Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective

Objective  To assess the efficacy of annual CA125 and transvaginal ultrasound (TVU) scan as surveillance for ovarian cancer.
Design  Retrospective audit.
Setting  NHS Trust.
Population  Three hundred and forty-one asymptomatic women enrolled for ovarian cancer screening: 179 were in a high-risk group (>10% lifetime risk of developing ovarian cancer), 77 in a moderate risk group (4–10% lifetime risk of developing ovarian cancer) and 71 in a near population risk group (<4% lifetime risk).
Methods  Retrospective audit of case records, laboratory CA125 results, radiology reports, histology records and local cancer registry data.
Main outcome measures  Ovarian cancers occurring in study population. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU, and CA125 as a screening tool for ovarian cancer.
Results  Four ovarian cancers and one endometrial cancer occurred. One ovarian cancer was detected at surveillance, three occurred in women who presented symptomatically between screenings. Thirty women underwent exploratory surgery because of abnormal findings at surveillance. Two women had cancer (PPV = 6.7%); one had ovarian cancer and the other endometrial cancer. Twenty-eight women (93.3%) had no malignancy. Sensitivity, specificity, PPV and NPV for TVU in the whole cohort were 33.3, 85.8, 0.6 and 99.8%, respectively. For high-risk individuals, the figures for TVU were 33.3, 84.5, 1.1 and 99.6, respectively. Combining both modalities for the whole cohort, the sensitivity, specificity, PPV and NPV were 66.7, 82.9, 1.5 and 99.8% and 50.0, 82.8, 1.3 and 99.7%, respectively, for the high-risk group alone.
Conclusions  Ovarian screening by annual TVU and CA125 is inefficient at detecting early-stage ovarian cancers.     

Screening for ovarian cancer by transvaginal ultrasound and serum CA125 measurement in women with a familial predisposition: a prospective cohort study

OBJECTIVE: This study evaluates the accuracy of transvaginal ultrasound (TVUS) in combination with CA125 to detect ovarian cancer in women at hereditary risk for ovarian cancer. METHODS: A semi-annual surveillance protocol comprising CA125 measurement and TVUS was offered to 676 women including 85 BRCA mutation carriers. Surgical intervention was performed if TVUS revealed a suspicious cyst or if elevated CA125 levels or cystic lesions persisted in two consecutive examinations. RESULTS: Ten women underwent histological verification that revealed one serous cystadenocarcinoma stage Ic. No interval ovarian cancer occurred. The specificity of surgical intervention reached 98.7% (95% confidence interval (CI): 97.5% to 99.3%) and a positive predictive value (PPV) of 10% (95% CI: 1.8% to 40.4%). CONCLUSION: The low PPV is due to the unexpectedly low incidence of ovarian cancer. Large scale investigations including details on potential confounders and modifiers are needed to further evaluate accuracy and effectiveness of ovarian cancer screening for women at high risk.     

Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study

Abstract.   Gaarenstroom KN, van der Hiel B, Tollenaar RAEM, Vink GR, Jansen FW, van Asperen CJ, Kenter GG. Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study. Int J Gynecol Cancer 2006; 16(Suppl. 1): 54–59.
The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.     

Screening in ovarian cancer.

Ovarian cancer will affect 20,000 American women this year and some 13,500 will die of the disease. Most patients will have stage III or IV disease at the time of diagnosis. Because ovarian cancer may be initially without symptoms, attempts have been made to develop screening tests that would lead to an early diagnosis. Two tests, serum CA 125 and pelvic ultrasonography, have been suggested by some to be accurate enough to be included in yearly screening for ovarian cancer. Although further testing of these techniques is encouraged, data to date do not justify yearly screening with CA 125 or pelvic ultrasonography in all women.     

How relevant are ACOG and SGO guidelines for referral of adnexal mass?

