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Obstetrics & Gynecology 2006;108:1176-1184
© 2006 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Ovarian Cancer Screening in Women With a Family History of Breast or Ovarian Cancer

James V. Lacey, Jr, PhD1,6, Mark H. Greene, MD1, Saundra S. Buys, MD2, Douglas Reding, MD3, Thomas L. Riley4, Christine D. Berg, MD5, Richard M. Fagerstrom, PhD5 and Patricia Hartge, ScD1

From the 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; 2Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah; 3Marshfield Clinic Research Foundation, Marshfield, Wisconsin; 4Information Management Systems, Inc., Rockville, Maryland; and 5Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To evaluate positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer.

METHODS: In the screening arm of a randomized controlled trial of screening compared with usual care, 28,460 women with family history data received baseline and annual CA 125 and transvaginal ultrasonography examinations. We analyzed CA 125 and transvaginal ultrasonography results from the first four rounds of screening. We classified women as average (n=22,687), moderate (n=2,572), or high (n=2,163) risk based on family history, or high risk due to a personal history of breast cancer (n=1,038). Cancers were identified by active follow-up of women with abnormal screening results and annual questionnaires. We calculated positive predictive values for screening combinations.

RESULTS: Similar proportions (4.8–5.0%) of women in each group had abnormal screening results. Higher-risk women were more likely than lower-risk women to undergo biopsy after a positive screen. Screening identified 43 invasive ovarian cancers. The positive predictive values for abnormal screening results were 0.7% in average-risk, 1.3% in moderate-risk, and 1.6% in high-risk groups; one ovarian cancer occurred among the breast cancer survivors. The positive predictive values for postbaseline abnormal screening results were also higher in the higher-risk groups. The positive predictive values did not significantly differ across risk groups.

CONCLUSION: Probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens were similar across groups based on family history of breast or ovarian cancer. However, ovarian cancer was more likely to be diagnosed after an abnormal screening result among women at higher family history–based risk than among women at lower risk.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00002540

LEVEL OF EVIDENCE: I

Most ovarian cancers are sporadic. Women whose relatives have been diagnosed with breast cancer or ovarian cancer are at increased risk of developing ovarian cancer.1 Approximately 33% of U.S. women report a positive family history,2 but only 2% of women will have a family history that is sufficiently strong to be considered for genetic testing for rare but high-penetrance mutations in the BRCA1 or BRCA2 cancer susceptibility genes.3 Prophylactic oophorectomy effectively reduces ovarian cancer risk in mutation carriers,1 but surgery carries morbidity4 and raises other concerns about surgically induced premature menopause.5 Prophylactic oophorectomy is therefore not a viable population-based prevention strategy.

In 2006, an estimated 20,180 U.S. women will be diagnosed with ovarian cancer, and an estimated 15,310 women will die from the disease.6 Detecting ovarian cancer at earlier stages by screening could reduce its mortality and, according to one model, extend survival by 3 years.7 Ovarian cancer screening in the general population has not been shown to be effective and is currently not recommended.8,9 Ongoing randomized clinical trials are evaluating whether ovarian cancer screening in the general population by the CA 125 in serum or transvaginal ultrasonography can reduce ovarian cancer mortality. These clinical trials, which have reported some preliminary results,10 will provide a standard for screening efficacy but will not be completed for several years.11,12

