in 66.3% of patients; it was the first of two primaries in 11.6% of patients; and it was a secondary or later primary in 22.1% of patients.

Calculating median survival using the Ederer II method, Gouda found that median observed survival for male breast cancer was 70.6% at 5 years and 48.8% at 10 years.

Five-year relative survival was estimated at 84.0%, and 10-year relative survival was 71.1%.

Speaking to Medscape Medical News, Gouda said that it is not clear why breast cancer in men should be found more often on the left hand side, but he speculated that it may be related to the disease occurring as a second primary in around a fifth of cases, rather than a phenomenon associated with case reporting.

He added that it "may be a further sequelae of prior treatment."

Gouda underlined that, despite the differences in baseline characteristics between male and female patients, male breast cancer "is treated in the same way that we treat female breast cancer." He added, "To our knowledge, it has a slightly different course."

These findings were echoed by a large study from in France. In that study, the average age and treatment profile were similar for male and female patients.

Jean-Sébastien Frénel, MD, from the Institut de Cancerologie de l'Ouest, Nantes, France, and colleagues collected data from the Epidemiological Metastatic Breast Cancer platform, which includes 18 French comprehensive cancer centers, for 2008 to 2014.

They identified 149 men (0.89%) of a total of 16,701 evaluable breast cancer patients.

Similar to the Gouda study, the mean age of male patients was 68.1 years, which was significantly older than that for women, at 60.6 years (P < .0001).

Men were also significantly more likely than women to have hormone receptor–positive (HR+) and human epidermal growth factor receptor–2 negative (HER2-) disease, at 78.4% vs 65.6% (P = .0019).

Among the HR+/HER2- male breast cancer patients, 42.9% received first-line hormonal therapy, which included tamoxifen (multiple brands) or an aromatase inhibitor with or without a luteinizing hormone–releasing hormone (LNRH) analogue.

Median progression-free survival (PFS) among these patients was 9.8 months, which was comparable to that seen in a group of women matched for age, breast cancer histology, breast cancer grade, metastasis location, and adjuvant therapy, at 13.0 months (P = .8).

For the 27.6% of HR+/HER2- male breast cancer patients who were treated with first-line chemotherapy, median progression-free survival was 6.9 months, which again was similar to the 6.3 months seen in a group of matched women.

Median overall survival was comparable between men and women, at 41.8 months and 34.9 months, respectively (P = .745).

"We found that men with HR+/HER2-disease had similar survival outcomes as women with the same form of breast cancer," Frénel said in a statement.

"Most of the patients receiving hormonal therapy were treated with tamoxifen, and the remainder received aromatase inhibitors," he continued. "But few patients received aromatase inhibitors plus LHRH analogues, despite some guidelines recommending that they should be given in combination."

Commenting for ESMO, Agnes Jager, MD, PhD, from Erasmus Medical University Cancer Institute, Rotterdam, the Netherlands, said that such a large study in men with primary breast cancer "was missing until now."

This justifies our current clinical practice. Dr Agnes Jager

"This new study shows the prognosis of men and women is similar, which is of great value, as this justifies our current clinical practice," she said. "We currently treat men with breast cancer in a similar way to women, which is now supported by these data."

She noted, however, that the study was small and that there was a lack of data on the extent of advanced disease, BRCA mutation status, and the type of chemotherapy used.

"More detailed information and longer-term follow-up will indicate whether there are characteristics or prognostic factors that are specific for men, which will allow us to change practice in the future, " she added.

First Randomized Trial

In the Male-GBG54 study, which is the first prospective randomized trial to examine different hormonal treatments in men with breast cancer, Mattea Reinisch, MD, PhD, from Kliniken Essen-Mitte, Essen, Germany, and colleagues compared tamoxifen with or without a gonadotrophin-releasing hormone analogue (GnRHa) with an aromatase inhibitor plus a GnRHa.

For the study, 55 male breast cancer patients with HR+ disease were randomly assigned to receive one of three regimens for 6 months:

  • tamoxifen 20 mg per day;

  • tamoxifen plus GnRHa given subcutaneously every 3 months; or

  • exemestane (Aromasin, Pharmacia and Upjohn) 25 mg/day plusa GnRHa.

Among the 46 men for whom full data were available, those treated with tamoxifen alone experienced an increase in estradiol levels of 67% at 3 months and 41% at 6 months.

In contrast, in the two arms in which men received hormonal treatment with a GnRH analogue, estradiol levels fell and continued to remain low. The group taking tamoxifen plus GnRHa experienced an 85% decrease at 3 months, whereas those given exemestane plus GnRHa experienced a 73% decrease. This continued for 6 months, with decreases of 59% and 63%, respectively.

Tamoxifen therapy had little effect on health-related quality of life or erectile function. However, both of those measures were severely affected in patients treated with exemestane + GnRHa, the researchers noted.

"The suppression of peripheral estradiol is a necessary condition for a therapeutic benefit of endocrine therapy in men with breast cancer when receiving an aromatase inhibitor plus GnRH analogue," Reinisch said in a press statement.

"Within the tamoxifen monotherapy arm, the estradiol values increased. These changes are known from female breast cancer patients and were expected," Reinisch said.

She concluded that "tamoxifen monotherapy should be kept as standard hormonal therapy for men with breast cancer. The side effects are moderate, hardly impairing sexual behavior.

"The combination with GnRH influenced patients' well-being and erectile function profoundly," she noted.

ESMO expert Jager commented that the researchers "are to be congratulated" for having conducted a randomized trial "in such a rare study population, which must have been a real effort.

"However, it is regrettable that the estradiol suppression at 3 months was the primary endpoint," she said.

"Although it is relevant to know whether and to what extent estradiol levels change over time during different endocrine treatment strategies, as far as I know, estradiol suppression at 3 months is neither a validated nor a clinically useful surrogate endpoint for the efficacy of endocrine treatment," she said.

She added that the finding that tamoxifen allowed an increase in estradiol levels at 3 and 6 months "is not new, although the degree of the increase is somewhat unexpected."

Overall, Jager emphasized that the endpoint used in the study means that the question of whether an LNRH agonist should be added to tamoxifen remains unanswered.

"Due to the severe side effects of LHRH agonists in men and the negative impact on quality of life, clarity about this is of great clinical importance," she said.

Also commenting for ESMO, Stefan Zimmerman, MD, Centre Hospitalier Universitaire Vaudois, Switzerland, said that, taken together, the studies show that "male breast cancer patients seem to benefit from endocrine therapy to a similar degree as women.

"These research results add to the current literature suggesting that the addition of GnRH analogues might improve on tamoxifen alone, but studies with clinical endpoints are needed," he said in a statement.

Zimmerman nevertheless stressed that it "is urgent that strategies that have proven effective in deferring resistance to endocrine therapy in women are explored in men with advanced breast cancer as well, including CDK4/6 inhibitors."

The Male-GBG54 study was funded by the Claudia von Schilling Foundation and was conducted in collaboration with Pfizer. Dr Gouda, Dr Frénel, and Dr Reinisch have disclosed no relevant financial relationships.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstracts 259P, 294PD, and 273PD, presented October 22, 2018.

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