Published Ahead of Print on December 3, 2012 as 10.1200/JCO.2012.45.4678 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.45.

4678

JOURNAL OF CLINICAL ONCOLOGY

Screening for Familial Ovarian Cancer: A Ray of Hope and a Light to Steer by
Kara C. Long and Noah D. Kauff, Memorial Sloan-Kettering Cancer Center, New York, NY See accompanying article doi: 10.1200/JCO.2011.39.7638

Since the identication of cancer antigen (CA) 125 in 1981,1 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.2 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 efcacious, there are several essential requirements of both the screening test and the disease (adapted from Mulley3): (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 sufciently specic 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 denitively 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 rst 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.4 Further, given the low annual incidence of invasive disease (0.07% during the rst 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 rst three annual incident screens, despite the combination of TV US and CA-125 leading to a biopsy, yielding a specicity greater than 98% in all rounds of screening. Given the lack of stage shift, it was not surprising that when the nal 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
Journal of Clinical Oncology, Vol 30, 2012

due to an abnormal screening result, with only 6.3% of these women having an invasive cancer identied.5 Do these discouraging results also suggest that ovarian cancer screening is unlikely to benet 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.6 Applying a screening approach similar to that employed in the PLCO trial with 98% specicity, 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 reect the natural history of the disease.7 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.8 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,9-13 with at least one of these studies suggesting that this effect is independent of platinum sensitivity.10 These different biologic features may allow treatment of familial ovarian cancer at time of screen detection to be more efcacious than has been the case in the setting of sporadic ovarian cancer. In the article that accompanies this editorial, Rosenthal et al14 present preliminary results from the United Kingdom Familial Ovarian Cancer Screen Study (UK FOCSS), the rst of two large-scale prospective trials testing the hypothesis that ovarian cancer screening may be benecial 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
2012 by American Society of Clinical Oncology

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Editorial

shift at diagnosis. In the UK FOCSS, only six of 23 (26%) cancers not associated with Lynch syndrome in women screened in the previous year were diagnosed at stage IIIc or higher as compared with six of seven (86%) cancers in women not screened in the year before diagnosis (P .009). Further, while not statistically signicant, there were also trends towards improvement in optimal cytoreduction (91.3% v 57.1%) and overall survival (mean overall survival, 71.9 months v 48.4 months) in patients screened per protocol as compared to those not screened in the previous year. These results suggest that a clinically meaningful stage shift occurred in women who were screened according to protocol as opposed to women who underwent delayed screening. Additionally, the false-positive rate was acceptable, with only 1.5% of women undergoing surgery prompted by false-positive screening results, ultimately achieving a 25.5% positive predictive value for screening. While the study was not designed to evaluate the impact of screening on familial ovarian cancer mortality, these results provide a ray of hope that, at least for patients at risk of familial ovarian cancer, an effective ovarian cancer screening program may be achievable. Given these promising results, what direction should future studies pursue? The UK FOCSS clearly demonstrates the importance of undergoing screening at the prescribed intervals and the negative impact of delayed evaluation. Therefore, for the ongoing phase II of this study, the screening interval for CA-125 determination has been decreased to 4 months, and the threshold and work-up for repeat tests is now protocol driven. With these changes, as well as the incorporation of the Risk of Ovarian Cancer (ROCA) algorithm to improve both the sensitivity and specicity of CA-125,15 it is hoped that the results of phase II will support the use of ovarian cancer screening as a viable alternative to RRSO, at least in the premenopausal years. The UK FOCSS also provides direction in regards to whom screening efforts should be targeted. The UK FOCSS trial included only participants meeting stringent familial risk criteria. Specically, if participants did not have a documented mutation in BRCA1, BRCA2 or a mismatch repair gene associated with Lynch syndrome, the participant had to have both a family history of ovarian cancer and a rst degree relative affected with either ovarian, early onset breast or colon cancer. These criteria specically excluded women from site-specic hereditary breast cancer families who are frequently thought to be at risk for familial ovarian cancer, but have previously been shown not to be at increased risk for this disease in the absence of a BRCA1 or BRCA2 mutation.16,17 Despite these relatively rigid inclusion criteria, almost all the cancers occurred in patients with documented mutations in known ovarian cancer susceptibility genes. During the course of the study, 30 (5.6%) of 538 known BRCA1 or BRCA2 mutation carriers were diagnosed with invasive cancer. Similarly, three (4.6%) of 65 mismatch repair mutation carriers were found to have invasive cancer. However, among the 2,960 participants without a known mutation, only four (0.14%) had an invasive cancer diagnosed over the mean 3.2 years of follow-up. This translates to an annual incidence of one in 2,368 which is likely not different than the one in 2,785 annual incidence of invasive ovarian cancer seen in women over age 50 years in the United States in 2008.18 Given these results, it likely can be argued that family history is no longer an acceptable surrogate for genetic risk of ovarian cancer and that genotyping should be a requirement for inclusion in trials assessing screening in individuals at inherited risk, as has similarly been argued for therapeutic trials in ovarian cancer.19-21 This approach has
2
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been taken in the recently completed, but not reported, Gynecologic Oncology Group 0199 trial, a prospective study of RRSO and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer.22 These results are expected in 2014 and combined with the results of phase II of the UK FOCSS should provide the rst clear guidance as to whether screening for ovarian and fallopian tube cancer will be a viable alternative to risk-reducing surgery for women at inherited risk for these cancers. Until these results are available, the results of phase I of the UK FOCSS support the current recommendation that women at inherited risk who decline RRSO in their 30s should consider screening for ovarian cancer from approximately age 35 years until they undergo denitive risk-reducing surgery as recommended no later than their early 40s.23,24 Further, the results provide strong support for the proposition that neither screening nor risk-reducing surgery should be offered to women at putative familial risk until formal genetic risk assessment and counseling with appropriate genetic testing has been completed.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an authors immediate family member(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Noah D. Kauff, Pzer (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: Noah D. Kauff, Pzer (C) Other Remuneration: None
AUTHOR CONTRIBUTIONS

