Low Incidence Of Ovarian Cancer Research Articles

Improving Specificity for Ovarian Cancer Screening Using a Novel Extracellular Vesicle–Based Blood Test: Performance in a Training and Verification Cohort

The low incidence of ovarian cancer (OC) dictates that any screening strategy needs to be both highly sensitive and highly specific. This study explored the utility of detecting multiple colocalized proteins or glycosylation epitopes on single tumor-associated extracellular vesicles (EVs) from blood. The novel OC Test employs immunoaffinity capture of tumor-associated EVs followed by proximity-ligation qPCR to detect combinations of up to three biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. A high-grade serous carcinoma (HGSC) case-control training set of EDTA plasma samples from 397 women was used to lock down the test design, the data interpretation algorithm, and the cut-off between cancer and non-cancer. Performance was verified and compared to CA125 in an independent blinded case-control set of serum samples from 390 women (132 controls, 66 HGSC, 83 non-HGSC OC, 109 benign). In the verification study, the OC Test showed a specificity of 97.0% (128/132; 95% CI: 92.4%-99.6%), a HGSC sensitivity of 97.0% (64/66; 95% CI: 87.8%-99.2%), and an AUC of 0.97 (95% CI 0.93-0.99) and also detected 73.5% (61/83; 95% CI: 62.7%-82.6%) of the non-HGSC OC cases. This test exhibited fewer false positives in subjects with benign ovarian tumors, non-ovarian cancers, and inflammatory conditions when compared to CA125. The combined sensitivity and specificity of this new test suggests it may have potential in OC screening.

Sensitivity and Specificity of Selected Biomarkers and Their Combinations in the Diagnosis of Ovarian Cancer.

One of the greatest challenges in modern gynecological oncology is ovarian cancer. Despite the numerous studies currently being conducted, it is still sometimes detected at late clinical stages, where the prognosis is unfavorable. One significant contributing factor is the absence of sensitive and specific parameters that could aid in early diagnosis. An ideal screening test, in view of the low incidence of ovarian cancer, should have a sensitivity of greater than 75% and a specificity of at least 99.6%. To enhance sensitivity and specificity, diagnostic panels are being created by combining individual markers. The drive to develop better screening tests for ovarian cancer focuses on modern diagnostic methods based on molecular testing, which in turn aims to find increasingly effective biomarkers. Currently, researchers' efforts are focused on the search for a complementary parameter to those most commonly used that would satisfactorily enhance the sensitivity and specificity of assays. Several biomarkers, including microRNA molecules, autoantibodies, cDNA, adipocytokines, and galectins, are currently being investigated by researchers. This article reviews recent studies comparing the sensitivity and specificity of selected parameters used alone and in combination to increase detection of ovarian cancer at an early stage.

Abstract A040: Improving specificity for ovarian cancer screening using a novel extracellular vesicle-based blood test

