Original population

Marked population decrease, migration, or isolation
Generations later

Figure 3-6. Founder effect. (From ASCO Curriculum: Cancer Genetics and Cancer Predisposition Testing, 2nd ed, 2004, Slide 1-38.)

Management: Screening and Risk Reduction Options

Ovarian Cancer. Although there is no evidence that ovarian cancer screening is efficacious in BRCA1 and BRCA2 mutation carriers or in the general population, at present mutation-positive women who have not completed their family are recommended to have annual pelvic examination, transvaginal ultrasound, and serum CA-125 (see Chapter 6 for more details). Studies examining the ability of this surveillance to detect early-stage ovarian cancers have had mixed results, with one group finding four of five cancers detected at stage I or II38 and a review of other studies finding that 63% of screen-detected ovarian cancers were stage IIC or greater.39 The authors of the latter study suggest that the features of BRCA-related ovarian tumors—primarily serous and endometrioid—progress relatively rapidly to an advanced stage, making early detection difficult. Oral contraceptives as chemopre-vention for ovarian cancer in BRCA mutation carriers have been suggested by studies showing significant reduction of risk. However, their use is not routinely recommended because of a possible increased risk of breast cancer.

For those who have completed childbearing, prophylactic bilateral salpingo-oophorectomy is the standard of care. Such surgery, when compared with increased surveillance, reduces the risk of ovarian cancer by 80% to 90%.40,41 The majority of the remaining risk is attributed to primary peritoneal cancer, although a small proportion may arise in the remnant of fallopian tube remaining in the uterus. There is also some suggestion of an association between uterine papillary serous carcinoma and BRCA1 mutations, although this is primarily based on case reports in the literature rather than large numbers of patients. For these reasons, some women also consider concurrent hysterectomy; however, this is not a standard recommendation for all mutation-positive women. In addition, up to 4% of mutation-positive women undergoing prophylactic oophorectomy have an occult cancer identified.42 For this reason, it is generally recommended that a gynecologic oncologist either perform the surgery or be available for staging, if necessary. So far, a survival benefit has been shown in the short term but not long term.43

Timing of prophylactic oophorectomy after childbearing may differ depending on the underlying gene mutation and the family history. It is typically recommended that BRCA1/2 mutation-positive women pursue surgery in their mid to late 30s or early 40s. An added benefit of bilateral oophorectomy, particularly when it occurs before menopause, is a reduction in breast cancer risk of up to 50%.40 What is unknown at this time is whether the reduction in breast cancer risk conferred by prophylactic bilateral salpingo-oophorectomy is of the same magnitude in BRCA1 compared with BRCA2 carriers. Recently, it was reported that bilateral salpingo-oophorectomy resulted in a 72% reduction in breast cancer risk in BRCA2 mutation carriers, with only a 45% risk reduction in BRCA1 mutation carriers,44 suggesting an age-dependent benefit.45 Ultimately, timing of the surgery depends on a combination of factors, including the gene, and the woman's own medical and psychosocial history.

Hormone replacement therapy is often an issue of concern for mutation-positive women, since they are usually premenopausal at the time of prophylactic oophorec-tomy. Thus, entry into menopause is sudden, and severity of symptoms varies. Short-term hormone replacement for severe menopausal side effects (e.g., vasomotor symptoms, insomnia) is an option to provide improvement in quality of life, particularly with the use of estrogen alone if the uterus has been removed. Current views on hormone replacement therapy in this high-risk population vary considerably, ranging from no hormone replacement therapy to use of hormone replacement therapy until the age at which menopause would have naturally occurred. Data on hormone replacement therapy in BRCA1 and BRCA2 carriers have been extrapolated from data from the general population, and there is a need to evaluate its use in this population prospectively. Long-term hormone replacement is not generally recommended because of the already greatly increased risk of breast cancer due to mutation status, but further studies on the long-term effects of ovarian removal on the brain, bone, and cardiovascular system are needed.

Breast Cancer. Screening and risk reduction strategies for the breast in female BRCA1 and BRCA2 mutation carriers fall into three general categories: intensive cancer screening, chemoprevention, and prophylactic surgery. According to recommendations of the National Comprehensive Cancer Network, women with BRCA1 or BRCA2 mutations should have a clinical breast examination by a healthcare provider at least every 6 months, beginning at age 25 years (www. Mammograms generally begin at age 25 years, but can be adjusted based on the cancer pattern in the family. Adjuvant ultrasound is also a consideration for women with dense breast tissue; studies are ongoing to determine its effectiveness.

Recently, magnetic resonance imaging (MRI) has become a more routine part of breast screening for mutation carriers. The American Cancer Society recommends that women with a high risk for breast cancer (greater than 20% lifetime risk) should get an MRI and a mammogram every year. The optimal interval between these procedures (i.e., staggered with one of the two every 6 months, or both at the same time each year) has not yet been established.46 A review of the effectiveness of MRI as an addition to mammography and ultrasound in screening high-risk young women found consistent evidence that MRI as a screening strategy provides high sensitivity compared with mammography alone or mammography and ultrasound, with or without clinical breast examination.47 Whether this higher sensitivity translates to detection of earlier stage disease or a reduction in patient mortality compared with mammography alone is presently unclear. Based on the high sensitivity of MRI compared with mammography, particularly in younger women, it is possible that these recommendations may change as more data are obtained on MRI as a screening tool.

Risk reduction options include chemoprevention and prophylactic bilateral mastectomy. Data on the effectiveness of chemoprevention with tamoxifen in BRCA1 and BRCA2 carriers have been extrapolated from large trials within the general population. The National Surgical Adjuvant Breast and Bowel Project (NSABP) prevention trials showed a 62% decrease in the risk of breast cancer in BRCA2-positive women who received tamoxifen for 5 years, versus no reduction in breast cancer incidence among BRCA1 -positive women.48 However, another study examined the effects of tamoxifen on prevention of contralateral breast cancer in mutation carriers and found that the drug did provide protection overall; however, the protection reached significance only in BRCA1 mutations carriers.49 This is interesting in light of the lack of hormone receptor expression seen in BRCA1 relative to BRCA2 cancers.

Another risk-reduction option is prophylactic bilateral mastectomy, which reduces the risk of breast cancer by at least 90% in unaffected mutation carriers.50,51 For women with breast cancer who opt for contralateral prophylactic mastectomy, the rate of a contralateral malignancy is also reduced by 90%.52 However, therapeutic and/or contralateral mastectomy does not reduce the risk of chest wall or distant recurrence. Furthermore, although such surgery results in the greatest reduction in breast cancer risk, it is often an emotionally difficult choice for women. Although expected to decrease mortality, the efficacy of bilateral prophylactic mastectomy in prolonging survival has not yet been shown.

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