There is growing evidence that drugs approved for the treatment of breast cancer in women are also effective and well tolerated in men, according to the largest real-life study yet to investigate treatment and outcomes in men with breast cancer and two further studies reported at ESMO 2018 Congress.
 

Approximately one in every 100 cases of breast cancer (1%) occurs in men. However, there have been few prospective studies in men, and clinical trials of breast cancer treatments have often excluded men so treatment recommendations are largely extrapolated from the results of clinical trials in women.

To learn more about the treatment of breast cancer in men researchers analysed clinical data collected by the Epidemiological Strategy and Medical Economics Metastatic Breast Cancer (ESME MBC) platform between January 2008 and December 2014. This national database collects real-life data from 18 French Comprehensive Cancer Centers for all patients newly diagnosed with metastatic breast cancer starting at least one treatment.

Researchers retrieved the data for men with metastatic breast cancer included in the database and compared their treatment and outcome with those in women. They found 149 men from the total of 16,701 patients (0.89%). The men were slightly older than the women (mean age 68.1 years vs 60.6 years, p<0.0001). Just over three-quarters of the men (105/149; 78.4%) had hormone receptor positive (HR+)/ human epidermal growth factor receptor 2 (HER2) negative breast cancer, which was a slightly higher proportion than in women (65.6%, p=0.0019).

Results showed men received similar treatments to women with metastatic breast cancer. Just under half of those with HR+/HER2-negative breast cancer (45/105, 42.9%) received frontline hormonal therapy: tamoxifen (20/45), aromatase inhibitor + luteinizing hormone-releasing hormone (LHRH) analogues (18/45) or others (7/45).

Their median progression-free survival was 9.8 months, which was similar to that seen in a matched group of women (13.0 months, p=0.8) with the same age, breast cancer histology and grade, location of metastasis and adjuvant treatment.

One in four men with HR+/HER2- breast cancer (29/105, 27.6%) were treated with front-line chemotherapy. Their median progression-free survival was also similar to a matched group of women receiving chemotherapy (6.9 months vs 6.3 months, hazard ratio 1.24, 95% confidence interval 0.69-2.23). Overall survival for the whole population of men included in the database was also similar to that for women (41.8 months vs 34.9 months, p=0.745).

“We have reported on one of the biggest series of men with metastatic disease, with comprehensive data on their management and outcome with different types of treatment,” said study author Jean-Sébastien Frénel, from the Institut de Cancerologie de l'Ouest, Nantes, France.

“We found that most of the men with HR+/HER2- metastatic disease had received frontline chemotherapy and around 40% had received hormonal therapy. Most of the patients receiving hormonal therapy were treated with tamoxifen and the remainder received aromatase inhibitors. But few patients received aromatase inhibitors plus LHRH analogues despite some guidelines recommending that they should be given in combination.”

Frénel reported: “The progression-free survival provided by chemotherapy or hormonal therapy was similar in men as in women.” In terms of clinical implications, he suggested: “Hormonal therapy should be given to men with HR+/HER2- metastatic breast cancer in the absence of visceral crisis.” He added that oncologists should be aware that aromatase inhibitors should not be given without LHRH analogues. The study is continuing and will next assess the prevalence of BRCA mutation in the patient population.

Commenting on the findings for ESMO, Agnes Jager, medical oncologist and associate professor at Erasmus Medical University Cancer Institute, Rotterdam, The Netherlands said: “A recent study looked at tumour characteristics and outcome in a large cohort of men with primary breast cancer but such extensive data on advanced breast cancer in men was missing until now.”

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

Jager noted that although the largest study of its kind, the number of men with breast cancer was still small and data were lacking on the extent of advanced disease, BRAC mutation status and type of chemotherapy. However, she said: “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.”

Hormonal treatment

Results from the first prospective randomised trial to assess different hormonal treatments in men with breast cancer showed that levels of estradiol, a form of the hormone estrogen, decreased steeply with a gonadotrophin-releasing hormone analogue (GnRHa) plus tamoxifen or the aromatase inhibitor exemestane but increased with tamoxifen alone measured after a 6 months’ treatment period.

More than 90% of male breast cancer patients have HR+ disease. Tamoxifen is currently the standard of care hormonal therapy but there is limited data on its efficacy and safety in men and little information on other hormone-blocking treatments.

The Male-GBG54 trial randomised 55 men with breast cancer to hormonal therapy with one of three regimens as adjuvant or metastatic therapy for six months: tamoxifen (20 mg per day); tamoxifen + gonadotrophin releasing hormone analogue (GnRHa) (subcutaneous every 3 months); exemestane (25 mg/day) + GnRHa.

Tamoxifen blocks estrogen from attaching to hormone receptors on cancer cells while exemestane is an aromatase inhibitor that inhibits estrogen synthesis. The use of GnRH analogues in men with breast cancer is controversial but is based on reducing levels of testosterone when used in combination with aromatase inhibitors or antiandrogens.

Results reported at ESMO 2018 showed the median level of estradiol increased by 67% at three months and by 41% at six months in men treated with tamoxifen alone.  In contrast, estradiol levels decreased by 85% after three months in men treated with a GnRH analogue plus tamoxifen and by 73% in those receiving a GnRH analogue plus exemestane. Estradiol levels continued to be decreased at six months with GnRH analogues plus tamoxifen or exemestane. These therapies were well tolerated with no safety signals.