Abstract Introduction: The low incidence of ovarian cancer (OC) in average risk individuals dictates any OC screening method needs to be both highly sensitive and highly specific. Even using the multimodal OC screening strategy combining longitudinal serum CA125 and transvaginal ultrasound, 16% of OCs were not detected and false positives due to benign ovarian tumors, which are 5-10 times more prevalent than OC, remained high. Due to lack of mortality benefit, population screening is still not recommended. We hypothesized that detecting multiple colocalized protein or glycosylation epitopes (PGEs) on single tumor-derived extracellular vesicles (EVs) would increase specificity and sensitivity for detection of OC. Methods: The Mercy Halo™ OC test employs immunoaffinity capture and proximity-ligation qPCR to detect combinations of up to 3 PGE biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. We selected 3 PGE combinations to form a panel test to distinguish high-grade serous ovarian cancer (HGSC) from benign ovarian tumors and normal patients and compared performance of our test to CA125. We used a case-control training set from university-associated Canadian biobanks comprised of EDTA plasma from 124 healthy controls, 89 HGSC cases (17 Stage I, 35 Stage II, 37 Stage III)(10 BRCA+), and 192 benign adnexal masses to lock down the test, the data interpretation algorithm, and the cut-off between cancer and non-cancer. Performance was verified in an independent blinded diagnostic case-control set of 397 serum samples from 138 healthy controls, 111 benign adnexal masses, 20 borderlines, 66 HGSC and 62 non-HGSC from the UK Ovarian Cancer Population Study. For comparison, a CA125 ELISA was run for all samples in both studies. Results: Using the locked assay, algorithm, and cut-off established in the training cohort, our test showed a specificity in healthy controls of 92.8% (128/138; 95% CI: 0.87-0.96), a sensitivity in HGSC of 97.0% (64/66; 95% CI: 0.90-0.99), and an AUC of 0.92 (95% CI 0.89-0.95) in the verification cohort. We correctly identified 11/13 Stage I and all 54 Stage II/III/IV HGSC cases. Our test also detected 76.8% (63/82) of the borderline and non-HGSC histotypes. CA125 detected 92.4% (61/66) of the HGSC cases and 84.1% (69/82) of the borderlines and non-HGSC. The greatest improvement in test performance relative to CA125 was seen with benign adnexal masses. In the verification cohort 35.1% (39/111) of the benign samples were CA125 positive compared to 21.6% (24/111) with our test. This reduction in false positives was seen across 10 benign histotypes tested. Conclusions: These results demonstrate that our test using colocalized PGEs on EVs can detect OC, especially HGSC, in both plasma and serum with high sensitivity and specificity. The combinations of 5 biomarkers rather than CA125 alone also decreased benign false positives. The test performance suggests that our test may be useful in average and/or high-risk ovarian cancer screening. Future studies will explore this in asymptomatic populations. Citation Format: Emily S. Winn-Deen, Sanchari Banerjee, Daniel Gusenleitner, Laura T. Bortolin, Jonian Grosha, Kelly M. Biette, Karen Copeland, Christopher R. Sedlak, Bilal Hamzeh, Anthony D. Couvillon, Delaney M. Byrne, Peter A. Duff, Lauren T. Cuoco, MacKenzie S. King, Aleksandra Gentry-Maharaj, Sophia Apostolidou, Dawn R. Mattoon, Christine D. Berg, David F. Ransohoff, Steven J. Skates, Usha Menon. Improving specificity for ovarian cancer screening using a novel extracellular vesicle-based blood test [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A040.

The Performance of HE4 Alone and in Combination with CA125 for the Detection of Ovarian Cancer in an Enriched Primary Care Population.

Simple SummaryOvarian cancer is the most common cause of death from gynaecological cancer in the UK. Survival is better when the disease is diagnosed early. However, identifying ovarian cancer is challenging because symptoms are non-specific. Simple, accurate tests are needed to help identify ovarian cancer in symptomatic women. HE4, a relatively new blood biomarker, has shown promise in the hospital setting. This study aimed to assess whether HE4 would improve ovarian cancer diagnosis in women with symptoms in primary care. We found combining HE4 levels with the currently used test (CA125) within an algorithm (Risk of Ovarian Malignancy Algorithm) improved the detection of ovarian cancer in primary care, particularly in women under 50 years of age, where diagnosis is more challenging. However, our results require validation in a larger sample. This study advances our knowledge of HE4 as an ovarian cancer biomarker in the primary care setting.Human epididymis 4 (HE4) is a promising ovarian cancer biomarker, but it has not been evaluated in primary care. In this prospective observational study, we investigated the diagnostic accuracy of HE4 alone and in combination with CA125 for the detection of ovarian cancer in symptomatic women attending primary care. General practitioner (GP)-requested CA125 samples were tested for HE4 at a large teaching hospital in Manchester, and cancer outcomes were tracked for 12 months. We found a low incidence of ovarian cancer in primary care; thus, the cohort was enriched with pre-surgical samples from 81 ovarian cancer patients. The Risk of Ovarian Malignancy Algorithm (ROMA) was calculated using age (</>51) as a surrogate for menopause. Conventional diagnostic accuracy metrics were determined. A total of 1229 patients were included; 82 had ovarian cancer. Overall, ROMA performed best (AUC-0.96 (95%CI: 0.94–0.98, p = <0.001)). In women under 50 years, the combination of CA125 and HE4 (either marker positive) was superior (sensitivity: 100% (95%CI: 81.5–100.0), specificity: 80.1% (95%CI 76.7–83.1)). In women over 50, ROMA performed best (sensitivity: 84.4% (95%CI: 73.1–92.2), specificity: 87.2% (95%CI 84.1–90)). HE4 and ROMA may improve ovarian cancer detection in primary care, particularly for women under 50 years, in whom diagnosis is challenging. Validation in a larger primary care cohort is required.

