Olufunmilayo I. Olopade, MD
Center for Clinical Cancer Genetics
Professor, Department of Medicine
University of Chicago Medical Center
Chicago, Illinois
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| Olufunmilayo I. Olopade, MD |
Although the cause of breast cancer remains unknown in the majority of patients, epidemiologic studies have identified several risk factors. A family history of breast cancer is one of the strongest, factors, particularly when it occurs in multiple first-degree relatives and at young ages. A history of bilateral breast cancer in a first-degree relative further increases the risk. About 5%--10% of breast cancer cases are due to inheritance of breast cancer susceptibility genes such as BRCA1 and BRCA2.
Women who have a history of prior invasive breast cancer or noninvasive breast lesions such as atypical hyperplasia and lobular carcinoma in situ (LCIS), carry an increased risk for developing invasive breast cancer. Moderate alcohol consumption and previous exposure to radiation, especially in survivors of childhood Hodgkin's disease are also important risk factors. Early menarche and late menopause are weak risk factors. The effect of hormone replacement therapy or oral contraceptives on breast cancer risk has been controversial. However, prolonged use (more than 5 years) of estrogen combined with progestins has been associated with increased breast cancer risk.
Considering the high prevalence of breast cancer, and the recent advances in chemoprevention or early detection of the disease, it is important to screen for the known risk factors so that women at high risk can be offered appropriate management options. Every woman with a family history of breast cancer requires a careful risk assessment and calculation of her lifetime risk of breast cancer.
Mutations in BRCA1 and BRCA2 predict probabilities of breast cancer by age 70 of 45%--87% and 26%--84%, respectively, making these the strongest known predictors of breast cancer known. The lifetime risks of ovarian cancer for BRCA1 and BRCA2 mutation carriers are 16%--63% and 10%--27% respectively. Genetic counseling and testing for breast cancer susceptibility genes, when appropriate, should be offered and provided as part of a comprehensive risk assessment plan.
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Women who are determined to be at high-risk for hereditary breast cancer may be interested in prophylactic surgery to reduce their risks. These women, including BRCA1 and BRCA2 carriers, reduce their risk of breast cancer more than 90% following prophylactic mastectomy. One study that looked at 139 women with BRCA1 and BRCA mutations; 76 chose prophylactic bilateral mastectomy to reduce their breast cancer risk, while the remaining women chose a strategy that included monthly breast self-examinations (BSE), a semiannual breast examination by a healthcare professional, and an annual mammogram. Beginning in 1995, annual magnetic resonance imaging (MRI) was offered. After a follow up period of about 3 years, no breast cancers were observed in the 76 women who underwent bilateral prophylactic mastectomy, whereas eight cancers were detected in the surveillance group. While prophylactic mastectomy is effective, it is only a minority of high-risk women who choose this option for risk reduction. Research into alternative methods for risk reduction are urgently needed.
The degree of risk reduction after prophylactic bilateral salpingo-oophorectomy (removal of the ovaries and Fallopian tubes) for women with either strong family histories of breast or ovarian cancer or of BRCA mutation carriers was demonstrated in two recent studies. Prophylactic oophorectomy appears to serve the dual purposes of eliminating the 'at risk' ovarian tissue and decreasing breast cancer risk by reducing blood estradiol levels (a naturally occurring estrogen produced by the ovaries) in premenopausal women. In a study that included 170 BRCA1 and BRCA2 mutation carriers older than age 35 years and who were offered the opportunity to enroll in a prospective follow-up study after receiving genetic test results, the 5-year cancer-free survival estimates for healthy women with BRCA1 and BRCA2 mutations who had prophylactic bilateral salpingo-oophorectomy was 94% compared to 69% for those women who chose surveillance. The surgical complication rate appeared to be minimal--only four of the 98 (4%) women had any surgical complications.
A benefit of prophylactic oophorectomy also has been demonstrated in a multicenter, case-control study. Among the 259 participants, six stage I ovarian cancers (2%) were diagnosed at the time of prophylactic surgery; two papillary serous peritoneal cancers were diagnosed at 3.8 and 8.6 years after prophylactic surgery. After an average follow up of almost 9 years, (with the exclusion of the six stage I ovarian cancers diagnosed at surgery), prophylactic oophorectomy significantly reduced the risk of ovarian and peritoneal cancers. Likewise, for the 241 women who had no history of breast cancer and who had not undergone mastectomy, a 53% breast cancer risk reduction was observed. The most benefit in breast cancer risk reduction was observed in women who had prophylactic oophorectomy by age 50.
Other strategies for primary prevention, including the use of tamoxifen for breast cancer or the use of oral contraceptives and tubal ligation for ovarian cancer have been proposed, although there are few data supporting the effectiveness of these various interventions. Secondary prevention options include early breast screening with advanced imaging techniques such as MRI and ultrasound or the use of transvaginal ultrasound and serial serum CA-125 or other ovarian cancer serum markers for ovarian cancer.