Screening should generate higher yields in groups at higher background risk. Screening women at elevated risk due to a family history of breast or ovarian cancer might prove advantageous compared with population-based screening,13 in which the low prevalence of ovarian cancer and even small numbers of false-positive screening results would reduce overall cost-effectiveness. Definitive data on screening high-risk women, such as BRCA mutation carriers, are not yet available. At least 11 studies have been conducted, but the results collectively include small numbers of ovarian cancers and are difficult to interpret because the studies used different populations, screening modalities, and methods of cancer ascertainment.12 Using preliminary data from the active screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,11 we evaluated whether ovarian cancer screening with CA 125 and transvaginal ultrasonography performs better in women with a family history of breast or ovarian cancer than in women without a family history.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Prorok et al11 previously described the full details of the PLCO trial, which seeks to determine whether routinely screening women with chest X-ray, flexible sigmoidoscopy, and CA 125 plus transvaginal ultrasonography could reduce mortality from lung, colorectal, and ovarian cancers, respectively. Recruitment occurred between November 1993 and July 2001. Women were considered eligible if they were between ages 55 and 74 years and had no previous diagnosis of lung, colon, or ovarian cancer. Women who were receiving cancer treatment, were participating in another cancer screening or prevention trial, or had received flexible sigmoidoscopy or colonoscopy in the past 5 years were not eligible. Women taking tamoxifen were initially excluded because, at the time of study initiation, the relationship between tamoxifen and ovarian cancer was unknown. This restriction was lifted in April 1999 when it became apparent that the association was null.14 The initial restriction of women who had undergone oophorectomy was lifted in 1996 because low accrual of women threatened to jeopardize screening endpoints for lung and colon cancer.

Within each center, age- and sex-stratified randomization assigned women to a control arm, where they were asked to follow their usual medical care, or an intervention arm, where they were offered lung, colorectal, and ovarian cancer screening at regular intervals.11 Recruitment occurred at 10 U.S. screening centers: The University of Alabama at Birmingham, Birmingham, AL; University of Colorado Health Sciences Center, Denver, CO; Georgetown University Medical Center, Washington, DC; Pacific Health Research Institute, Honolulu, HI; Henry Ford Health System, Detroit, MI; University of Minnesota School of Public Health, Minneapolis, MN; Washington University School of Medicine, St. Louis, MO; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Utah Health Sciences Center, Salt Lake City, UT; and Marshfield Medical Research and Education Foundation, Marshfield, WI. Institutional review boards at the National Cancer Institute and each screening center approved the study. Although the current analysis does not address the PLCO trial’s main objectives, the PLCO trial follows Consolidated Standards of Reporting Trials guidelines.15

At entry, participants completed a self-administered general risk factor questionnaire that queried demographics, smoking, history of cancer in first-degree relatives, anthropometry, personal medical and medication use history, reproductive history, exogenous hormone use, gynecologic surgeries, and personal history of cancer screening tests. The precoded questionnaires were optically scanned at each screening center.

We stratified these participants into four risk groups based on their reported personal history of breast cancer or first-degree family history of breast or ovarian cancer. We considered participants who reported no breast cancer or ovarian cancer in relatives to be at average risk. We considered participants who reported only one relative with breast cancer (and no relatives with ovarian cancer) to be at moderate risk if that relative was diagnosed after age 50. We considered participants who reported any relative diagnosed with breast cancer before age 50, two or more relatives diagnosed with breast cancer (regardless of age at diagnosis), or any relative diagnosed with ovarian cancer (regardless of age at diagnosis) to be at high risk. We placed participants who had a personal history of breast cancer into a separate risk category.

After randomization, women in the intervention arm received a concurrent CA 125 test and transvaginal ultrasonography at baseline, plus five additional annual CA 125 tests and three additional annual transvaginal ultrasonography screens. Trained examiners used a 5- to 7.5-MHz transvaginal probe to measure each ovary and describe any observed abnormalities.11 Serum samples were locally obtained and frozen before shipment to the central laboratory, at University of California at Los Angeles, for processing. The Centocor CA-125II RIA assay (Centocor, Inc., Malvern, PA) provided test results, and we considered values of 35 units/mL or more to be abnormal (positive). Coefficients of variation ranged from 4.1% at lower concentrations to 3.8% at higher concentrations.16 We analyzed CA 125 on a logarithmic scale.

Participants and their personal physicians received the CA 125 and transvaginal ultrasonography results within 3 weeks of blood draw. Women whose CA 125 levels were abnormal or whose ultrasonography revealed abnormalities suspicious for cancer were referred to their physicians for further care. Study staff collected medical records for all procedures related to the abnormal screens and recorded data on standardized forms. Each screening center contacted these women to determine whether ovarian cancer was diagnosed. Trained tumor registrars abstracted pathology reports for all ovarian neoplasms, which study staff reviewed. All of the cancers included in this analysis had been confirmed by pathology.