Association between pelvic inflammatory disease and subsequent salpingectomy on the risk for ovarian cancer

AimSalpingectomy is associated with a lower risk for ovarian cancer, suggesting that the fallopian tubes constitute the origin of the disease. It is unclear whether the observed effect is mediated by pelvic inflammatory disease (PID); a major indication for salpingectomy and implicated in the aetiology of ovarian cancer. MethodsIn this population-based cohort study, we used nationwide registry-based data on women exposed for PID with and without subsequent salpingectomy (n = 97,912) compared with the unexposed population (n = 5,429,174) between 1973 and 2010. The effect of hormone treatment was considered in a subanalysis. ResultsOf the exposed women, 9538 women underwent salpingectomy during the study period. There was a significant association between PID and ovarian cancer (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.31–1.59), whereas an inverse association was observed for exposed women with subsequent salpingectomy (HR 0.55, 95% CI 0.36–0.83). Salpingectomy performed on other indications (n = 24,895) was associated with a lower incidence of ovarian cancer (HR 0.72, 95% CI 0.56–0.93). No effect modification was observed for the use of oral contraceptives or hormonal replacement therapy. ConclusionSalpingectomy is associated with a lower incidence of ovarian cancer regardless of indication.

CAG repeat size in Huntingtin alleles is associated with cancer prognosis.

The abnormal expansion of a ≥36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (≥27) than in those with a CAG tract <27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).

Opportunistic Salpingectomy to Reduce the Risk of Ovarian Cancer

Substantial medical evidence shows that about half of ovarian cancers originate in the fallopian tube. Some medical organizations and clinical articles have suggested opportunistic salpingectomy to reduce the risk of ovarian cancer in patients at average risk of developing it. This entails removing the fallopian tubes at the same time as another procedure that would occur anyway. The authors argue that the principles of totality and double effect can justify such salpingectomies, even though there is a low incidence of ovarian cancer. Since screening tools for ovarian cancer are ineffective and treatment options are poor, the good effect of reducing the risk of death from this type of ovarian cancer can be proportionate to the bad effects of the minor increase in surgical risk over the other procedure, the unintended side effect of infertility, and the removal of normally functioning tissue. The authors conclude that it is within the purview of a patient and physician to determine whether the benefits are proportionate to the risks in a particular case.

Contraceptive methods and ovarian cancer risk among Chinese women: A report from the Shanghai Women's Health Study.

Oral contraceptive use is associated with reduced ovarian cancer risk; however, associations with other contraceptive methods, such as intrauterine device (IUD) and tubal ligation, are less clear. Women in China differ from western women in regard to mechanisms and duration of use of contraception. This study was undertaken to evaluate associations between contraceptive methods and ovarian cancer risk using data from the prospective Shanghai Women's Health Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. A total of 174 epithelial ovarian cancer cases were found to occur among 70,259 women who were followed-up for a total of 888,258 person-years. The majority of women had ever used any contraception (77.0%), including IUD (55.6%), oral contraceptive (20.4%), tubal ligation (14.7%) or contraceptive shots (2.6%). Ever use of any contraception was associated with a nonsignificant reduction in ovarian cancer risk (HR: 0.86, 95% CI: 0.60-1.24). Longer duration of IUD use was associated with lower ovarian cancer risk (p-value for trend = 0.04). Compared with never users, women with durations of IUD use longer than the median (20 years) were 38% less likely to develop ovarian cancer (HR: 0.62, 95% CI: 0.40-0.97). Based on the high prevalence and long duration of IUD use among Chinese women, we estimate a preventive fraction of 9.3%, corresponding to approximately 16 ovarian cancer cases. High prevalence of long-term IUD use may, therefore, contribute to the low incidence of ovarian cancer observed in China.

