US Pharm. 2008;33(10)(Oncology suppl):15-23.

ABSTRACT: Male breast cancer is an uncommon but potentially deadly disorder. One man for every 100 women is affected. There were approximately 2,000 cases in 2007, with 450 deaths. Male breast cancer is diagnosed and treated much like female breast cancer, with surgery the primary treatment. Other treatment modalities include radiation, hormone therapy with tamoxifen or aromatase inhibitors, biological agents such as trastuzumab, and chemotherapy with agents such as doxorubicin and paclitaxel. Because male breast cancer often metastasizes to the bone, bisphosphonates are used to prevent skeletal problems and alleviate pain. Survival is based on the extent of the cancer's invasiveness (staging).

Breast cancer is thought of as a woman's disease; however, men's breast tissue also can undergo cancerous alterations. The disease is rare in men, representing less than 1% of all cancers in the male population.1 Not too many years ago, male breast cancer was believed to have a poor prognosis; newer studies, however, have shown that the prognosis is similar to that for women at any given stage. Knowledge of the signs and symptoms of breast cancer may lead to earlier detection and diagnosis, which, in turn, offers the opportunity for more treatment options and a better chance of survival. The problem is that men typically put off seeking treatment, resulting in poorer survival statistics. This circumstance may be due to denial of the growth's existence, as well as lack of awareness that breast cancer can develop in men.

Epidemiology
The average age for the development of breast cancer in men is 68 years, versus 61 years in women.2-4 According to 2007 cancer statistics, 2,030 cases of breast cancer were reported in men, compared with 178,480 cases in women.5 These cases were responsible for 450 deaths in men in 2007 versus 40,460 deaths in women.5 The mortality rate for male breast cancer is higher in black men than in white men, even after adjustment for demographic and treatment factors.6 The female-to-male ratio in the United States is usually about 100 to 1.3 The incidence of male breast cancer varies by ethnic and national origin.2

Risk Factors
Family history of breast cancer is a major risk factor for men. From 15% to 20% of men with breast cancer have a family history, compared with 7% of the general population.3 The BRCA2 gene mutation confers significant risk, but the BRCA1 mutation does not seem to increase the risk in men as it does in women.7 There are other genetic mutations that predispose men to breast cancer.8 Another risk factor involves estrogen and androgen imbalance, or the ratio of male to female hormones in the body.8 Other risk factors are testicular defects or injury, infertility, obesity, cirrhosis, breast trauma, gynecomastia, increasing age, Jewish ancestry, chest radiation (particularly before age 30), and estrogen exposure. Exogenous hormone therapy, such as in the treatment of prostate cancer, does not appear to be associated with increased risk.8 Klinefelter's syndrome, a rare genetic condition occurring in 1 of every 850 males born with two or more X chromosomes, can cause gynecomastia and also increases the risk of breast cancer; in fact, men with Klinefelter's syndrome have a breast cancer rate approaching that of women.9

Types of Breast Cancer
More than 90% of all cases of male breast cancer are invasive ductal or unclassified carcinomas, whereas in women the frequency of ductal histology is 70% to 75%.10 Infiltrating ductal carcinoma is a cancer that has spread beyond the cells lining the ducts of the breast. Infiltrating lobular carcinoma is exceedingly rare in men, probably due to the existence of less glandular tissue in male breasts.10 Inflammatory breast cancer makes the breast appear red, swollen, and warm. Paget's disease of the breast is a tumor that involves the areola and the surface of the nipple.11 Ductal carcinoma in situ, also called intraductal carcinoma, is also seen in men; it is the earliest stage of breast cancer, confined to just the affected breast ducts.1

Signs and Symptoms
Male breast cancer is most commonly found through the discovery of a lump or thickening in the breast similar to that occurring in women. Usually this abnormal lump is painless and found accidentally. Other symptoms include skin dimpling or puckering, nipple discharge, development of a retraction of or indentation in the nipple, and changes in the nipple or breast skin, such as scaling or redness.1 Another breast abnormality is gynecomastia, which occurs in roughly a third of males.12 This enlargement of breast tissue may occur in one or both breasts (i.e., either asymmetrically or bilaterally) and is often due to benign causes, although rarely it may indicate a malignancy in the breast.12

Diagnosis
A lump or abnormality felt or seen in the breast should be brought to the attention of an experienced physician. A clinical breast examination should be performed, along with a complete physical. Diagnostic mammography may be helpful in some cases. Additional tests, like ultrasound, MRI, and nipple-discharge examination, may also be ordered. If the tests reveal the possibility of cancer, a breast biopsy is necessary.1 Options are fine-needle aspiration biopsy (in which a small amount of tissue or fluid is removed using a thin needle) and core biopsy (in which breast tissue is removed using a wide needle). Frequently, excisional biopsy (which removes the entire lump or tissue) is performed. An estrogen receptor (ER) and progesterone receptor (PR) test may be performed to measure the amounts of ER and PR present. These tests can show whether hormonal therapy may be used to stop the cancer's growth.1 Human epidermal growth factor receptor (HER) 2/neu is a growth factor protein that sends growth signals to cancer cells, telling them to replicate and spread. The HER 2 test measures the amount of HER2/neu-type protein on the surface of the cancer cells and is helpful for determining whether a monoclonal antibody drug may be used to fight this type of cancer.13

