Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

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Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

Male breast cancer is a rare condition, with limited prospective studies and clinical trials often excluding men.

Treatment recommendations for breast cancer are mostly based on clinical trials involving female patients.

In the past decade, efforts have been made to better understand the biological characteristics, most effective treatments, and outcomes of male breast cancer, highlighting the clinical differences based on gender.

In June 2018, the prestigious New England Journal of Medicine (NEJM) published a comprehensive review titled “Breast Cancer in Men” by the MD Anderson Cancer Center in the United States.

Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

The review delves into the current epidemiology, pathological and clinical features, prognosis, and treatment data of male breast cancer, emphasizing the latest advancements in our understanding of this disease.

Epidemiology and Risk Factors

While male and female breast cancers share some similarities, male breast cancer has distinct characteristics, as summarized in Table 1.

It represents approximately 1% of all breast cancers, with an estimated 2,500 diagnosed cases and around 500 deaths projected in the United States in 2018.

The age-adjusted incidence of male breast cancer has steadily increased from 0.85 per 100,000 men in 1975 to 1.43 per 100,000 men.

Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

Table 1 – Main characteristics of male and female breast cancer

The lifetime risk of male breast cancer is about 1 in 1,000, significantly lower than the 1 in 8 risk for females. Similar to many cancers, male breast cancer is age-related, with an increased incidence as men age.

The average age at diagnosis for men is approximately five years older than for women (67 years vs. 62 years), and Black men have a higher risk compared to non-Hispanic White men.

A family history of the disease doubles the risk for men. Table 2 outlines the risk factors for male breast cancer.

Male Breast Cancer: Rare but Underdiagnosed with Poorer Prognosis

Table 2–Male breast cancer risk factors

Clinical Presentation and Assessment

Most male breast cancer patients present with painless, palpable masses behind the nipple. Other symptoms may include nipple retraction, nipple discharge, skin ulcers, and palpable lymph node enlargement in the axilla. Differential diagnosis often includes gynecomastia, a prevalent condition. Breast imaging is recommended if cancer is suspected, with ultrasound recommended as the initial examination for men under 25 with palpable masses. For men over 25 or those with uncertain physical examination findings, mammography is recommended as the initial diagnostic test, with ultrasound as follow-up if results are inconclusive or suggest cancer. Male breast cancer typically appears on mammography as eccentric, protuberant, and irregularly shaped masses.

Due to low public awareness and the absence of screening programs, male tumors may be larger than those in females and more likely to have local lymph node involvement.

Given the association of male breast cancer with germline BRCA gene mutations, all male breast cancer patients should be referred to cancer genetics experts for genetic testing.

(Note: Germline mutations refer to mutations occurring during the formation of gametes and are inheritable, while somatic mutations are not inheritable.)

Pathological Features

As breast X-ray screening is not routinely recommended for the general male population, only about 10% of male breast cancers are ductal carcinomas, and lobular carcinoma in situ is rare. The majority of male breast cancers are invasive ductal carcinomas, the most common histological type. Uncommon histological subtypes in men include papillary carcinoma (2%-3%) and mucinous carcinoma (1%-2%). While lobular carcinomas constitute approximately 12% of invasive breast cancers in women, they are less prevalent, accounting for only 1%-2% in men.

Overall, male breast cancer is more likely to be estrogen receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative compared to female breast cancer. However, the incidence of these markers is similar to postmenopausal women of older age. In an international study of 1,483 male breast cancer tumors, 99% were positive for estrogen receptor, 82% for progesterone receptor, and 97% for androgen receptor. Only 9% were HER2-positive.

The study also evaluated breast cancer subtypes using immunohistochemical surrogates: 42% were luminal A, 49% were luminal B and HER2-negative, 9% were HER2-positive, and less than 1% were triple-negative (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative). Other studies have indicated that the genomic spectrum of male breast cancer is mostly luminal A or luminal B.

While some somatic mutations found in male breast tumors resemble those in estrogen receptor-positive breast tumors in women, the frequency of these mutations differs. Male tumors are less likely to exhibit 16q loss, PIK3CA mutations, and TP53 mutations. Additionally, male breast cancer is more likely to have somatic mutations affecting genes related to DNA repair and less likely to have mutations affecting the PI3K-AKT-mTOR pathway. Gene expression studies reveal two unique breast cancer subgroups in men: M1 and M2, distinct from intrinsic subtypes seen in female breast cancer. These findings suggest potential clinical significance in the biological differences between male and female breast cancer.\

Prognosis

Several studies have assessed the prognosis of male breast cancer, generally showing lower overall survival rates for men compared to women with breast cancer. This is largely attributed to later diagnoses, older age at discovery, and shorter life expectancy for men in general.