Abstract B60: Contraceptive methods and ovarian cancer risk among Chinese women: A report from the Shanghai Women Health Study

Abstract Background: Oral contraceptive (OC) use is known to be associated with reduced ovarian cancer risk; associations with other contraceptive methods, such as intrauterine devices (IUD) and tubal ligation (TL), are less clear. The majority of studies conducted to date have used case-control designs; fewer cohort studies have been conducted, especially among Asian women. As contraception use is popular among Chinese women, and the use of different contraceptive methods differs from Western countries, differences in associations with ovarian cancer risk may exist. Methods: Data from the prospective Shanghai Women's Health Study (SWHS) was used to evaluate associations between different contraceptive methods and risk of ovarian cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression; models included adjustment for age, education, years of ovulation, body mass index (BMI), first-degree family history of cancer (yes/no), and regular physical activity within 5 years (yes/no). Results: A total of 164 ovarian cancer cases occurred among 70,349 women after an average follow-up time of 11.74 years. The majority of women had ever used any contraception (77.0%), including OC use (20.4%), contraceptive shots (2.6%), IUD use (55.6%) and TL (14.7%). Ever use of any contraception method was associated with a non-significant reduction in ovarian cancer risk (HR: 0.83, 95% CI: 0.58-1.19). Similarly, among users of contraception, women with durations of OC use longer than the median (≥2 years) tended to have lower ovarian cancer risk (HR: 0.60, 95% CI: 0.26-1.39), while women with durations of IUD use longer than the median (≥23 years) had significantly decreased ovarian cancer risk (HR: 0.48, 95% CI: 0.30-0.75). Conclusion: Longer durations of IUD use had beneficial effects on ovarian cancer risk among Chinese women. Due to the high prevalence and long duration of IUD use among Chinese women, and the protective association seen in this study, we estimate that approximately 20 ovarian cancer cases (12.0%) were prevented in this study population. Therefore, patterns of use of different contraceptive methods in China may contribute to the lower incidence of ovarian cancer observed in this country. Citation Format: Zhezhou Huang, Alicia Beeghly-Fadiel, Honglan Li, Wanqing Wen, Yutang Gao, Wei Zheng, Xiao-Ou Shu. Contraceptive methods and ovarian cancer risk among Chinese women: A report from the Shanghai Women Health Study. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B60.

Genistein as a Potential Anticancer Agent against Ovarian Cancer

Genistein is known as the major component of isoflavone, which is present in high-soy diets. Genistein has received much attention because of its chemopreventive and therapeutic effects on various types of cancers. Numerous studies have shown that genistein has antineoplastic effects against ovarian cancer. Several epidemiological studies have shown that women who have high consumption of isoflavones have a relatively low incidence of ovarian cancer. Genistein inhibits ovarian carcinogenesis by pleiotropic mechanisms. A higher affinity to estrogen receptor β is one probable explanation for its ability to reduce the risk of ovarian cancer. Genistein also targets multiple cellular signal transduction pathways associated with cell cycle regulation and apoptosis. In addition, genistein has been suggested to have antiangiogenic and antioxidant activities. Herein, we summarize recent results from epidemiological and experimental studies to identify the role of genistein in ovarian cancer. Further studies are needed to achieve conclusive results and determine the clinical applications of genistein.

Screening for Ovarian Cancer

Ovarian cancer remains the most deadly of the gynecologic cancers. It is difficult to diagnose until in advanced stages. An effective screening test may help to decrease mortality from ovarian cancer. Due to the low incidence of ovarian cancer in the general population, a good screening test must have high sensitivity and specificity to allow accurate detection without excessive false-positive results. Thus, effective screening for ovarian cancer has remained elusive. Studies evaluating screening methods for ovarian cancer are reviewed. Screening methods investigated include ultrasound, CA-125, and serum proteins. The use of CA-125 or ultrasound alone does not result in adequate sensitivity or specificity for routine screening. A combination of the two modalities improves sensitivity, specificity, and positive predictive value. Using a combination of serum proteins may also improve sensitivity, specificity, and positive predictive value, but such studies have yet to be validated. No effective screening methods for ovarian cancer that have been adequately validated are available. Routine screening for ovarian cancer in the general population is not currently recommended.