Manuscript writing: All authors Final approval of manuscript: All authors

REFERENCES
1. Bast RC Jr, Feeney M, Lazarus H, et al: Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 68:1331-1337, 1981 2. Campbell S, Goessens L, Goswamy R, et al: Real-time ultrasonography for determination of ovarian morphology and volume: A possible early screening test for ovarian cancer? Lancet 1:425-426, 1982 3. Mulley AG: Health maintenance and the role of screening, in Goroll AH, Mulley AG: Primary Care Medicine: Ofce Evaluation and Management of the Adult Patient (ed 6). Philadelphia, PA, Wolters Kluwer/Lippincott Williams & Wilkins, 2009 4. Partridge E, Kreimer AR, Greenlee RT, et al: Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 113:775-782, 2009 5. Buys SS, Partridge E, Black A, et al: Effect of screening on ovarian cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 305:2295-2303, 2011 6. 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 7. Hogg R, Friedlander M: Biology of epithelial ovarian cancer: Implications for screening women at high genetic risk. J Clin Oncol 22:1315-1327, 2004 8. Kurman RJ, Visvanathan K, Roden R, et al: Early detection and treatment of ovarian cancer: Shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 198:351-356, 2008 9. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, et al: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: The national Israeli study of ovarian cancer. J Clin Oncol 26:20-25, 2008
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10. Gallagher DJ, Konner JA, Bell-McGuinn KM, et al: Survival in epithelial ovarian cancer: A multivariate analysis incorporating BRCA mutation status and platinum sensitivity. Ann Oncol 22:1127-1132, 2011 11. Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474:609-615, 2011 12. Hyman DM, Zhou Q, Iasonos A, et al: Improved survival for BRCA2associated serous ovarian cancer compared with both BRCA-negative and BRCA1-associated serous ovarian cancer. Cancer 118:3703-3709, 2012 13. Bolton KL, Chenevix-Trench G, Goh C, et al: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307:382-390, 2012 14. Rosenthal AN, Fraser L, Manchanda R, et al: Results of annual screening in phase I of the United Kingdom Familial Ovarian Cancer Screening Study highlight the need for strict adherence to screening schedule. J Clin Oncol doi:10.1200/JCO.2011.39.7638 15. Skates SJ, Menon U, MacDonald N, et al: Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J Clin Oncol 21:206s-210s, 2003 (suppl 10) 16. Kauff ND, Mitra N, Robson ME, et al: Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst 97:1382-1384, 2005 17. Metcalfe KA, Finch A, Poll A, et al: Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 100:421-425, 2009

18. Surveillance, Epidemiology, and End Results (SEER) Program: SEER*Stat Database: Incidence - SEER 18 Regs Research Data 2011 Sub (2000-2009), 2011. http://seer.cancer.gov/data/metadata.html 19. Kauff ND: Is It time to stratify for BRCA mutation status in therapeutic trials in ovarian cancer? J Clin Oncol 26:9-10, 2008 20. Long KC, Kauff ND: Hereditary ovarian cancer: Recent molecular insights and their impact on screening strategies. Curr Opin Oncol 23:526-530, 2011 21. Hyman DM, Spriggs DR: Unwrapping the implications of BRCA1 and BRCA2 mutations in ovarian cancer. JAMA 307:408-410, 2012 22. Greene MH, Piedmonte M, Alberts D, et al: A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: Design and baseline characteristicsA Gynecologic Oncology Group study. Cancer Epidemiol Biomarkers Prev 17:594-604, 2008 23. American College of Obstetricians and Gynecologists, ACOG Committee on Practice BulletinsGynecology, ACOG Committee on Genetics, et al: ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol 113:957-966, 2009 24. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2012. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

DOI: 10.1200/JCO.2012.45.4678; published online ahead of print at www.jco.org on December 3, 2012

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2012 by American Society of Clinical Oncology