In a study of male breast cancer patients in Europe and Asia, the 5-year survival rate for men was lower than that for unadjusted women, but after adjusting for demographic characteristics, disease stage, and treatment, the survival rate was higher for men. Results for Black male breast cancer patients were worse than for White male patients, but this difference diminished after adjusting for insurance coverage and income.

Survival rates are lower for older men, those with advanced disease, and those with triple-negative breast cancer compared to younger men, early-stage patients, and those with non-triple-negative subtypes. Improvements in survival rates for male breast cancer patients have occurred, but the progress lags behind that for female patients.

Similar to female breast cancer, male breast cancer patients have an increased risk of developing a second primary cancer compared to unaffected individuals. The absolute risk of a second breast cancer in affected men is slightly less than 2%. Affected men also have an increased risk of melanoma, small intestine cancer, colorectal cancer, pancreatic cancer, prostate cancer, and hematologic malignancies. It is currently unclear whether these increased risks are due to potential mutations such as BRCA2, increased vigilance in detection, or other factors.

Treatment of Male Breast Cancer

The treatment methods for male breast cancer are primarily inferred from studies on the treatment of breast cancer in females. While females with newly diagnosed breast cancer often undergo breast-conserving therapy, the majority of males undergo mastectomy followed by axillary lymph node dissection or sentinel lymph node biopsy. Even in early-stage male breast cancer patients, breast-conserving therapy is uncommon, with only 18% of T1N0 early-stage male breast cancer patients undergoing breast-conserving surgery, according to the Tumor, Node, Metastasis (TNM) staging system.

Although less common, observational studies suggest a correlation between breast-conserving therapy and survival rates, indicating that data from female surgical trials can be safely applied to males. Additionally, breast-conserving therapy may improve cosmetic and functional outcomes. Sentinel lymph node biopsy, a standard approach for clinically node-negative females, appears feasible and accurate in male breast cancer.

Guidelines developed for female breast cancer should also be followed to provide adjuvant radiotherapy. However, in practice, radiotherapy is often underutilized in male breast cancer patients. Data from the Surveillance, Epidemiology, and End Results (SEER) program for the period 1988-2012 indicates that only 42% of stage I male breast cancer patients received radiation therapy after breast-conserving surgery.

Internationally, a similar trend is observed. Between 1990 and 2010, nearly half of males treated with breast-conserving surgery did not receive radiation therapy. While no randomized trials have assessed the role of post-mastectomy radiation therapy in male breast cancer, observational studies suggest benefits for males with lymph node-positive breast cancer.

According to national treatment guidelines developed for female breast cancer, male breast cancer patients should receive adjuvant or neoadjuvant chemotherapy and HER2-targeted therapy, especially considering their high risk of recurrence and death. Studies show improved survival rates for males receiving adjuvant chemotherapy. Clinicians should be aware that males are often diagnosed at older ages with shorter life expectancies than females when evaluating the risks and potential benefits of chemotherapy.

Genomic testing, such as the 21-gene recurrence score testing (Oncotype DX and MammaPrint), is increasingly used to determine prognosis and the likelihood of chemotherapy in female breast cancer. Results of Oncotype DX testing have been reported in male breast cancer patients, indicating its prognostic value in males.

Although genes related to estrogen receptors, proliferation, and invasion show greater average quantitative gene expression in males compared to females, the overall average recurrence scores are similar between genders. However, males with recurrence scores above 31 are more prevalent than females (12% vs. 7%), and males with scores below 11 are also more common (34% vs. 22%). High recurrence scores in males are associated with worse outcomes, but this group is relatively small (42 individuals) and must be considered cautiously.

Since most male breast cancers are hormone receptor-positive, endocrine therapy is a crucial component of cancer treatment. Tamoxifen is the standard adjuvant endocrine therapy for hormone receptor-positive male breast cancer, administered for 5 to 10 years. Tamoxifen has demonstrated efficacy in metastatic cancer patients, and observational studies on adjuvant tamoxifen therapy suggest survival benefits. Side effects in males may include venous thrombosis, cataracts, sexual dysfunction, mood changes, hot flashes, and leg cramps. Limited research has specifically compared the side effects of tamoxifen between males and females.