In reply: A large-scale study on the role of ovarian symptom index is necessary

We appreciate the comments by Dr. Kim YT on our study. We agree to his comment that the population of our study cannot represent the whole Korean population. A population-based prospective study would be necessary to determine the usefulness of ovarian symptom index (OSI). However, it requires enormous resources to perform a large-scale prospective study. As a preparatory step to a large-scale prospective study, our study was designed as a hypothesis-generating, case-control study. It is already well-known that OSI is associated with ovarian cancer.1,2 However, we thought that the validation of OSI is necessary in Korean women because symptoms in English could be different from those in Korean. Recently, results of large-scale, case-control study regarding the predictive value of OSI were published.3 Researchers conducted an in-person interview with 812 women with epithelial ovarian cancer or borderline tumor and 1,313 population-based control subjects. Although OSI was more frequently positive in women with ovarian cancer than in control, the interval from symptom onset to diagnosis was shorter than six months in over 70% women. The sensitivity and specificity of OSI was 68% and 95%, respectively. The estimated positive predictive value of OSI based on the assumed prevalence of ovarian cancer was about 1%. In other words, only one of 100 women with positive OSI actually had an ovarian cancer. Although OSI would trigger unnecessary medical evaluations in 99 of 100 women with positive OSI, the OSI still could play a role in screening of ovarian cancer. Specifically, the OSI could improve the cost-effectiveness of ovarian cancer screening programs using CA-125 and ultrasonography (USG). For example, in the PLCO trial, nearly 29,000 women underwent CA-125 and USG to detect 29 malignant ovarian, tubal or peritoneal tumors.4 If the OSI was examined in women participating in PLCO trial, 20 of 29 women with malignant tumors would have positive OSI (68% sensitivity). In addition, to detect 20 women with positive OSI and malignant tumors, only 2,000 women should undergo CA-125 and USG (positive predictive value 1%). In our study, all patients in ovarian cancer arm had an epithelial ovarian cancer. Borderline ovarian tumor and non-epithelial ovarian cancer were not included in our study. Although there is no definitive evidence supporting the benefit of OSI, we believe that the OSI should be regularly performed by the women herself like a self-breast examination because the OSI do not require any resources and is potentially beneficial. Considering the low incidence of ovarian cancer, we believe that OSI could be useful in screening of ovarian cancer. More studies on OSI in Korean women are necessary.

Age at first birth, parity, and risk of death from ovarian cancer in Taiwan: a country of low incidence of ovarian cancer

This study was undertaken to examine whether there is an association between parity and age at first birth and risk of ovarian cancer. The study cohort consisted of all women with a record of a first and singleton childbirth in the Birth Register between 1978 and 1984. We tracked women from the time of their first childbirth to December 31, 2003, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the relative risks (RR) of death from ovarian cancer associated with parity and age at first birth. There were 322 ovarian cancer deaths during 27,402,995.5 person-years of follow-up. The mortality rate of ovarian cancer was 1.18 cases per 100,000 person-years. A trend of increasing risk of ovarian cancer was seen with increasing age at first birth. The adjusted RR was 0.69 (95% CI = 0.52-0.90) for women who bore two children, and 0.30 (95% CI = 0.21-0.42) for women with three or more births, respectively, when compared with women who had given birth to only one child. There was a significant decreasing trend in the adjusted RR of ovarian cancer with increasing parity. This study provides evidence that parity may confer a protective effect on the risk of ovarian cancer.

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

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. 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. 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%). 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.

Assisted reproductive technology and the incidence of ovarian cancer: a meta-analysis.

