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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