OBJECTIVE: To evaluate referral guidelines published by American College of Obstetricians and Gynecologists (ACOG) and Society of Gynecologic Oncologists (SGO), which provide guidance about when to refer a patient with a pelvic mass to a gynecologic oncologist. METHODS: Data from consecutive patients evaluated for pelvic mass were collected prospectively over a 5-year period. The performance characteristics of the ACOG/SGO referral guidelines for detection of primary and metastatic ovarian cancer were calculated by using menopausal status, CA 125 level, imaging results, physical findings, and family history. RESULTS: Eight hundred thirty-seven patients met inclusion criteria. Forty-four percent (263/597) of postmenopausal women were diagnosed with ovarian cancer, whereas 20% (48/240) of premenopausal women had ovarian cancer. Seventy-four percent of primary cancers were stage III or IV. The referral guidelines were 79.2% sensitive and 69.8% specific for premenopausal women, with a positive predictive value of 39.6%. For postmenopausal women, the guidelines were 93.2% sensitive and 59.9% specific, and positive predictive value was 64.6%. The referral guidelines performed better for late-stage than early-stage cancers in both sensitivity and positive predictive value, especially in postmenopausal women. Although only 28 patients would not have been referred by the guidelines, the majority of these had early stage (I or II) disease. Lowering the CA 125 cutoff level required for referral of premenopausal patients increased the sensitivity of the guidelines in this group. CONCLUSION: The ACOG/SGO guidelines perform well in predicting advanced-stage ovarian cancer, probably owing to the nature of advanced-stage disease. The guidelines perform poorly in identifying early-stage disease, especially in premenopausal women, primarily due to lack of early markers and signs of ovarian cancer.     

Ovarian cancer screening in women with a family history of breast or ovarian cancer

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. LEVEL OF EVIDENCE: I.     

Gynecologic screening in hereditary nonpolyposis colorectal cancer

OBJECTIVE: In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program. METHODS: Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files. RESULTS: Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected. CONCLUSIONS: These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance.     

Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: implications for ovarian cancer screening

OBJECTIVE: Our purpose was to report the cancers arising during a familial ovarian cancer screening program and investigate the tumor's clonality and association with BRCA1 and BRCA2 mutations. STUDY DESIGN: Program participants with a diagnosis of ovarian cancer or peritoneal serous papillary carcinoma were identified and their demographic characteristics, ultrasonographic findings, CA 125 results, operative reports, and pathology slides reviewed. Immunohistochemical analysis of p53, bcl-2, HER-2/neu, and nm23 H1 expression was performed on tumor tissues from multiple metastatic sites, and germline BRCA1 and BRCA2 mutations were identified. RESULTS: Three stage I ovarian cancers and 7 cases of peritoneal serous papillary carcinoma were diagnosed from among 1261 program participants. Ultrasonographic abnormalities triggered surgical exploration in all 3 cases of stage I disease. Elevated levels of CA 125 were the harbinger in 2 of 7 cases of peritoneal serous papillary carcinoma, abnormal ultrasonographic findings prompted diagnosis in 2 of 7 cases, and 3 of 7 women had abdominal symptoms 5, 6, and 16 months after screening. Results of immunohistochemical studies suggested multifocal disease in 5 of 7 patients with peritoneal serous papillary carcinoma. At least 3 of the patients with peritoneal serous papillary carcinoma carry BRCA1 185delAG mutations. CONCLUSION: Multifocal peritoneal serous papillary carcinoma may be a phenotypic variant of familial ovarian cancer, and screening strategies for these women cannot rely on ultrasonography and CA 125 testing to detect early disease.     

The role of ultrasound evaluation in the detection of early-stage epithelial ovarian cancer