The efficacy of aromatase inhibitors in males is unclear and may be lower than in females. Population-based series studies indicate lower survival rates for males receiving adjuvant aromatase inhibitor therapy compared to tamoxifen. Aromatase inhibitor effects on hormone levels in males have been assessed in several studies, revealing significant reductions in estradiol levels and increases in testosterone levels. However, the lack of complete estrogen suppression in males using aromatase inhibitors is attributed to feedback loops in the hypothalamus and pituitary, which can be overcome by adding gonadotropin-releasing hormone (GnRH) analogs. For males not suitable for tamoxifen due to previous thrombosis, GnRH analogs can be used as adjuvant therapy, with or without aromatase inhibitors. However, single-agent aromatase inhibitor therapy is not considered a standard adjuvant treatment.

While data on the efficacy of specific hormone therapies are limited, the treatment of metastatic male breast cancer generally reflects the approaches used in females. Early studies explored surgical methods, including orchidectomy, adrenalectomy, and hypophysectomy, but these procedures led to severe morbidity and are no longer commonly used.

Current approaches to treating metastatic male breast cancer with endocrine therapy involve the same drugs used for metastatic female breast cancer, including tamoxifen, aromatase inhibitors, and fulvestrant. Clinical responses have been reported for single-agent aromatase inhibitors and aromatase inhibitors plus GnRH analogs, with the latter potentially being the preferred approach. Fulvestrant, a selective estrogen receptor downregulator, has demonstrated activity in hormone receptor-positive metastatic male breast cancer. A summary analysis of 23 males treated with fulvestrant (without GnRH analogs) showed partial relief in 26%, stable disease in 48%, comparable to females.

Although the summary analysis suggests the efficacy of fulvestrant as a single agent, data comparing the efficacy of fulvestrant alone versus fulvestrant combined with GnRH analogs are unavailable. While adding cyclin-dependent kinase (CDK) inhibitors or mTOR inhibitors to endocrine therapy significantly improves prognosis in female breast cancer patients, data for treating male breast cancer with these combinations are lacking. Nevertheless, NCCN guidelines recommend treating males similarly to postmenopausal females, with caution that aromatase inhibitors alone may be less effective than aromatase inhibitors plus GnRH analogs. Therefore, using CDK inhibitors or mTOR inhibitors as part of combination endocrine therapy is a reasonable approach for metastatic male breast cancer.

Follow-Up After Treatment

In general, post-treatment care for male breast cancer should resemble the care provided for female breast cancer. However, due to the low incidence of second primary tumors and the lack of imaging recommendations for male BRCA mutation carriers, the utility of mammography for breast cancer screening has not been established, and imaging may not be necessary. Males receiving GnRH analog therapy face an increased risk of osteoporosis, and NCCN recommends bone density assessments every two years for such patients. Hot flashes are a common side effect of GnRH analogs and tamoxifen. Venlafaxine can be considered for relief in males undergoing treatment for breast cancer, effectively reducing hot flashes in prostate cancer males receiving GnRH analogs.

Future Directions

There is still a significant gap in our understanding of male breast cancer, and efforts should focus on preventing undertreatment of this condition.

Better understanding the biological characteristics of the disease is crucial, particularly in differentiating between male and female breast cancer and determining whether these differences have therapeutic significance.

The International Male Breast Cancer Program has collected samples from over 1400 male breast cancer patients and is currently undergoing further analysis, including RNA sequencing studies. This international project’s overall goal is to conduct therapeutic clinical trials focused on male breast cancer.

Other clinical trials are ongoing, including the study of the safety and efficacy of oral selective CYP17 lyase inhibitors and androgen receptor blockers in male breast cancer patients (ClinicalTrials.gov identifier: NCT02580448).

A German phase II clinical trial includes 55 males comparing tamoxifen, tamoxifen plus GnRH analogs, and aromatase inhibitors plus GnRH analogs (NCT01638247).

Although most treatment trials were previously limited to female breast cancer patients, many trials are now recruiting both males and females.

Breast cancer treatment research should be open to both genders whenever feasible to establish an evidence base supporting future treatment recommendations.

Recent efforts suggest that clinical trials for male breast cancer treatment are feasible and essential for improving standards of care for male breast cancer.

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