Around each anniversary of their initial screening, all participants received a mailed annual questionnaire, which ascertained the type and date of any cancer diagnosed in the previous year. Study staff contacted participants by mail and telephone if participants did not return their updates. To validate the self-reported cancers, staff retrieved medical records (for standardized medical record abstraction of pathology reports), death certificates, data from state cancer registries, and information from next-of-kin for deceased participants. Trial participants are scheduled to be followed up for at least 13 years after randomization.17

The trial enrolled 78,232 women and randomly assigned 39,117 to the usual-care arm and 39,115 to the screening arm. We first restricted analysis to the 39,115 women in the screening arm, then excluded 4,913 women who had bilateral oophorectomy before enrollment and 5,696 women who never received a screening examination. We also excluded 46 women who did not complete the baseline risk factor questionnaire.16 The final analysis included 28,460 women.

We included neoplasms detected through the first four screening examinations—ie, baseline plus the first three annual screens, for up to four CA 125 and transvaginal ultrasonography tests. We defined a screen-detected endpoint as any invasive ovarian, peritoneal, or fallopian tube cancer or borderline tumor (ie, low malignant potential) that was identified within the 12 months after a positive screening result. We calculated the positive predictive values for endpoint combinations as the number of study endpoints divided by the number of positive screening results. We compared positive predictive values across risk groups using a {chi}2 test where applicable and Fisher exact test, as needed.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We classified reported personal or family history of breast or ovarian cancer at baseline into four risk groups (Table 1). The 22,687 participants with no family history of ovarian or breast cancer were considered average risk. Moderate risk included the 2,572 participants who reported breast cancer in only one relative who was at least 50 years old at diagnosis. We considered the 2,163 women who reported breast cancer in at least one relative who was aged younger than 50 years at diagnosis, breast cancer in multiple relatives, or at least one relative with ovarian cancer to be high risk. The 1,038 women with a personal history of breast cancer at baseline formed a separate risk group. The distribution of trial randomization date was similar in the four groups; the mean and median randomization dates were July 1997.


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  		Table 1. Personal and First-Degree Family History of Breast and Ovarian Cancer at Baseline

 

Table 2 shows the characteristics of the study population. Two thirds of the women were between ages 55 and 64 years. Approximately 87% were white, more than 90% reported at least a high school diploma, approximately 52% had used oral contraceptives, and approximately 92% of women had been pregnant at least once. Almost all women were postmenopausal at entry


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  		Table 2. Characteristics of Study Population

 

Table 3 shows the results of the combined CA 125 and transvaginal ultrasonography screening examinations in the four risk groups. Similar percentages (4.8–5.0%) of women in each of the four risk groups had elevated CA 125 levels or abnormal transvaginal ultrasonography findings (ie, positive screening results). Slightly higher percentages of women with positive screens underwent biopsy in the moderate- and high-risk groups, but approximately one fifth of women with positive screens in the other two groups underwent biopsy.


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  		Table 3. Results of Screening Examinations By Risk Group For 28,460 Participants.

 

A total of 43 invasive ovarian cancers, 9 invasive fallopian tube or peritoneal cancers, and 13 low malignant potential tumors were diagnosed in the study population. The positive predictive value of elevated CA 125 levels or abnormal transvaginal ultrasonography findings for invasive ovarian cancer was 0.7% in the average-risk group, 1.3% in the moderate-risk group, and 1.6% in the high-risk group. These differences were not statistically significant (P=.18). Only one invasive cancer was detected among the 1,038 breast cancer survivors. Based on these values, screening 1,000 women in similar risk groups would be expected to identify no more than one invasive ovarian cancer in each group. Inclusion of low malignant potential tumors, fallopian tube cancers, and peritoneal cancers only slightly increased the positive predictive values, and the pattern of higher positive predictive values in the higher-risk groups held.

