B

Figure 6-8. Cumulative risk of breast and ovarian cancer in BRCA1 (A) carriers and BRCA2 carriers (B). (From Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003: Figs. 3 and 4.)

was not reported, and cases of ovarian cancer were not clearly identified as prevalent or incident. Therefore, although these studies can be helpful in describing the type of ovarian cancer that develops in a high-risk cohort and can inform the reader of the limitations of current screening modalities, no comment can be made as to the efficacy of a screening regimen, including sensitivity, specificity, and positive predictive value.

In Canada, Laframboise and colleages47 reported on their screening experience of 311 women with a high risk for ovarian cancer who underwent CA-125 and TVUS screening every 6 months. Nine women underwent surgery for an abnormal screening test. Six of the nine had abnormal TVUS but no cancer found at surgery. Two of the nine had an abnormal CA-125 only but no cancer found at surgery. One patient of the nine had both an abnormal CA-125 and an abnormal TVUS and was found to have stage IA, grade 1 endometrioid ovarian cancer. Overall, 2.7% of CA-125 results were abnormal (more than 35 U/mL), and 17% of ultrasounds were abnormal. Detailed follow-up information for these individuals with abnormal values was not provided.

A study by Liede and colleagues48 included 290 high-risk women from a high-risk clinic in Los Angeles. Women were screened twice yearly until 1995, then annually. Eight cancers developed in the cohort, with six of the eight being primary peritoneal cancer. In all six cases of primary peritoneal cancer, the TVUS findings of the ovaries were normal. Of the eight cases, only three were incident, screen-detected cases. Of these three, one was a stage IC serous tumor with an abnormal TVUS showing complex ovarian cysts but a normal CA-125. The other two incident cases included a stage IIIC peritoneal cancer with elevated CA-125 and normal TVUS and a stage IIIC fallopian tube/peritoneal cancer with mildly elevated CA-125 and a TVUS showing a complex mass adjacent to the ovary. This study highlights the over-representation of primary peritoneal cancers in high-risk women and the lack of efficacy of screening in identifying early-stage disease.

In a study by Stirling and colleagues,49 annual CA-125 level testing and TVUS screening were performed in 1110 women in the United Kingdom. Thirteen cancers developed in the cohort. Three of the 13 cancers were interval cancers not detected by screening; two were stage III and one was stage IV. Ten cancers were detected by screening, including three prevalent cancers and seven incident cases. The stage breakdown of the 10 screen-detected cases included three stage IC tumors (including one borderline and one tubal cancer) two stage II tumors, four stage III tumors, and one stage IV tumor. Unfortunately, not all women had both CA-125 and TVUS simultaneously, so it was not possible to calculate positive predictive value for both tests in detecting ovarian cancer.

A study by Olivier and associates50 from the Netherlands described their experience of 6-month screening for women who had a BRCA1 or BRCA2 mutation and annual screening for women for whom genetic test results were unknown. There were 312 women enrolled in the program. Four cancers were found in the cohort, and it is unclear whether these cancers were prevalent or incident cases. All four women had symptoms. Given the fact that screening is meant to detect asymptomatic disease, it is unclear whether there were any true screen-detected cases. In addition, all four women had elevated CA-125 levels and abnormal TVUS results.

Several observations can be made from the retrospective studies. First, in high-risk persons, the combination of TVUS and CA-125 appears to be better than either single modality alone. Second, in premenopausal high-risk women, there is a high false-positive rate for both CA-125 and TVUS screening. Women should be forewarned of this fact. Third, the optimal interval for screening is unknown, and even advanced-stage cancers can be detected in women having frequent screening.

Hogg and colleagues13 published a review of ovarian cancer screening studies in low-risk and high-risk women. They reported that in the general population almost half of stage I ovarian cancers detected by CA-125 or ultrasound (transvaginal or transabdominal) were borderline ovarian tumors, granulosa cell tumors, or germ cell tumors. Of the invasive, epithelial ovarian cancers that were stage I and detected by screening, most were of endometrioid, clear cell, or mucinous histologies. Given the lack of stage I high-grade serous cancers among the screen-detected ovarian cancers, the authors suggest that, biologically, high-grade serous tumors may not act the same as endometrioid, clear cell, mucinous, or well-differentiated serous ovarian cancers. They propose that endometrioid, clear cell, mucinous, and well-differentiated serous ovarian cancers start as small tumors, get bigger but remain confined to the ovary, and then metastasize. These histologies can therefore be detected by current screening strategies. In contrast, the authors state that high-grade serous tumors are multi-focal early, undergo a rapid progression to metastatic disease, and are therefore difficult to detect by screening. It is precisely these high-grade serous tumors that develop in women with BRCA1 and BRCA2 mutations. It is interesting to note that when occult ovarian and fallopian tube cancers in prophylactic oophorectomy specimens in BRCA1 and BRCA2 mutation carriers are examined, multifocal high-grade serous tumors are clearly seen.51-54 In these studies, the microscopic foci of tumor are often present in multiple areas of the fallopian tubes and ovaries. In most of the cases, the preoperative CA-125 is normal, and the TVUS reveals unremarkable findings.