Staging
Stage 0 cancers, also called noninvasive or in situ, have not spread to other parts of the body or invaded normal breast tissue. It is important to have these cancers removed early for the best chance of survival. Cancers that are stage I through IV are invasive and have the ability to spread to other areas of the body.14 (See TABLE 1 for prognosis based on stage.) Initially, breast cancer cells spread via the lymphatic system to local and regional lymph nodes. From there, the cells metastasize through the bloodstream to distant sites, particularly the bones (especially the spine), lung, liver, central nervous system (both brain and spinal cord), and skin.14



Treatment
Surgery: Surgery remains the initial and primary treatment for breast cancer. After biopsy has established a diagnosis of breast cancer, stage I and II patients may be treated with modified radical mastectomy, which involves mastectomy with axillary-node sampling and, if positive, axillary-node dissection.1,3

Radiation Therapy: Radiation therapy uses high-energy x-rays to kill cancer cells and shrink tumors. Radiotherapy also is used for adjuvant or preventive intent after mastectomy in patients with locally advanced tumors or a large number of involved axillary nodes.1,14

Even in the early stages of the disease, cancer cells can metastasize. These cells usually do not cause symptoms, do not show up on x-rays, and cannot be felt during a physical examination. If left untreated, however, they can establish new tumors elsewhere in the body. Systemic treatment of patients who have no evidence of cancer spread but are at risk for developing it is called adjuvant therapy. The goal of adjuvant therapy is to kill undetected cancer cells that have traveled from the breast. Adjuvant therapy such as radiation and chemotherapy may be used when the cancer is locally advanced or has spread to one or more lymph nodes.15

Hormonal Therapy3,15: The presence of ERs and PRs-- intracellular receptors that selectively bind to estrogen and progesterone--in breast cancer cells has considerable implications for treatment of the disease. The presence or absence of these receptors gives insight into the biological behavior of the cancer and potential responsiveness to hormonal therapy. About 76% of male breast cancers are ER-positive (sensitive) and 83% are PR-positive.16 As in women, male breast cancers that do not express these receptors (ER/PR-negative) are considered more aggressive and unresponsive to hormonal therapy.

Several classes of hormonal agents are used in the treatment of male breast cancer. One of the most widely used agents is tamoxifen, which belongs to a class of drugs known as selective estrogen receptor modulators. Tamoxifen can act as an agonist or as an antagonist, depending on the type of tissue involved. In the breast, tamoxifen is an estrogen antagonist, which is why it is the treatment of choice for most men with hormone receptor (HR)–sensitive breast cancer. In adjuvant treatment, 20 mg of tamoxifen is taken orally for approximately five years. Common side effects include fatigue, hot flashes, and impotence. More severe effects are cataracts and thromboembolic events such as deep venous thrombosis and pulmonary embolism.

While tamoxifen is the standard treatment, other hormonal classes may be used. These include the aromatase inhibitors, luteinizing hormone-releasing hormone (LHRH) agonists, and megestrol. Aromatase inhibitors (e.g., anastrozole, exemestane, letrozole) block the conversion of testosterone to estrogen. They are used to treat hormone-sensitive breast cancer in postmenopausal women. A few case reports have been published, but the role of aromatase inhibitors in male breast cancer has not been established. Side effects include arthralgias, myalgias, osteoporosis, and bone fractures.

Androgens play a role in the growth of male breast cancer. The use of LHRH agonists such as leuprolide and goserelin effectively reduce the spread of cancer. These agents affect the pituitary gland and cause the testes to decrease their production of androgens. LHRH agonists are administered by injection, with the frequency depending on the formulation. Several current clinical trials are investigating the use of aromatase inhibitors with LHRH agonists in male breast cancer.

Megestrol is a synthetic oral progestin that may be used in the treatment of male breast cancer. Its mechanism of action in breast cancer remains to be clarified. Side effects include blood clots and weight gain from increased appetite. With the availability of other hormonal agents, it is now used rarely and only after other agents have been tried.

