Management Options 71 Screening

Even though no method exists which can reliably identify patients with early ovarian cancer (146), attempts have been made to screen populations of women at elevated risk. In 1995, the National Institutes of Health Consensus Conference on Ovarian

Table 5

Individuals Likely to Benefit From BRCA Mutation Testing

Ashkenazi Jewish heritage with personal or family history of breast or ovarian cancer Personal history of breast cancer and family history of breast cancer < age 50 Personal history of breast cancer and family history of two or more cases of breast cancer

Personal history of breast cancer and family history of ovarian cancer Personal history of ovarian cancer < age 50 Personal or family history of bilateral breast cancer

Family history of one first-degree relative with both breast and ovarian cancer

Family history of two or more cases of breast cancer < age 50

Family history of two or more cases of ovarian cancer

Family history of male breast cancer

First-degree relative with BRCA1 or BRCA2 mutation

Adapted from refs. 123,142,195-197.

Cancer (147) recommended a combination of annual or semiannual bimanual pelvic examination, transvaginal ultrasonography (TVUS), and serum CA-125 measurement to screen high-risk women. In 1997, the Cancer Genetics Studies Consortium recommended annual or semiannual screening of women with known BRCA mutations using TVUS and CA-125 testing starting at the age of 25-35 (145). Another strategy, the Risk of Ovarian Cancer Algorithm (ROCA), utilizes yearly longitudinal CA-125 measurements in a computerized Bayesian algorithm to calculate risk of ovarian cancer (148). Each patient's CA-125 levels are compared with known patterns for patients with ovarian cancer and controls. This strategy is currently being evaluated clinically in small trials in the United States and the United Kingdom.

Despite multiple screening strategies, no methods have been shown to reduce morbidity or mortality (147). The use of TVUS remains problematic as a screening modality, although small, potentially curable, ovarian tumors may be detected (149), TVUS might miss primary peritoneal cancers or ovarian cancers with normal sized ovaries. Also, TVUS is unable to reliably distinguish the difference between benign and malignant tumors, sometimes leading to unnecessary surgical intervention. CA-125 is the most commonly used tumor marker to screen for ovarian cancer, but the value is elevated in only 80% of cases. A prospective study of more than 20,000 women indicated a specificity of 99%, but a sensitivity of only 71% (150). For patients with the best potential for cure, those with stage I disease, only half present with elevated CA-125 levels (151) and again, false-positives may lead to unneeded surgical intervention.

For patients with elevated risk for breast cancer, BRCA mutation carriers are recommended to perform monthly breast self examinations beginning at the age of 18, to undergo annual or semiannual clinical breast examination and to obtain annual mam-mography beginning at the age of 25-35 (145). Patients with MMR gene mutations are recommended to undergo colonoscopy every 1-3 years beginning at the age of 25, and annual endometrial biopsy and/or TVUS for endometrial stripe evaluation beginning at the age of 25-35 (128). Surveillance options are summarized in Table 6.

Despite the well-documented increased risk of cancer, many women do not adhere to recommendations for surveillance. A recent study by Botkin et al. (152) noted that

Table 6

Surveillance Options for High-Risk Women

Disease Recommendations

Ovarian cancer 1. Annual or semiannual bimanual pelvic examination

2. Annual or semiannual transvaginal ultrasound

3. Annual or semiannual CA-125 measurement starting at age 25-35 Breast cancer 1. Monthly breast self exam starting age 18

2. Annual or semiannual clinical breast exam

3. Annual mammography starting age 25-35 Colon cancer Colonoscopy every 1-3 years beginning at age 25 Endometrial cancer 1. Annual endometrial biopsy

2. Annual transvaginal ultrasound starting at age 25-35

only 26% of women obtained a TVUS in the first year after testing positive for a mutation in the BRCA genes. This rate dropped to 11% in the second year. Similarly, even less invasive CA-125 testing was only utilized by 32% of women in the first year, and 37% of women in the second year after testing positive. In contrast, increased screening for breast cancer appears to be more acceptable. The authors noted that 71% of women obtained a mammogram within 2 years of mutation testing, and that more than 80% followed recommendations for clinical and breast self examination.

Future directions for screening of high-risk women will likely focus on the identification of biomarkers for early cancer detection and improved risk assessment. Several promising strategies under active investigation include differential protein and gene expression. Petricoin et al. (153) generated proteomic spectra using mass spectroscopy for 50 patients with ovarian cancer and 50 controls. These spectra were analyzed to identify a proteomic patter that discriminated cancer from noncancer. The identified pattern was used to classify a test set of 116 samples. The investigators' algorithm correctly identified all 50 cases of ovarian cancer (including all 18 stage I cases) in the test set. Of the 66 control cases, 63 were correctly classified by the algorithm, yielding a sensitivity of 100%, specificity of 95%, and positive predictive value of 94%. The high positive predictive value indicates that this technique may be promising for high-risk patients, but given the low disease incidence in the general population, it may not yet be advisable for general screening.

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