To systematically evaluate the available literature regarding the relationship between assisted reproductive technology and ovarian cancer. Computerized search of 6 databases from 1966 (or closest) to present: Cochrane Controlled Trials Register, Cancerlit, CINHAL, Current Contents, PubMed in process (formerly called PreMEDLINE), and MEDLINE. We collected references from the bibliographies of reviews, original research articles, content experts, and conference proceedings to find published and unpublished literature. Case-control and cohort studies are included. The population of interest is treated infertile women, the control population is untreated infertile women, and the intervention or exposure of interest includes the following fertility medications: clomiphene citrate, gonadotropins, human chorionic gonadotropin, and gonadotropin releasing hormone agonists. The primary outcome is incident, primary ovarian cancer. Three cohort and 7 case-control studies were included in the quantitative analyses. The Newcastle-Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. The following information was recorded: publication information, subject characteristics, intervention information and outcomes. Studies combined were sufficiently homogeneous for quantitative summary. Case-control and cohort data showed a significantly elevated risk for exposure of infertility medications and ovarian cancer in subjects who underwent assisted reproductive technology compared with general population controls (1.52; 95% confidence interval [CI] 1.18 to 1.97). When cases of ovarian cancer were compared with infertile controls for exposure to infertility medications, the odds ratio (0.99; 95% CI 0.67, 1.45) was not elevated. However, cohort data comparing outcome in treated infertile patients with untreated infertile patients suggests that treated patients may tend to a lower incidence of ovarian cancer-odds ratio = 0.67 (95% CI 0.32, 1.41). Ovarian cancer does not appear to be increased in treated infertile patients versus untreated infertile patients. Treated infertile patients may have a lower incidence of ovarian cancer than untreated infertile patients.

Influence of hospital procedure volume on ovarian cancer survival in Japan, a country with low incidence of ovarian cancer

The survival of ovarian cancer patients has been reported to be superior at hospitals with a high volume of operations. A population-based study was carried out to assess whether this is true in Japan, where the incidence rate is relatively low as compared with other developed countries. The Osaka Cancer Registry's data were used to investigate associations between hospital procedure volume and survival of ovarian cancer patients. Hospitals were ranked according to the number of operations for ovarian cancer performed per year (high/medium/low/very low). Survival analysis was restricted to the reported 2450 cases who lived in Osaka Prefecture (except for Osaka City) diagnosed in 1975-1995, or those who resided in Osaka City in 1993-1995, since active follow-up data on vital status 5 years after the diagnosis were available. The relative 5-year survival for all ovarian cancer cases was 38.8%, and the survival was higher with greater hospital volume (22.3% / 34.2% / 46.2% / 55.0%). After adjustment for age, histologic type and cancer stage by the Cox regression model, patients receiving care in very-low-volume hospitals were seen to have a 60% higher risk of death than patients receiving care in high-volume hospitals (P < 0.01). Although some limitations existed in this study, the results indicated that further centralization of operative treatment in high-volume hospitals might improve survival of ovarian cancer patients in Japan.

New nonsense mutation in the breast cancer-1 gene in a French site-specific breast cancer family.

BRCA-1 is a tumor suppressor gene involved in ∼45% of breast cancer families (Miki et al., 1994) and 92% of breast-ovarian cancer families with no male breast cancer. We report a new nonsense mutation detected in a French breast-cancer family with three early-onset breast cancers but no ovarian cancers. By sequencing, a C to T substitution in codon 1604 (exon 16) was detected creating a stop codon (Gln1604ter). The BRCA-1 mutation was detected in an affected woman and her unaffected mother, > 80 years old. It strengthened the evidence of incomplete penetrance of BRCA-1 mutations, which is estimated to be nearly 85%. Remarkably, the nonsense mutation is not found in another sister with mammary dysplasia. Until now, 90 mutations of BRCA-1 have been described; 64% are frameshift and 18% are nonsense mutations, which truncate the protein product leaving no doubt about their deleterious effect in cancer hereditary predisposition. In exon 16, three other mutations have been detected: one missense mutation (Pro1637Leu) in an American ovarian cancer family (Futreal et al., 1994), one frameshift mutation at codon 1656, generating a stop codon in an American breast/ovarian cancer family (Castilla et al., 1994), and one nonsense mutation (Tyr1563fter) in a French breast/ovarian cancer family (Serova et al., 1996). The relationship between genotype and phenotype hints that mutations in the 3′ third of the gene are associated with lower incidence of ovarian cancer in affected families (Gayther et al., 1995). Interestingly, our mutation occurred in a site-specific breast cancer family corroborating this trend.

