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BRCA1, BRCA2, AND HEREDITARY BREAST-OVARIAN CANCER

SYNDROME
Diperkirakan 5 10% karsinoma mammae berkaitan dengan genetic.
Terutama pada wanita dengan onset awal karsinoma mammae (usia 40
tahun atau lebih muda), hamper 10% memiliki mutasi germline padagen
BRCA1 atau BRCA2.
Mutasi yang lebih umum terjadi pada wanita yang me
It is estimated that 5 to 10% of breast cancers are hereditary. Of women
with early-onset breast cancer (aged 40 years or younger), nearly 10%
have a
germline mutation in one of the breast cancer genes BRCA1 or BRCA2.42
Mutation carriers are more prevalent among women who have a first- or
seconddegree
relative with premenopausal breast cancer or ovarian cancer at any age.
The likelihood of a BRCA mutation is higher in patients who belong to a
population in which founder mutations may be prevalent, such as in the
Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the
cumulative
risks of developing breast cancer and ovarian cancer by age 70 have been
estimated to be 87 and 44%, respectively.43 The cumulative risks of
breast cancer
and ovarian cancer by age 70 in families with BRCA2 mutation have been
estimated to be 84 and 27%, respectively.44 Although male breast cancer
can occur
with either BRCA1 or BRCA2 mutation, the majority of families (76%)
with both male and female breast cancer have mutations in BRCA2.44
Besides breast
and ovarian cancer, BRCA1 and BRCA2 mutations may be associated with
increased risks for several other cancers. BRCA1 mutations confer a
fourfold
increased risk for colon cancer and threefold increased risk for prostate
cancer.43 BRCA2 mutations confer a fivefold increased risk for prostate
cancer,
sevenfold in men younger than 65 years.45 Furthermore, BRCA2
mutations confer a fivefold increased risk for gallbladder and bile duct
cancers, fourfold
increased risk for pancreatic cancer, and threefold increased risk for
gastric cancer and malignant melanoma.45
BRCA1 was the first breast cancer susceptibility gene identified and has
been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly
afterward.
BRCA1 and BRCA2 encode for large nuclear proteins, 208 kDa and 384
kDa, respectively, that have been implicated in processes fundamental to
all cells,

including DNA repair and recombination, checkpoint control of the cell

cycle, and transcription.46 Although early studies suggested that the two
proteins
function together as a complex, subsequent data demonstrated that they
have distinct functions.47,48 In fact, breast cancers arising from BRCA1
or BRCA2
mutations are different at the molecular level and have been found to
have distinct gene expression profiles.49BRCA1-associated tumors are
more likely to be
estrogen receptor negative, whereas BRCA2-associated tumors are more
likely to be estrogen receptor positive. Currently, studies are ongoing to
determine
whether BRCA1 and BRCA2 status can be used to guide systemic therapy
choices for breast cancer.

Male Breast Cancer

Fewer than 1% of all breast cancers occur in men.209,210 The incidence
appears to be highest among North Americans and the
British, in whom breast cancer constitutes as much as 1.5% of all male
cancers. Jewish and African American males have the
highest incidence. Male breast cancer is preceded by gynecomastia in
20% of men. It is associated with radiation exposure,
estrogen therapy, testicular feminizing syndromes, and Klinefelter's
syndrome (XXY). Breast cancer is rarely seen in young males
and has a peak incidence in the sixth decade of life. A firm, nontender
mass in the male breast requires investigation. Skin or
chest wall fixation is particularly worrisome.
DCIS makes up <15% of male breast cancer, whereas infiltrating ductal
carcinoma makes up >85%. Special-type cancers,
including infiltrating lobular carcinoma, have occasionally been reported.
Male breast cancer is staged in the same way as female
breast cancer, and stage by stage, men with breast cancer have the same
survival rate as women. Overall, men do worse
because of the advanced stage of their cancer (stage III or IV) at the time
of diagnosis. The treatment of male breast cancer is
surgical, with the most common procedure being a modified radical
mastectomy. Sentinel node dissection has been shown to be
feasible and accurate for nodal assessment in men presenting with a
clinically node-negative axillary nodal basin. Adjuvant
radiation therapy is appropriate in cases in which there is a high risk for
local-regional recurrence. Eighty percent of male breast
cancers are hormone receptor positive, and adjuvant tamoxifen is
considered. Systemic chemotherapy is considered for men with
hormone receptornegative cancers and for men with large primary
tumors, multiple positive nodes, and locally advanced

disease.

Gynecomastia
Male breast excess or gynecomastia can be caused by a host of medical
diseases and pharmacologic agents. Medical conditions
associated with gynecomastia include liver dysfunction, endocrine
abnormalities, Klinefelter's syndrome, renal disease, testicular tumors,
adrenal or pituitary adenomas, secreting lung carcinomas, and male
breast cancer. Causative pharmacologic agents include marijuana,
digoxin, spironolactone, cimetidine, theophylline, diazepam, and
reserpine. Although these numerous causes must be considered, a
majority of patients present with either idiopathic enlargement of the
breast parenchyma (more common in teenagers) or simple skin
ptosis and excess adipose deposits on the chest wall (considered
pseudogynecomastia; more common in adult males). To obtain a flat
chest, both liposuction and/or skin excision techniques can be used.90