OBJECTIVE: Epithelial ovarian cancer kills more women than all other gynecologic malignancies combined because of our inability to detect early-stage disease. Ultrasonography has demonstrated usefulness in the detection of ovarian cancer in asymptomatic women, but its value for the detection of early-stage epithelial ovarian cancer in women of increased risk is uncertain. We examined the usefulness of sonography in the detection of early-stage epithelial ovarian cancer in asymptomatic high-risk women who participated in the National Ovarian Cancer Early Detection Program. STUDY DESIGN: Only asymptomatic women of increased risk for the development of ovarian cancer with initial normal gynecologic and ultrasound examinations were eligible to participate in the institutional review board-approved National Ovarian Cancer Early Detection Program. Participants underwent comprehensive gynecologic and ultrasound examinations every 6 months. Increased risk includes women with at least 1 affected first-degree relative with ovarian cancer; a personal history of breast, ovarian, or colon cancer; > or =1 affected first- and second-degree relatives with breast and or ovarian cancer; inheritance of a breast cancer mutation from an affected family member, or membership within a recognized cancer syndrome. RESULTS: The average age of the 4526 women who were evaluated was 46 years; 2610 women were premenopausal, and 1916 women were postmenopausal. A total of 12,709 scans have been performed since 1990. Visualization of both ovaries was noted in 98% of premenopausal and in 94% of postmenopausal women. Fourteen women had undergone unilateral salpingo-oophorectomy. Recall rates at less than the routine 6-month interval were 0.4% in the premenopausal and 0.3% in postmenopausal women. A total of 98 women with persistent adnexal masses were identified, and 49 invasive surgical procedures were performed that diagnosed 37 benign ovarian tumors and 12 gynecologic malignancies. All cancers were detected in asymptomatic women who had normal ultrasound and physical examinations 12 and 6 months before the cancer diagnosis. The detected malignancies were fallopian tube carcinoma (stage IIIC; n = 4 women), primary peritoneal carcinoma (n = 4 women; stage IIIA, 1 woman; stage IIIB, 2 women; stage IIIC, 1 woman), epithelial ovarian cancer (stages IIIA and IIIB; n = 2 women), and endometrial adenocarcinoma (stage IA; n = 2 women). Additionally 37 primary and 12 recurrent breast carcinomas were detected by physical examination. A total of 184 women with genetic predisposition (breast cancer positive) have undergone a prophylactic bilateral salpingo-oophorectomy; 23% of these procedures found atypical hyperplasia, and unexpectedly, 2 women (1%) were found to have stage III (A and B) primary peritoneal carcinoma. CONCLUSION: This study demonstrates the limited value of diagnostic ultrasound examination as an independent modality for the detection of early-stage epithelial ovarian cancer in asymptomatic women who are at increased risk for disease.     

Prospective evaluation of serum CA 125 levels for early detection of ovarian cancer.

Detection of ovarian cancer at an early stage should reduce the mortality associated with this disease. Through the Stockholm Population Registry, 5550 apparently healthy women were enrolled in a study designed in part to define the use of the CA 125 radioimmunoassay (RIA) as an initial test for early detection of ovarian cancer. Women whose CA 125 levels were elevated and an equal number of age-matched controls with normal levels were followed by means of pelvic examinations, transabdominal sonography, and serial CA 125 determinations. Of the 175 women with high CA 125 levels, six were found to have ovarian cancer: two each in stages IA, IIB, and IIIC. Of those with normal-range CA 125 levels, three had ovarian cancer as identified through the Swedish Cancer Registry; all three were under 50 years of age. Ovarian cancer was diagnosed on laparotomy in six of the women age 50 or over. Using thresholds of 30 and 35 U/mL, the rates of specificity for the CA 125 RIA were 97 and 98.5%, respectively, for women age 50 or older, and 91 and 94.5%, respectively, for those younger than 50 years of age. Thus, the specificity of the CA 125 RIA is adequate in postmenopausal women to undertake a larger study to determine whether screening using CA 125 influences survival of patients with ovarian cancer.     

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Objective

In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics.

Methods

The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n = 121); all CA125+/TVU+ (n = 46); and a random sample of TVU+ (n = 373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ², Fisher's exact, or Wilcoxon-Mann-Whitney tests.

Results

Women with a false-positive TVU were younger (P < 0.001), heavier (P < 0.001), and reported a higher frequency of prior hysterectomy (P < 0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P < 0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P = 0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P < 0.001).

Conclusions

False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.     

