Screening for Familial Ovarian Cancer: A Ray of Hope and a Light to Steer by

Since the identification of cancer antigen (CA) –125 in 1981, this serum marker has been extensively evaluated as a potential screening test for ovarian cancer. At approximately the same time, pelvic ultrasonography was also suggested as a potential alternative approach to screen for this disease. Despite the initial promise of both of these techniques, screening for ovarian cancer in the general population has remained an intractable challenge. In order for a cancer screening program to be efficacious, there are several essential requirements of both the screening test and the disease (adapted from Mulley): (1) the screening test must be sensitive enough to detect cancer at an earlier point in its natural history (generally indicated by stage shift); (2) the test must be sufficiently specific to provide an acceptable positive predictive value (for ovarian cancer this has been somewhat arbitrarily set at a minimum of 10%, ie, there should be no more than nine surgeries performed due to false positive screening tests for each case of invasive cancer diagnosed); and (3) treatment at time of screen detection must improve outcome compared to treatment delayed until symptoms appear. Unfortunately, for ovarian and fallopian tube cancer in the general population, these criteria have not yet been definitively met. While both ultrasound and CA-125 are highly sensitive for detecting advanced stage cancer, neither has proved as good at detecting early stage disease. During the first four ovarian cancer screening rounds of the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial, in which 78,216 women aged 55 to 74 years were randomized to either usual care or ovarian cancer screening with annual transvaginal ultrasound (TV US) for 4 years and annual CA-125 serum testing for 6 years, 42 (69%) of 61 incident invasive ovarian and fallopian tube were screen detected. However, 28 (67%) of these 42 screen-detected cancers (and 76% of all cancers in women undergoing screening) were stage III or stage IV cancers. Further, given the low annual incidence of invasive disease (0.07% during the first 3 years of the PLCO study), the positive predictive value of screen-indicated surgical biopsy was only 3.2% on prevalent screen and 4.9 to 9.5% in each of the first three annual incident screens, despite the combination of TV US and CA-125 leading to a biopsy, yielding a specificity greater than 98% in all rounds of screening. Given the lack of stage shift, it was not surprising that when the final results of the PLCO trial were reported last year, there was no improvement in mortality in the screened group. Additionally, more than one out of 30 women participating in the screening arm underwent surgical exploration due to an abnormal screening result, with only 6.3% of these women having an invasive cancer identified. Do these discouraging results also suggest that ovarian cancer screening is unlikely to benefit women at familial risk of ovarian cancer? Before we reach that conclusion, it is important to acknowledge several important differences between sporadic and familial ovarian cancer. First, the incidence of ovarian cancer in women with BRCA1 or BRCA2 mutations (the most common known causes of familial ovarian cancer) over the age of 50 years is 1.0 to 2.5% per year and 0.4-0.8% per year respectively. Applying a screening approach similar to that employed in the PLCO trial with 98% specificity, positive predictive values of 16% to 56% are theoretically achievable. Furthermore, recent research on the pathogenesis of pelvic serous cancers has led to the hypothesis that our current staging system may not reflect the natural history of the disease. With this in mind, a more appropriate target for a screening test may be low-volume stage III disease, instead of necessarily stage I or II disease. Lastly, the biology of inherited ovarian cancer may be inherently different than that of sporadic ovarian cancer. Multiple studies have demonstrated improved survival for BRCA-associated ovarian cancer, with at least one of these studies suggesting that this effect is independent of platinum sensitivity. These different biologic features may allow treatment of familial ovarian cancer at time of screen detection to be more efficacious than has been the case in the setting of sporadic ovarian cancer. In the article that accompanies this editorial, Rosenthal et al present preliminary results from the United Kingdom Familial Ovarian Cancer Screen Study (UK FOCSS), the first of two large-scale prospective trials testing the hypothesis that ovarian cancer screening may be beneficial in women at familial risk. In this series, 3,563 women at greater than a 10% risk of ovarian or fallopian tube cancer were screened with annual TV US and annual CA-125 for a mean of 3.2 years. At the time of consent, women were counseled that riskreducing salpingo-oophorectomy (RRSO) was the recommended management; however, the majority of participants declined or deferred this approach throughout the course of the study, highlighting the need for screening options in these patients. This well-designed and -executed prospective study, while not randomized, provides the best data to date evaluating the role of ovarian cancer screening in women at familial risk. As noted above, an effective ovarian cancer screening regimen must at a minimum be associated with a clinically meaningful stage JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 1 JANUARY 1 2013