Screening for Familial Ovarian Cancer: The Need for Well-Designed Prospective Studies

Abstract

The issue of ovarian cancer screening (OCS) among women with a strong family history or genetic predisposition has a tendency to generate more heat than light. The report by Stirling et al continues that trend. The authors report a cohort of 1,110 women screened in three centers from 1991 to 2004, with CA-125 and/or ultrasound (U/S). Unfortunately, the article does not provide information about compliance with screening, the screen interval actually achieved, the detailed screening protocols used for U/S and CA-125 (which apparently varied over time and possibly among centers), the interval between screen-positive results and surgical intervention, or the method of followup. Despite these caveats and the small number of cancers (n 13), the authors were sufficiently confident in their results to state that “annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis.” They may be correct, but it is not possible to reach this conclusion from the data they have presented. The impression left after reading this article and the other literature on this topic is that there is a need for well-designed, rigorously conducted, and properly funded prospective trials of OCS among women at high risk. The identification of the BRCA1 and BRCA2 genes was an important step in refining risk assessment in families with a high incidence of breast and ovarian cancer (OC). However, the challenge of managing the risk of cancer remained. One option for OC is prophylactic surgery to remove the ovaries and tubes. This can be performed laparoscopically in the majority of cases with low morbidity, and is an effective method for prevention provided the ovaries are entirely removed and an occult malignancy is excluded. Oophorectomy does not eliminate primary peritoneal cancer but seems to reduce the risk of breast cancer. Although oophorectomy is an effective preventative measure, many women at increased risk of OC do not wish to take this step for a range of reasons. The alternative to oophorectomy for women at risk is OCS with the objective of intervening sufficiently early in the natural history of the disease to reduce mortality. There currently are two methods available for OCS: U/S to measure ovarian morphology, size, and blood flow, and measurement of the serum tumor marker CA-125. Given the markedly increased incidence of OC in high-risk families, it may have been anticipated that this would be the ideal group to include in definitive clinical trials. Unfortunately, that has not proven to be the case. The widespread provision of screening on a clinical basis for the high-risk group has made it difficult to implement rigorous prospective research protocols in this population. There are data available about the performance of OCS in the high-risk group from more than 10 reports of screening using CA-125 and/or U/S involving more than 6,000 women. Unfortunately, criteria for interpreting the test results vary from study to study, the screening protocols are not always clearly reported, and the completeness of follow-up is variable, making it difficult to reach firm or sound conclusions. Hogg and Friedlander reviewed the literature in 2004 and reported the detection of 38 primary invasive cancers, of which 14 (38%) were stage I or II. However, they included seven patients with OC reported twice in separate publications. When a correction is made for this, 14 of 31 patients detected were stage I or II (45%). They also noted 15 “interval” patient cases but did not relate this to the screening interval. When corrected for patients whose disease occurred within the screening interval, rather than later, the number of interval OCs in the publications reviewed was only two, giving an apparent sensitivity for detection of OC at 1-year follow-up of 94% (31 of 33). However, this is subject to the important caveat of incomplete reporting of follow-up. Hogg and Friedlander’s key JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2