Screening for familial ovarian cancer—management and outcome of women with moderate to high risk of developing ovarian cancer

Abstract.   Rieck GC, Lim K, Rogers MT, France E, Gray JR, Amso N, Evans AS, Howells RH, & Fiander AN. Screening for familial ovarian cancer—management and outcome of women with moderate to high risk of developing ovarian cancer. Int J Gynecol Cancer 2006; 16(Suppl. 1): 86–91.
Five percent to ten percent of ovarian cancers are hereditary. Individual genetic risk of developing ovarian malignancy is discussed in women. Currently, prophylactic surgery is advised to women with a moderate to high risk of developing ovarian cancer. Workload and outcome of the multidisciplinary familial ovarian screening clinic in South Wales were assessed. This was an observational study of 145 women registered with the Familial Ovarian Screening Clinic between January 1998 and December 2003. The data were retrieved from the medical notes. Yearly follow-ups were investigated with a transvaginal scan and CA125 level. Post-surgery women were followed up with yearly CA125 estimations: 46.9% fell into moderate-risk and 50.3% into high-risk category. The median age was 42 (SD 10.4), 71.7% were pre menopausal, and 10.3% had a personal history of breast cancer and 1.4% colon cancer. Whereas 36.5% opted for surgery, the remaining women (but two) opted for annual follow-up. Histology of the women who had surgery showed three cases of malignancies (fallopian tube carcinoma, atypical ovarian epithelial cells, and metastatic breast cancer). Seven women developed breast cancer during the observation period. The follow-up period is too short to come to a final conclusion as to the benefits of yearly screening in this group of women. In our series, a significant number of patients developed malignancies, despite prophylactic surgery.     

Preoperative plasma osteopontin level as a biomarker complementary to carbohydrate antigen 125 in predicting ovarian cancer

AIM: New biomarkers other than carbohydrate antigen (CA) 125 are needed for the detection of ovarian cancer. Osteopontin (OPN) is one of the candidates identified by high-throughput complementary DNA microarray techniques. We evaluated the preoperative plasma OPN level as a diagnostic biomarker for ovarian cancer in comparison with CA125. METHODS: Preoperative plasma OPN and CA125 levels were measured and compared in 32 patients with ovarian cancer, 34 patients with benign ovarian tumor, 30 patients with other gynecologic cancers and 31 healthy women. Preoperative plasma OPN levels were also assessed according to tumor stage, the volume of ascites and histological types. The sensitivity and specificity for predicting ovarian cancer was compared between OPN and CA125. RESULTS: Preoperative plasma OPN levels were significantly higher in patients with ovarian cancer than in those with benign ovarian tumor, in other gynecologic patients or in healthy women. Stage IV ovarian cancer patients and ovarian cancer patients with ascites had higher plasma OPN levels than those without ascites and in a lower stage. There was no relation between OPN and the histological type. The sensitivity of preoperative plasma OPN in detecting ovarian cancer was 81.3% and almost reached that of CA125. The specificity was moderate. Sensitivity increased to 93.8% with the combination of CA125, compared to 84.4% with CA125 alone. CONCLUSION: Preoperative OPN is a useful biomarker for predicting ovarian cancer. It is especially useful when used complementary to CA125. Larger studies of patients with ovarian cancer showing a low CA125 level or in early stages of ovarian cancer are needed.     

Attitudes toward prophylactic oophorectomy and screening utilization in women at increased risk of developing hereditary breast/ovarian cancer.

OBJECTIVES: The aim of this study was to evaluate ovarian cancer screening uptake and attitudes toward prophylactic oophorectomy in women at risk of developing hereditary breast/ovarian cancer. STUDY METHODS: Ninety-five unaffected women, who approached 1 of 14 familial cancer clinics for advice about their breast/ovarian cancer risk and surveillance and prophylactic options, were assessed in a cross-sectional design when they attended the clinic. RESULTS: Among high-risk women ages 30 and over who had not had a prophylactic oophorectomy, 48% reported ever having had an ovarian ultrasound, and among women ages 50 and over 23% had had a serum CA 125 test. Twenty-three percent of women would consider, and 27% would not consider, a prophylactic oophorectomy should the genetic test indicate a germline mutation associated with hereditary breast/ovarian cancer, while 38% were unsure. Twelve percent had already undergone a prophylactic oophorectomy. Interest in prophylactic oophorectomy was associated with increased breast/ovarian cancer anxiety (chi(2) = 5.14, P = 0.023), but not objective cancer risk (chi(2) = 0.40, P = 0.53). CONCLUSION: Findings demonstrate that breast/ovarian cancer anxiety, rather than objective risk, is the major factor which determines women's attitude to prophylactic oophorectomy. Women are likely to benefit from interventions aimed at reducing breast/ovarian cancer anxiety. Research on the impact of prophylactic oophorectomy would be helpful in the development of educational strategies and decision aids to assist women who are trying to make a decision under conditions of uncertainty.     