We assumed that the PLCO trial was the first ovarian cancer screening opportunity for most of these participants. Because a woman whose first screening results are positive might receive careful subsequent clinical observation, we stratified screening results for all subsequent screening examinations according to whether the baseline screen was normal or positive (Table 4). Regardless of baseline screening results, the percentages of subsequent positive examinations were higher in the moderate-risk and high-risk groups than in the average-risk group. The percentages of subsequent positive examinations in the breast cancer survivors were similar to the average-risk groups. The positive predictive values increased across risk groups among women with a normal baseline screening result, but again did not differ statistically.


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  		Table 4. Results of Postbaseline Screening Examinations Stratified by Baseline Screening Results, by Risk Group for 28,460 Participants

 

For all four risk groups, transvaginal ultrasonography screens generated higher percentages of positive test results and prompted more biopsies than did CA 125 screens (Table 5). Because similar numbers of neoplasms were detected by CA 125 and transvaginal ultrasonography, the CA 125 positive predictive values exceeded the transvaginal ultrasonography positive predictive values. The numbers of detected endpoints steadily increased as family history-based risk increased. More cancers were detected based on CA 125 (n=33) than transvaginal ultrasonography (n=26).


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  		Table 5. Results of All CA-125 and Transvaginal Ultrasonography Screening Examinations by Risk Group for 28,460 Participants

 

Mean baseline CA 125 levels did not differ across risk groups, although the mean slightly increased with each additional year of screening. There was no difference in maximal ovarian volume across risk groups (data not shown).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The low prevalence of ovarian cancer in unselected populations presents a major challenge to ovarian cancer screening programs. We hypothesized that screening in high-risk groups, based on family history of breast and ovarian cancers, would identify more ovarian cancers and generate higher positive predictive values than screening in lower-risk groups. In our study, abnormal CA 125 or transvaginal ultrasonography test results led to similar proportions of average-risk, moderate-risk, and high-risk women and breast cancer survivors being referred for diagnostic follow-up. The probability of subsequently detecting cancer was two to three times higher in the high-risk group than in the average- and moderate-risk groups. However, these differences translated into only marginally higher positive predictive values in the higher-risk groups.

High specificity, reasonable positive predictive values, and low sensitivity have been reported in some studies of screening in high-risk women,10,18–21 but no strategy has yet been demonstrated and validated as effective.9,22 The critical metric for screening success is reduced mortality, which can only be determined from sufficiently large, randomized, controlled clinical trials that compare screening modalities with each other or usual care. The PLCO16 and other ongoing trials12 in both general populations and high-risk populations will answer those questions. Until then, however, our data indicate that routine screening, even in high-risk groups, is unlikely to generate meaningfully higher positive predictive values for ovarian cancer.

Women at elevated risk due to family history but without known BRCA mutations comprise less than 10% of the population.1 Screening recommendations for these women vary.23 Several clinics have screened women at high familial risk using CA 125 and ultrasonography, typically in studies of a few hundred women. The estimates of screening characteristics are thus quite imprecise, but an earlier review8 found positive predictive values ranging from 10% to 50%. Our data from the screening arm of the PLCO Trial included 28,460 women but generated positive predictive values below 5%. Because positive predictive value reflects both the probability that a woman with an abnormal screening examination truly has ovarian cancer and the number of procedures that must be performed to detect one cancer, these results indicate that many women would undergo clinical procedures (usually oophorectomy) to detect even a few cancers.

Apart from age, a positive family history of breast or ovarian cancer is the strongest recognized risk factor for developing ovarian cancer. Family history risks can arise from certain cancer susceptibility syndromes, such as hereditary nonpolyposis colorectal cancer or hereditary breast and ovarian cancer, or result from mutations in high-penetrance cancer susceptibility genes.30 Women with confirmed BRCA1 or BRCA2 mutations represent less than 1–2% of all women3 but have up to a 50% lifetime probability of developing ovarian cancer.30 These women can consider risk-reducing prophylactic salpingo-oophorectomy, but not all women elect to have surgery.1 Women who are likely mutation carriers are recommended to receive genetic testing,3 but not all women comply.1 Risk gradients certainly exist within the large population of women not at high risk, but no consensus definition of risk exists for this group.