The published, single-institution, retrospective studies have highlighted the difficulties that we face using currently available screening technologies for high-risk women. However, there are key reasons to push forward with well-designed, prospective ovarian cancer screening trials for these women. First, important information about positive predictive value and negative predictive value, compliance, and stage of incident cancers cannot be adequately determined in small single-institution studies. Second, prospectively collected serum can be banked to more rapidly evaluate potential serum markers. As more unaffected women with BRCA1 or BRCA2 mutations are identified, physicians will need data to guide these patients in managing their increased risk of ovarian cancer. Not all women will choose prophylactic bilateral salpingo-oophorectomy, and some will choose to delay the procedure as long as possible (Box 6-3). For these women, evidence-based strategies for the early detection of ovarian cancer are crucial.

There are two large ongoing ovarian cancer screening studies in high-risk individuals. The first is a joint Cancer Genetics Network (CGN)/Gynecologic Oncology

Box 6-3. Reasons Why Young High-Risk Women Might Choose Ovarian Cancer Screening Rather Than Prophylactic Surgery

Young age

Concerns about iatrogenic premature menopause Concerns about use of hormone replacement therapy Wish to retain fertility Unwillingness to undergo surgery Psychological impact of oophorectomy

Poor operative risk (e.g., medical comorbidity/multiple adhesions)

From Rosenthal A, Jacobs I: Familial ovarian cancer screening. Best Pract Res Clin Obstet Gynaecol 20(2):321-338, 2006, Box 2.

Box 6-4. Risk of Ovarian Cancer Algorithm

Box 6-4. Risk of Ovarian Cancer Algorithm

Detailed analysis of over 50,00 serum CA-125 values involving 22,000 volunteers followed up for a median of 8.6 years in the study by Jacobs et al20 revealed that CA-125 levels in women without ovarian cancer were static or decreased with time, whereas preclinical levels associated with malignancy tended to rise.

This allowed the formulation of separate complex change-point statistical models of the behavior of serial preclinical CA-125 levels for cases and controls. These models take into account a woman's age-related risk of ovarian cancer and her CA-125 profile with time. The ROC for an individual is calculated using a computerized algorithm based on the Bayes theorem, which compares each individual's serial CA-125 levels with the pattern in cases compared with controls.

The closer the CA-125 profile to the CA-125 behavior of known cases of ovarian cancer, the greater the risk of ovarian cancer. The final result is presented as the individual's estimated risk of having ovarian cancer so that a ROC of 2% implies a risk of 1 in 50.

ROC, risk of ovarian cancer.

From Jacobs I, Menon U: Progress & Challenges in Screening for Early Detection of Ovarian Cancer. MCP Papers in Press, February 5, 2004, Table 1.

Group (GOG) study led by Dr. Steven Skates (GOG 199). This trial is examining an algorithm of CA-125 values over time (Risk of Ovarian Cancer Algorithm, ROCA) to increase sensitivity over a single CA-125 value (Box 6-4). Participants had their CA-125 values determined every 3 months, and the risk of ovarian cancer was designated as high, medium, or low, as calculated for each woman on the basis of the ROCA algorithm. Women with a high ROCA score were sent for TVUS and evaluation by a gynecologic oncologist. Women with a medium ROCA score were referred for TVUS only, and women with a low ROCA score had a repeat CA-125 at 3 months. Over 2000 high-risk women were enrolled in the study; preliminary results are forthcoming.

The second study is a United Kingdom Screening Study (UKFOCSS), which examines annual CA-125 and TVUS, with serial serum collection every 4 months. Similar to the U.S. study, an algorithm of CA-125 over time is being used, rather than a single value. Although neither of these studies is powered to demonstrate a mortality benefit of the screening test, important information about positive predictive value and negative predictive value, compliance, and stage of incident cancers will be available. In addition, in both these studies, serum is being banked to test future potential serum markers.

While we await the results of the prospective high-risk ovarian cancer screening studies, it is important to note that there can be anxiety, depression, and alteration in quality of life as a result of screening. A study by Hensley and colleagues55 examined 146 high-risk women who underwent ovarian cancer screening. Using the Impact of Events Scale, for which the "stressful event" was ovarian cancer screening, 37.8% of premenopausal women had high anxiety, and over 20% of premenopausal women had intermediate anxiety. Overall, 30% of women required a repeat test of CA-125 or TVUS after first screening, and this occurred more often in premenopausal versus postmenopausal women. All of these premenopausal women, on repeat testing, were found to have false-positive test results.55 Although the authors did not measure the anxiety related to the need for repeat testing in premenopausal women, the high false-positive rate associated with CA-125 and TVUS in this cohort is likely to increase the anxiety levels of these high-risk individuals. It will be important as we develop screening strategies in this population to be mindful of the negative effects that screening can have.

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