Identifying and managing hereditary risk of breast and ovarian cancer

In the past, all women with a family history of breast or ovarian cancer were considered to be at increased risk of cancer themselves. The discovery of BRCA1 and BRCA2 demonstrated that susceptibility to breast and ovarian cancer can be inherited by women as a single-gene autosomal dominant disorder. For such women, evaluation of family history is an important screening tool to identify the possibility of hereditary cancer risk but only genetic testing can provide definitive, individualized risk assessment. Women who have inherited mutations in BRCA1 or BRCA2 now have several medical management options to address their increased risk of cancer. A well-educated community of health care providers and patients can use hereditary risk assessment, including genetic testing, to improve health care.     

The Potential Role of Serum CA 125 in an Ultrasound-Based Screening Program for Familial Ovarian Cancer

We have assessed the potential role of a test based upon the measurement of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. A sample of peripheral blood was taken from 1502 self-referred, asymptomatic women whose pedigree showed that at least one close relative had developed the disease. All women in the study underwent one screening by transvaginal ultrasonography (consisting of one or more scans) to detect any persistent lesion and a change in ovarian volume. Women with a positive result were referred for surgery. The concentration of serum CA 125 was measured in all samples at the end of the study. Seven ovarian cancers (4 invasive and 3 of borderline malignancy; 5 FIGO stage Ia, 1 stage IIa, 1 stage III) and 55 benign lesions were detected. We calculated the effect that a prescreening test (based on different threshold values for serum CA 125) would have had on the number of women entering the ultrasound-based screening program, and on the detection rate and false-positive rate of the overall procedure. There was a direct relationship between the number of women referred for ultrasound screening and the detection rate. The use of a threshold value for serum CA 125 20 U/ml would have meant that 380 women (25.3%) were referred for ultrasonography and 5 out of 7 cancers (71%) would have been detected with a false-positive rate of 1.1%. The odds of a woman with a positive screening result having cancer at surgery would have been about 1:3 (which would improve to about 1:1 if observational indices of color Doppler imaging and a morphological score had been used throughout). We concluded that a prescreening immunochemical test based on the measurement of serum CA 125 (with a threshold value of 20 U/ml) would increase the prior odds for familial ovarian cancer by 2.8, but would lower the overall detection rate by 29% at the prevalence screening.     

The multidisciplinary management of a family with epithelial ovarian cancer.

OBJECTIVE: To describe the management of a family with an inherited predisposition to ovarian and breast cancer. Particular attention is paid to the problems of contraception, screening, prophylactic surgery and hormone replacement therapy. SETTING: The multidisciplinary Grampian Familial Epithelial Ovarian Cancer Study Group. SUBJECTS: 162 members of a family extending over five generations. In the third generation, five of the 10 women died with epithelial ovarian cancer. Three women in generation IV have developed pre-menopausal breast cancer. There are now 78 family members in the fifth generation aged between 2 and 22 years. INTERVENTIONS: Counselling of female family members is started at the age of 18 years. The combined oral contraceptive pill is advocated to suppress ovulation. Gynaecological follow-up after the age of 28 includes yearly pelvic examination, transvaginal ultrasonography and serum CA125 estimation. Laparoscopy with peritoneal cytology is indicated if any part of this yearly assessment is abnormal. Prophylactic oophorectomy is advised between the ages of 35 and 40 years after the family is complete. In generation IV, 20 of the 29 women have undergone prophylactic oophorectomy. Oestrogen hormone replacement therapy with a cyclical progestogen is recommended after prophylactic oophorectomy. Breast cancer screening starts at the age of 25 and involves annual clinical breast examination augmented by mammography and breast ultrasound. CONCLUSIONS: Only by the careful questioning and recording of family history, including at least third degree relatives (cousins), will similar groups with familial ovarian/breast cancer be identified. When predisposing genes are characterized it will be possible to identify carriers within the family and concentrate clinical effort on them while offering appropriate reassurance to those with decreased risk.     

Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer

Epithelial ovarian cancer is most commonly detected in an advanced stage, when the overall 5-year survival rate is 20–30%. Detection of early-stage ovarian cancer results in improved survival. Currently, there is no effective strategy for ovarian cancer screening. Women with persistent and progressive symptoms, such as an increase in bloating, pelvic or abdominal pain, or difficulty eating or feeling full quickly, should be evaluated, with ovarian cancer being included in the differential diagnosis. Evaluation of the symptomatic patient includes physical examination and may include transvaginal ultrasonography and measurement of levels of the serum tumor marker CA 125. Patients suspected of having ovarian cancer should be managed by a gynecologic surgeon, such as a gynecologic oncologist, who is trained to perform comprehensive surgical staging and cytoreductive (debulking) surgery.     

Advances in the understanding of risk factors for ovarian cancer

The identification of risk factors for ovarian cancer is central to the goal of preventing deaths from this disease. Reproductive and hormonal history clearly modulate the risk of ovarian cancer. Continuous ovulation associated with nulliparity increases the likelihood of ovarian malignancy. Protective factors include conditions that suspend ovulation, such as pregnancy, lactation and oral contraceptive use. Hereditary syndromes account for 10% of ovarian cancer cases. The breast ovarian cancer syndrome is caused by mutations in the BRCA1 and BRCA2 genes and is associated with an 11-40% risk of developing ovarian cancer. The hereditary nonpolyposis colorectal cancer syndrome (HNPCC, or Lynch II) is caused by mutations in DNA mismatch repair genes and carries a 12% risk of ovarian cancer. Due to a lack of adequate screening techniques, women with BRCA1, BRCA2 or HNPCC mutations should consider prophylactic removal of the ovaries and fallopian tubes when childbearing is complete. Genetic polymorphisms are hereditary genetic variations that may act in concert with other genetic, hormonal or environmental factors to potentiate the risk of ovarian cancer. Finally, ovarian cancer risk is altered by environmental and behavioral factors. Further study of the risk factors for ovarian cancer is needed to develop effective preventive strategies.     

Use of CA-125 and ultrasound in high-risk women

Abstract. Laframboise S, Nedelcu R, Murphy J, Cole DEC, Rosen B. Use of CA-125 and ultrasound in high-risk women.
Our objective was a retrospective study reporting on ovarian cancer screening in a high-risk female population using both CA-125 and ultrasound over a 7-year period. We used risk estimates of carrying a BRCA mutation that were based on family history. Subjects were screened with CA-125 and ultrasound every 6 months.
Each of 311 high-risk subjects had between 1 and 17 screening visits. Overall, 33 of 1209 (2.7%) CA-125 results were abnormal (>35 U/ml); 226 of 1342 (17%) ultrasounds were abnormal, with abnormalities ranging from benign appearing cystic changes to more ominous patterns. Since entry into the program, 29 subjects (9%) have undergone surgery. In 20 of these, the preoperative screening was normal; in six, only the ultrasound was abnormal, and in two, only the CA-125 was abnormal (46–91 U/ml). In only one subject undergoing surgery were both serial CA-125 levels (52–91 U/ml) and ultrasound abnormal. In 7 years of screening, one patient (0.3%) has been diagnosed with ovarian cancer (stage IA, grade 1 endometrioid adenocarcinoma). Overall, 31 (10%) subjects have completed BRCA testing. We conclude that despite screening results comparable to other studies, the detection of only one ovarian cancer over 7 years is lower than expected. Explanations for this observation are discussed. Despite the limitations of CA-125 and ultrasound, we continue to recommend these screening modalities for high-risk women. At the present time, they offer the best opportunity to detect ovarian cancers early. With increasing knowledge of BRCA testing, more women may benefit from this testing in assessing their personal risk.