1. May, Brandon

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Male breast cancer is a rare, often aggressive condition that typically presents itself in the late course of disease. Approximately 1 percent of all breast malignancies are found in the male patient (CA Cancer J Clin 2013;63(1):11-30). The rarity of the disease in this population has made it challenging to study, considering the etiology of male breast cancer has been difficult to elucidate.

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Review of SEER data indicates there has been an increase in the incidence of male breast cancer since the late 1970s to the early 2000s (1.0 per 100,000 men to 1.2 per 100,000 men, respectively) (Crit Rev Oncol Hematol 2010;73(3):246-254). A family history of breast cancer, environmental factors, hormonal changes, as well as gene mutations (i.e., BRCA) are likely contributors to breast cancer incidence in males (Cancer Radiother 2009;13:103-107, J Med Genet 2010;47:710-711). A review of 101 cases and 217 matched controls found that circulating estradiol levels are significantly associated with a high risk for breast cancer in men, with a similar association also found in female patients (J Clin Oncol 2015;33(18):2041-2050, J Mammary Gland Biol Neoplasia 2002;7(1):3-15).


Men are typically 5-10 years older than women at diagnosis, with an average age of 67 years at time of disease detection (Crit Rev Oncol Hematol 2010;73(3):246-254, Cancer Radiother 2009;13:103-107). Due to the lack of awareness of the potential for breast cancer in males, many patients are diagnosed in the late stages of disease, resulting in poorer prognosis compared with female patients (J Breast Health 2016;12(1):1-8). Spread of the disease to the lymph nodes is also more common in men and typically requires more aggressive treatment than in women. Additionally, disease spread tends to be associated with a higher risk for an additional carcinoma in the prostate, skin, or opposite breast compared with women (J Natl Cancer Inst 2002;94(17):1330-1332).


According to Louise A. Brinton, MPH, PhD, a recently retired leading researcher from the Division of Cancer Epidemiology and Genetics at the NCI, there are noticeable differences between women and men with regards to breast cancer.


"Although there are some similarities between male and female breast cancers, there are some notable differences," explained Brinton, "including a propensity for male breast cancers to be detected at later stages and for them being most commonly ER+."


Molecular Characteristics

In a large genomics study led by Suleiman Alfred Massarweh, MD, investigators examined the molecular characteristics of male breast cancer (J Clin Oncol 2018;36(14):1396-1404). This new study represents an innovative piece of research with regard to its level of granularity. Typically, studies on breast cancer focus primarily on women or blur the lines between the two sexes, he noted, and these studies may not result in findings that can be fully extrapolated to men in clinical practice.


In Massarweh's study, researchers compared men (n=3,806) and women (n=571,115) in terms of genetic expression for estrogen and its association with breast cancer recurrence, as well as 5-year breast cancer-specific survival (BCSS) and overall survival (OS). Men demonstrated higher expression for the estrogen receptor (ER), proliferation, and invasion groups. In the analysis of males only, participants aged <50 years showed lower ER and progesterone receptor compared with older patients. Additionally, the BCSS and OS were lower in male breast cancer patients than women patients.


"This study is definitely not the last-ditch effort [to determine molecular characteristics of male-dominated breast cancer], but it gives us a good idea to help manage men with more specificity," said Massarweh. "When we look at outcomes, we see that men do comparable to women in risk scores of low-risk disease; but in high-risk disease, they have worse outcomes related to breast cancer." With regard to how clinicians treat men with breast cancer, many treatment options include the use of aromatase inhibitor therapy (e.g., anastrozole and letrozole). In metastatic breast cancer, however, the impact these inhibitor medications have on improving outcome and overall survival has yet to be fully elucidated. Despite the clinical benefit associated with this treatment protocol in women, it's unsure whether or not it achieves particularly high OS outcomes in male patients.


Treatment Considerations

"Men are more like pre-menopausal women and should be treated as such in regard to their carcinoma," explained Massarweh. "The data are more robust in women regarding outcomes, [so] there's not enough research or guidance on how to treat [male] breast cancer, which may explain the poor outcomes in high-risk male patients." He further compares men and women in terms of the hormonal factor behind the disease and its impact on treatment choice: "Hormonal physiology in men resembles pre-menopausal women because of the presence of gonadal function, as opposed to postmenopausal women who no longer have gonadal function because of menopause. This means that use of unopposed aromatase inhibitors in men instead of tamoxifen would be ineffective and possibly counterproductive."


Massarweh emphasizes the need for de-escalation of therapy in males, even if nodes are positive and risk scores are low. "For patients who have a high-risk score, the answer is not chemotherapy," he added. "There is a lot of over-treatment in breast cancer, so we need to focus on de-escalating therapy, which is appropriate for many patients," he explained. "Chemo is not always the right answer, so we need to focus on research that looks at de-escalating and the quality of therapy, as well as studies that look at optimizing care and reducing costs."