Women who have survived breast cancer comprise a separate high-risk group.31 Only one ovarian cancer occurred in the PLCO’s 1,038 breast cancer survivors; therefore, the positive predictive values in this group are likely too unstable to be immediately informative. Surgical and medical treatments for breast cancer, including oophorectomy, can complicate the interpretation of an ovarian screening program. Recent treatment developments, such as selective estrogen receptor modulators and aromatase inhibitors,32 alone or sequentially,33 seem to favorably influence breast cancer survival. Whether those treatments influence ovarian cancer risk is unknown, although the available data from early selective estrogen receptor modulator trials indicated no relationship.34

The design and conduct of the PLCO Screening Trial offer a number of particular strengths compared with observational studies of screening in selected populations, nonrandomized clinical trials, or multicenter trials that lack standard protocols. Because of the small number of ovarian cancers expected in most studies to date, even minor variations in design or conduct could dramatically affect application of study results to other populations. The PLCO participants were recruited from defined populations and screened according to a standard protocol. Each screening center collected identical data, and all screening examinations were consistently administered, evaluated, and analyzed. The PLCO’s large size (even when restricted to only one arm of the trial) generated a large number of postmenopausal women in each of the four risk groups, including over 1,000 breast cancer survivors.

Our analysis has important limitations. The baseline questionnaire did not assess second-degree family history of breast or ovarian cancer. Family history status has not been updated, so we cannot identify women whose family history-based risk increased after baseline. BRCA1 or BRCA2 mutation status has not been determined for trial participants, and therefore the generalizability of these data to confirmed mutation carriers is unknown. We relied on participants’ standard health care providers to determine follow-up of suspicious screening results, including when and in whom to perform biopsies. Because the PLCO Cancer Screening Trial only enrolled women who were at least 55 years old, these results are not generalizable to premenopausal, perimenopausal, or younger women. Finally, the relatively small numbers of ovarian cancers that were identified in this analysis, although it compares favorably to previous publications,12 generates unstable estimates of positive predictive value, and thus additional data from larger populations with longer follow-up are required to fully assess ovarian cancer screening.

Ongoing randomized clinical trials, including the PLCO study, will evaluate the efficacy of ovarian cancer screening. Until such data are available, however, this analysis shows that stratifying women into risk groups based on family history slightly increased the positive predictive value of a combined CA 125- and transvaginal ultrasonography–based screening algorithm. Determining whether those differences prove to be efficacious, cost-effective, or clinically useful in screened populations awaits the results of the PLCO and other screening studies.


   Footnotes
 
Supported in part by the Intramural Research Program of the National Institutes of Health and by individual contracts from the National Cancer Institute to each of the 10 screening centers and the coordinating center.

The authors thank Craig Williams at IMS, Inc., Silver Spring, MD, for computing support.

Corresponding author: James V. Lacey, PhD, 6120 Executive Boulevard MSC 7234, Rockville, MD 20852-7234; e-mail: jimlacey{at}nih.gov.

doi:10.1097/01.AOG.0000239105.39149.d8


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Nelson HD, Huffman LH, Fu R, Harris EL, U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force [published erratum appears in Ann Intern Med 2005;143:547]. Ann Intern Med 2005;143:362–79.[Abstract/Free Full Text]

2. Hughes KS, Roche C, Campbell CT, Siegel N, Salisbury L, Chekos A, et al. Prevalence of family history of breast and ovarian cancer in a single primary care practice using a self-administered questionnaire. Breast J 2003;9:19–25.[Medline]

3. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005;143:355–61.[Abstract/Free Full Text]

4. Kauff ND, Barakat RR. Surgical risk-reduction in carriers of BRCA mutations: where do we go from here? Gynecol Oncol 2004;93:277–9.[Medline]

5. Rosen B, Kwon J, Fung Kee Fung M, Gagliardi A, Chambers A, Cancer Care Ontario’s Practice Guidelines Initiative Gynecology Cancer Disease Site Group. Systematic review of management options for women with a hereditary predisposition to ovarian cancer. Gynecol Oncol 2004;93:280–6.[Medline]

6. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–30.[Abstract/Free Full Text]

7. Urban N. Screening for ovarian cancer. We now need a definitive randomised trial. BMJ 1999;319:1317–8.[Free Full Text]

8. Bell R, Petticrew M, Sheldon T. The performance of screening tests for ovarian cancer: results of a systematic review. Br J Obstet Gynaecol 1998;105:1136–47.[Medline]

9. Fung MF, Bryson P, Johnston M, Chambers A, Cancer Care Ontario Practice Guidelines Initiative Gynecology Cancer Disease Site Group. Screening postmenopausal women for ovarian cancer: a systematic review. J Obstet Gynaecol Can 2004;26:717–28.[Medline]

10. Menon U, Skates SJ, Lewis S, Rosenthal AN, Rufford B, Sibley K, et al. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol 2005;23:7919–26.[Abstract/Free Full Text]

11. Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21:273S–309S.[Medline]

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13. Bell R, Petticrew M, Luengo S, Sheldon TA. Screening for ovarian cancer: a systematic review. Health Technol Assess 1998;2:1–84.[Medline]

14. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

15. Moher D, Schulz KF, Altman D, CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:1987–91.[Abstract/Free Full Text]

16. Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial [published erratum appears in Am J Obstet Gynecol. 2005;193:2183–4]. Am J Obstet Gynecol 2005;193:1630–9.[Medline]

17. Gohagan JK, Prorok PC, Hayes RB, Kramer BS, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Project Team. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Control Clin Trials 2000 Dec;21:251S–72S.

18. Scheuer L, Kauff N, Robson M, Kelly B, Barakat R, Satagopan J, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002;20:1260–8.[Abstract/Free Full Text]

19. Vasen HF, Tesfay E, Boonstra H, Mourits MJ, Rutgers E, Verheyen R, et al. Early detection of breast and ovarian cancer in families with BRCA mutations. Eur J Cancer 2005;41:549–54.[Medline]

20. Meeuwissen PA, Seynaeve C, Brekelmans CT, Meijers-Heijboer HJ, Klijn JG, Burger CW. Outcome of surveillance and prophylactic salpingo-oophorectomy in asymptomatic women at high risk for ovarian cancer. Gynecol Oncol 2005;97:476–82.[Medline]

21. Olivier RI, Lubsen-Brandsma MA, Verhoef S, van Beurden M. CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. Gynecol Oncol 2006;100:20–6.[Medline]

22. Hogg R, Friedlander M. Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol 2004;22:1315–27.[Abstract/Free Full Text]

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24. Bourne TH, Campbell S, Reynolds KM, Whitehead MI, Hampson J, Royston P, et al. Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. BMJ 1993;306:1025–9.[Medline]

25. Karlan BY, Raffel LJ, Crvenkovic G, Smrt C, Chen MD, Lopez E, et al. A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. Am J Obstet Gynecol 1993;169:494–501.[Medline]

26. Muto MG, Cramer DW, Brown DL, Welch WR, Harlow BL, Xu H, et al. Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecol Oncol 1993;51:12–20.[Medline]

27. Schwartz MD, Kaufman E, Peshkin BN, Isaacs C, Hughes C, DeMarco T, et al. Bilateral prophylactic oophorectomy and ovarian cancer screening following BRCA1/BRCA2 mutation testing. J Clin Oncol 2003;21:4034–41.[Abstract/Free Full Text]

28. Dorum A, Heimdal K, Lovslett K, Kristensen G, Hansen LJ, Sandvei R, et al. Prospectively detected cancer in familial breast/ovarian cancer screening. Acta Obstet Gynecol Scand 1999;78:906–11.[Medline]

29. Belinson JL, Okin C, Casey G, Ayoub A, Klein R, Hart WR, et al. The familial ovarian cancer registry: progress report. Cleve Clin J Med 1995;62:129–34.[Medline]

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34. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005;97:1652–62.[Abstract/Free Full Text]





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