The researchers also assessed the impact of treatment on quality of life and sexual function in men with breast cancer treated with hormonal therapy for the first time, using a validated questionnaire (Aging Males’ Symptoms Scale Questionnaire) and assessment of erectile function (International Index of Erectile Function). Results showed that tamoxifen had little impact on health-related quality of life or erectile function in men with breast cancer while the combination of GnRH analogue plus exemestane had a major adverse effect on both measures.

Lead author Mattea Reinisch, from Klinikum Essen-Mitte, Essen, Germany, said: “We observed a deep and stable decrease of estradiol in patients receiving the combination of tamoxifen or an aromatase inhibitor plus GnRH for six months of therapy within the Male trial.

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

Reinisch added: “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.”

Commenting on the study, associate professor Agnes Jager said: “The authors are to be congratulated with a randomised 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. Although it is relevant to know whether and to what extent E2 levels change over time during different endocrine treatment strategies, as far as I know E2 suppression at 3 months is neither a validated nor a clinically useful surrogate endpoint for the efficacy of endocrine treatment.”

Jager added: “The finding that tamoxifen without an LHRH agonist led to a pronounced increase of E2 levels after 3 and 6 months of treatment is not new, although the degree of the increase is somewhat unexpected.” But she cautioned that the endpoint used in the study did not answer the question of whether an LHRH agonist should be added to tamoxifen in men and further research is needed on this. “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.”

Prolonging sensitivity to hormonal therapies

The cyclin dependent kinase 4 and 6 inhibitor (CDK4/6 inhibitor) ribociclib plus the aromatase inhibitor letrozole has comparable safety and tolerability as first-line therapy in men with HR+/HER2- advanced breast cancer to that seen in women, according to preliminary results from an international phase 3 trial reported at ESMO 2018.

Most patients with HR+ breast cancer become resistant to hormonal therapies over time so there is a lot of interest in finding treatments to prolong or restore sensitivity. Inhibiting the CDK4/6 has been identified as a potential target for overcoming or delaying resistance to hormonal therapy in advanced HR+/HER2-breast.

The CDK4/6 inhibitor ribociclib is approved for use in combination with an aromatase inhibitor for treating postmenopausal women with HR+/HER2- advanced breast cancer who have received no previous treatment for advanced breast cancer based on results from a trial showing significantly prolonged progression-free survival. However, men were not included in the study.

The international CompLEEment-1 trial included 20 men with HR+, HER2- advanced breast cancer in the first 1008 patients enrolled who completed 56 days of follow-up or discontinued before data cut-off. They were treated on an open-label basis with ribociclib (600 mg per day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day). Male patients also received concomitant goserelin (3.6 mg subcutaneous implant every 28 days). A pre-planned interim analysis was conducted approximately 15 months after the first patient’s first visit for the primary outcome of safety and tolerability.

Results reported at ESMO 2018 showed the most frequent adverse events in men were hot flushes (30.0%), neutropenia (20.0%) and constipation (20.0%). Adverse events of grade 3 severity or higher included neutropenia (4 patients, 20.0%), increased alanine aminotransferase (2 patients, 10%) and increased aminotransferase (1 patient, 5.0%). QT prolongation was infrequent, occurring in 3 men (15.0%) and all events were grade 1 or 2.

Just over one-third (35.0%) of men required dose reduction or interruption due to adverse events, while two men discontinued treatment due to adverse events.

“We can conclude in this sub-population of men that the tolerability and the expected toxicity with ribociclib in men is no different to women. And this increases our confidence in data obtained in large trials with women in order to translate the results and the applicability to men,” said lead author Claudio Zamagni, Head of Breast and Gynaecological Medical Oncology, Sant’Orsola Malpighi Hospital, Bologna, Italy.

The combination of hormonal therapy plus ribociclib should be considered as an option also for male patients with metastatic HR+ HER2- breast cancer,” he suggested. He noted that this was the first study to assess the safety of a CDK4/6 inhibitor in men, adding that efficacy data will be reported with longer-term follow-up in the future.

Commenting on the study, associate professor Agnes Jager considered that limitations were the small numbers and the lack of efficacy data at the time of reporting. She said: “As expected, there were no major differences in safety compared to previously published toxicity data for women, with the exception of the prevalence of neutropenia.” This was less frequent compared with female breast cancer patients in the MONALEESA 2 study (grade 3/4:  20.0% in men vs 59.3% in women).

Jager suggested that if similar results were shown in other studies, this could be of interest from a mechanistic point of view. “One of the explanations might be that there is a gender-dependent toxic effect on bone marrow. Alternatively, it could be a reflection of different plasma concentrations of ribociclib in men and women,” she suggested. If this were the case, efficacy could be lower in man. She continued: “The first step forwards is to compare the outcome between the men and women within the CompLEEment study, as well as cross-comparing with other studies in women.”

Summing up the three studies, Dr. Stefan Zimmerman, Centre Hospitalier Universitaire Vaudois, Switzerland, said: “Male breast cancer patients seem to benefit from endocrine therapy to a similar degree as women. Furthermore, 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. Lastly, 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.”