Biological Therapy17: In addition to hormonal status, male breast cancers are screened for the expression of HER2. This receptor is involved in the growth of cancer cells. Recent data suggest that there is a smaller percentage of HER2 overexpression in male breast cancer than is seen in female breast cancer. Therapies commonly used in women with HER2 overexpression are trastuzumab and lapatinib. Although no randomized trials investigating these agents in male breast cancer have been published, their use is based on their success in women. Trastuzumab is a monoclonal antibody that is given IV. Side effects are uncommon, but may include cardiotoxicity (decreased ejection fraction and heart failure), fever, chills, nausea and vomiting, weakness, diarrhea, and headache.18 Cardiac-function tests should be performed prior to instituting trastuzumab, especially if the patient receives an anthracycline-based (e.g., doxorubicin) chemotherapy regimen. Lapatinib, an oral drug, also targets the HER2 protein. It is given along with the oral chemotherapy drug capecitabine. This combination is currently recommended for metastatic breast cancer in women who are no longer responding to trastuzumab and other chemotherapy.19 The most common side effects of lapatinib are diarrhea, dizziness, rash, and hand–foot syndrome (which may lead to numbness, tingling, redness, swelling, and discomfort in the hands and feet). In rare cases, it may cause a decrease in heart function that leads to shortness of breath, but this seems to go away once treatment is finished. Clinical trials are currently investigating both of these agents in male breast cancer.

Chemotherapy20: Chemotherapy is the main treatment modality after surgery in male breast cancer. Systemic chemotherapy is used in both early-stage and late-stage breast cancer. In early breast cancer, it is often given as adjuvant therapy postmastectomy to patients with a significant risk of future recurrence. The most commonly used combinations of adjuvant chemotherapy drugs are given in TABLE 2. Most regimens contain an anthracycline-type drug (e.g., doxorubicin) and a taxane (e.g., docetaxel). The treatment of stage IV breast cancer consists of the use of combinations of drugs (TABLE 2) as well as single agents. Other chemotherapies used in metastatic disease are vinorelbine, gemcitabine, and capecitabine. Chemotherapy cycles often are administered every two or three weeks. Patients may receive anywhere from four to eight cycles of these regimens, depending on their response and the specific regimen chosen. Currently, initiation of chemotherapy is recommended when the breast cancer is larger than 1 cm, is HR-negative, has positive nodes, or has metastasized.



The severity and duration of side effects depend on the dose of the drug, the length of treatment, and prior chemotherapy treatments. These side effects are usually short-term and subside after treatment is completed. In addition to the common side effects, there are some rare side effects associated with chemotherapy. Because anthracyclines such as doxorubicin have the potential to cause long-term heart damage, preliminary tests including echocardiograms and ejection-fraction tests are done prior to and during therapy. Anthracyclines typically are discontinued when the left ventricular ejection fraction is less than 40%. There is also an increased risk of leukemia, primarily acute myelogenous leukemia. This typically occurs within 10 years of receiving chemotherapy and is associated with a poor prognosis.

Bisphosphonates: Breast cancer often metastasizes to the bone. Patients usually experience painful skeletal events such as fractures, spinal cord compression, and hypercalcemia of malignancy.19 Intravenous bisphosphonates are used to reduce the incidence of skeletal events and help alleviate the pain of bone disease. Zoledronic acid and pamidronate are given monthly once bone metastases are identified.21 They are administered IV over 15 minutes and two hours, respectively. Oral bisphosphonates are not used because of poor bioavailability.21

Pharmacist Involvement
Although the incidence of male breast cancer is low, it is important to recognize the risk of developing this condition, especially with advancing age.3 With early diagnosis, better prognosis can be expected, depending on the stage of the disease. Unless men are aware that they can develop breast cancer, they may fail to recognize the signs or seek medical advice. A man can easily assume that a growth in his breast is something else if he thinks that only women can develop breast cancer. Pharmacists can help educate patients about male breast cancer, its epidemiology, and its presentation.

Pharmacists should counsel patients being treated for male breast cancer about the drugs' side effects (e.g., mouth sores, loss of appetite, nausea and vomiting, fatigue) and how to minimize these effects. For example, nausea and vomiting can be minimized by eating bland foods and smaller meals. Treatment of nausea and vomiting within the first 24 hours of chemotherapy should include a 5-hydroxytryptamine (5HT)-3 antagonist (such as ondansetron), dexamethasone, and an agent for breakthrough nausea and vomiting to be used as needed.22 The 5HT-3 antagonists are not appropriate for delayed (more than 24 hours postchemotherapy) nausea and vomiting; agents such as metoclopramide, prochlorperazine, and promethazine are more appropriate.22 Pharmacists should counsel patients on the use of their nausea medication as well as on any resultant side effects, such as dizziness or drowsiness.

Patients taking aromatase inhibitors have the potential for bone injuries such as fractures. Pharmacists should counsel patients about taking supplemental calcium and vitamin D if dietary intake is inadequate. Patients receiving tamoxifen should be monitored and advised that taking the drug for more than five years has not been shown to confer any added benefit in women.



Conclusion
No large-scale trials have specifically studied the treatment of male breast cancer, which limits knowledge of this gender-dominated disease. Nonetheless, physicians have been using data gathered from studies in women and extrapolating these treatment protocols to men. Despite some small differences between male and female breast cancer, these treatment regimens seem to be effective in men.

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