The treatment approach for metastatic breast cancer in both men and women is typically built on similar foundations. In approximately 5-15 percent of cases, metastasis can be detected at the time of a breast cancer diagnosis (J Breast Health 2016;12(1):1-8). Tamoxifen is commonly used in HR-positive tumors in males, considering the response rate to hormone therapy ranges between 25 percent and 58 percent (Ann Intern Med 1992;117(9):771-77). Male HR-negative patients who present with a rapidly progressing visceral disease are often recommended systemic chemotherapy (J Breast Health 2016;12(1):1-8).


Management Challenges

"People don't even know that men can get breast cancer and there's a stigma associated with having the disease," noted Massarweh. In clinical practice, it's common for male patients who have or are suspected of having breast cancer to feel awkward when discussing their concerns with their doctor.


"Given that male breast cancer is so much rarer than female breast cancer and it is not commonly screened for, it is often a missed diagnosis, leading to later stages at detection," added Brinton. "There may also be some cultural and sociological ramifications of a diagnosis in men given that it so rarely encountered."


Few clinical trials are developed that focus specifically on males, primarily due to the low number of patients available to enroll and the difficulty in successfully recruiting and retaining participants. In studies that do include males, many may drop out due to disinterest or lack of perceived benefit. "There's nothing in it for them, so some patients may drop out. We have nothing tailored to males," said Massarweh.


Despite the lack of studies available, there seems to be an increase in the number of male breast cancer patients each year. "There's progressively more patients being seen every year," he added, "and many patients are not being seen by an endocrinologist at the beginning." Due to the lack of awareness around the risk of male breast cancer, many patients are diagnosed in the advanced stages of disease, consequently resulting in worse prognosis overall.


Advancements in Research & Care

"There are some interesting and really cool things happening in current research," noted Massarweh, "the most interesting of which is the use of circulating tumor DNA for identifying new and effective targets for therapy." His statements echo that made by other researchers in the field who are actively evaluating the utility of circulating tumor cells (CTCs) for early breast cancer management in the male and female patient (In Vivo 2014;28(4):605-614, J Cancer Res Clin Oncol 2015;141(1):87-92).


A simple blood test can detect CTCs, subsequently assisting clinicians in predicting prognosis and clinical outcome in both metastatic and non-metastatic breast cancer (Crit Rev Oncog 2016;21(1-2):125-139). Additionally, evaluating CTCs may extend beyond its potential prognostic capability into predicting an individual's response to therapy, further improving breast cancer management by aiding in risk stratification and treatment optimization (Ther Adv Med Oncol 2010;2(6):351-365).


A case report by Paola Gazzaniga, et al, in 2011 analyzed CTC in a blood sample of a male breast cancer patient, finding that the patient was possibly resistant to anthracycline-taxane-based chemotherapy (Cancer Biol Ther 2011;12(5):379-382). The finding "was consistent with the rapid progression of disease after three courses of epirubicin-docetaxel chemotherapy" and demonstrated the utility of CTCs in predicting treatment response in male breast cancer. Additional blood samples and CTC assessments also showed the patient to be sensitive to a carboplatin-gemcitabine treatment regimen based on "the negative expression of multidrug resistance-associated protein 5 and positive expression of human equilibrative nucleoside transporter 1 on CTCs." The researchers concluded that assessment of CTCs may in fact hold clinical benefit in male patients with breast cancer.


Few clinical trial data are available to suggest that CTCs may conclusively help in the management of breast cancer in all men affected by the disease, but one study shows that the prevalence of CTC in the blood, as well as disseminated tumor cells in bone marrow, are similar to those observed in female breast cancer (J Cancer Res Clin Oncol 2015 Jan;141(1):87-92). Considering the research involving CTCs in predicting prognosis (e.g., metastatic spread) and treatment response is more robust as well as promising in terms of outcomes in female breast cancer patients, it's possible that these findings can be generalized to the male patient population (Breast Cancer Res 2014;16(5):440, Sci Rep 2017;7:43464). Despite the wealth of research available on evaluating CTCs as an independent prognosticator, however, it's unclear whether CTCs can be reliably used as a predictive marker for treatment outcomes in all patients (J Natl Compr Canc Netw 2013;11(8):977-985).


According to Massarweh, the future of clinical care in male breast cancer appears promising, but only if practices can evolve to meet the cultural, social, psychological, and physical characteristics that are specific to men. "We would like to have a practice carved out specifically for men with breast cancer," he said, "and we want to be able to see men with breast cancer in an environment that's conducive for collecting data, outcomes analysis, genomics work, and clinical trials. We could attract patients from all over and do some collaboration with others." This collaboration, he said, may involve reaching out to small practices to gather data and conduct wider-scaled analyses on a more heterogeneous patient population.


Brandon May is a contributing writer.


2018 Statistics of Male Breast Cancer

New cases: 2,550


Deaths: 480


Age of Detection: 60-70 years of age


Incidence: 1% of all breast carcinomas


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