Page 450 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 agermline mutation in one of the breast cancer genes BRCA1 or BRCA2.42 Mutation carriers are more prevalent among women who have a first- or seconddegreerelative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to apopulation in which founder mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumulativerisks 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 cancerand 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 occurwith either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.44 Besides breastand ovarian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfoldincreased 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, fourfoldincreased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.45BRCA1 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 proteinsfunction together as a complex, subsequent data demonstrated that they have distinct functions.47,48 In fact, breast cancers arising from BRCA1 or BRCA2mutations are different at the molecular level and have been found to have distinct gene expression profiles.49BRCA1-associated tumors are more likely to beestrogen receptor negative, whereas BRCA2-associated tumors are more likely to be estrogen receptor positive. Currently, studies are ongoing to determinewhether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer.

Male Breast CancerFewer than 1% of all breast cancers occur in men.209,210 The incidence appears to be highest among North Americans and theBritish, in whom breast cancer constitutes as much as 1.5% of all male cancers. Jewish and African American males have thehighest 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 malesand has a peak incidence in the sixth decade of life. A firm, nontender mass in the male breast requires investigation. Skin orchest 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 femalebreast cancer, and stage by stage, men with breast cancer have the same survival rate as women. Overall, men do worsebecause of the advanced stage of their cancer (stage III or IV) at the time of diagnosis. The treatment of male breast cancer issurgical, with the most common procedure being a modified radical mastectomy. Sentinel node dissection has been shown to befeasible and accurate for nodal assessment in men presenting with a clinically node-negative axillary nodal basin. Adjuvantradiation therapy is appropriate in cases in which there is a high risk for local-regional recurrence. Eighty percent of male breastcancers are hormone receptor positive, and adjuvant tamoxifen is considered. Systemic chemotherapy is considered for men withhormone receptor–negative cancers and for men with large primary tumors, multiple positive nodes, and locally advanceddisease.

GynecomastiaMale breast excess or gynecomastia can be caused by a host of medical diseases and pharmacologic agents. Medical conditionsassociated 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, amajority of patients present with either idiopathic enlargement of the breast parenchyma (more common in teenagers) or simple skinptosis and excess adipose deposits on the chest wall (considered pseudogynecomastia; more common in adult males). To obtain a flatchest, both liposuction and/or skin excision techniques can be used.90