Is there any value in bimanual pelvic examination as a screening test?

To assess the place of bimanual pelvic examination as a routine procedure in healthy women. 2623 healthy, asymptomatic volunteers (mean age, 51 years; range, 25-92 years) underwent pelvic examination as part of an ovarian cancer screening program. The presence of a bulky or fibroid uterus and adnexal abnormality was noted. Pelvic ultrasonography was used to investigate adnexal abnormalities and was also performed in all women with an elevated serum CA-125 antigen level (> 35 U/mL). Laparoscopy or laparotomy was performed as clinically indicated. A bulky or fibroid uterus was detected in 12.9% of women. The prevalence of abnormal adnexal findings was 1.5%, with a positive predictive value for a subsequent diagnosis of benign adnexal abnormality of 22%. The specificity of vaginal examination for malignancy was 99.9%. No ovarian malignancies were identified at initial screening. This "routine" procedure is undertaken in the belief that it serves a screening purpose. The detection of benign uterine abnormality is of no clear benefit as progression to malignancy is rare. Bimanual pelvic examination is of questionable value as a screening strategy in view of the low incidence of ovarian cancer in healthy women, and the relatively high prevalence (1.5%) of relatively unimportant adnexal abnormalities.

Diet and ovarian cancer: A case‐control study in greece

In a hospital-based case-control study of common malignant epithelial tumors of the ovary, conducted in Athens (1989-1991), 189 cases were compared with 200 hospital visitor controls. Personal interviews were conducted in all cases and diet was ascertained through a semi-quantitative food frequency questionnaire. Nutrient intakes for individuals were estimated by multiplying the nutrient content of a typical portion size for each specified food item by the frequency at which the food was consumed per month and summing these estimates for all food items. Data were analyzed using logistic regression, controlling for non-dietary confounding factors, total energy intake and, among nutrients, mutual confounding influences. Adjusted odds ratios (rate ratios) for ovarian cancer, associated with particular nutritional variables, were expressed in terms of increments approximately equal to the standard deviations of (the residual of) the respective nutrients, on a daily basis. The adjusted odds ratios (and 95% confidence intervals) were 0.80 (0.65-0.99) for mono-unsaturated fat and 0.73 (0.61-0.87) for crude fiber. No substantial, statistically significant or consistent independent associations were noted for total energy, total protein, saturated fat, polyunsaturated fat, dietary cholesterol, total carbohydrates, sucrose, vitamin C, vitamin A, riboflavin or calcium. These associations, if causal, could explain to some extent the relatively low incidence of ovarian cancer in Greece and other Mediterranean countries as well as the increasing incidence trends noted in these countries during the last few decades.

Oral Contraceptive Use and Malignancies of the Genital Tract

Of 47,000 women followed since 1968, those who had used oral contraceptives (ever-users) had a significantly higher incidence rate of cervical cancer than never-users. After standardisation of rates by age, parity, smoking, social class, number of previously normal cervical smears, and history of sexually transmitted disease, the excess was 41 per 100,000 woman-years for carcinoma-in-situ and 8 per 100,000 woman-years for invasive cervical cancer. Incidence increased with increasing duration of use: the standardised incidence rate for cervical cancer in women who had taken the pill for more than 10 years was four times than in never-users. Ever-users had a lower incidence of other uterine cancers (deficit 5 per 100,000 woman-years); a lower incidence of ovarian cancer was also found (deficit 4 per 100,000), but was not statistically significant. Overall, ever-users had an excess incidence for genital tract cancers 37 per 100,000 woman-years. This excess was mainly from carcinoma-in-situ of the cervix; the excess incidence of invasive cervical cancer was offset by the deficits in other uterine and ovarian cancers. Standardised mortality rates from genital cancer were similar in ever-users and never-users. Of relevance to clinical practice is the substantially different distribution of primary cancer sites: cervical cancer accounted for 75% of the invasive genital cancers and 74% of deaths from genital cancer in ever-users, but only 31% of the invasive cancers and 30% of deaths in never-users.