Average Risk Of Ovarian Cancer Research Articles

Elective Oophorectomy in the United States

To examine trends in rates of elective bilateral salpingo-oophorectomy in the United States and to assess the association of perioperative complications with elective bilateral salpingo-oophorectomy. This cross-sectional study uses 1998-2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, a nationally representative sample of inpatient hospitalizations. Analyses were limited to women aged 15 years or older at average risk for ovarian cancer who underwent hysterectomy for a benign gynecologic condition. Tests for trends in elective bilateral salpingo-oophorectomy rates were performed using weighted least squares regression for two time periods, 1998 to 2001 and 2002 to 2006. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for risks of complications associated with elective bilateral salpingo-oophorectomy were estimated using logistic regression. During the period from 1998 to 2006, 39% of the 2,250,041 women who underwent hysterectomy for benign gynecologic indications had elective bilateral salpingo-oophorectomy (rate, 8.3 per 10,000). The elective bilateral salpingo-oophorectomy rate increased from 7.8 per 10,000 in 1998 to 9.0 per 10,000 in 2001 (P trend <.05) and decreased from 9.0 per 10,000 in 2002 to 7.4 per 10,000 in 2006 (P trend <.05). The largest decline from 2002 to 2006 (20.3%) occurred among those aged 45 to 49 years. Compared with hysterectomy only, elective bilateral salpingo-oophorectomy was associated with an increased risk of complications when performed vaginally (OR 1.12; 95% CI 1.08-1.17) and a decreased risk of complications when performed abdominally (OR 0.91; 95% CI 0.89-0.94) or laparoscopically (OR 0.89; 95% CI 0.83-0.94). Elective bilateral salpingo-oophorectomy rates declined since 2002. However, the risks compared with the benefits of the procedure have not been clearly established. Prospective studies examining elective bilateral salpingo-oophorectomy with and without estrogen therapy are needed to guide practice patterns. III.

Prophylactic and Risk-Reducing Bilateral Salpingo-oophorectomy

Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.

A prospective U.S. ovarian cancer screening study using the risk of ovarian cancer algorithm (ROCA).

5003 Background: There are currently no effective screening tools for the early detection of ovarian cancer in women at average population risk. We evaluated a screening strategy that incorporates change of CA-125 over time and age of the participant to estimate risk of ovarian cancer, referring a small fraction (∼2%) of apparently healthy individuals annually to transvaginal sonography (TVS). Methods: A single arm, prospective, multicenter screening study enrolled postmenopausal women age 50 to 74 with no significant family history of breast or ovarian cancer. Participants underwent a CA-125 blood test annually. Based on the Risk of Ovarian Cancer Algorithm (ROCA) result, women were triaged to the next annual CA-125 (low risk), repeat CA-125 in 3 months (intermediate risk), or TVS and referral to a gynecologic oncologist (high risk). Based on clinical findings and TVS, the gyn onc made the decision whether to proceed with surgery. Results: 3238 women participated over an eight year period. The average annual rate of referral to 3 monthly CA125 was 6.8%, and the average annual rate of TVS and gyn onc referral was 0.9%. Cumulatively 85 women (2.6%) received TVS and referral to a gyn onc. Eight women subsequently underwent surgery based on the TVS and referral, with 3 invasive ovarian cancers, 2 borderline ovarian tumors and 3 benign ovarian tumors, providing a positive predictive value of 37.5% (95% CI 8.5%,75.5%).The combined specificity of ROCA followed by TVS for referral to surgery is 99.7% (95% CI 99.5%, 99.9%). The 3 invasive ovarian cancers were high-grade epithelial tumors that were all early stage (two stage 1C and stage IIB). All 3 women with invasive ovarian cancer had at least 3 years with low risk, annual CA-125 values prior to a rising CA-125. Conclusions: In this prospective, single arm study, the ROCA followed by TVS demonstrated excellent specificity and PPV in a population of U.S. women at average risk for ovarian cancer. As expected, less than 1% of participants annually required a TVS. In addition, the invasive high-grade ovarian cancers that were detected were early stage. This study provides early evidence that ROCA followed by TVS is a feasible strategy for screening women over 50 years of age. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fujiresio Diagnostics Inc Roche Diagnostics Royalties for CA 125

Prophylactic oophorectomy in premenopausal women and long-term health.

To review the data on long-term outcomes in women who underwent prophylactic bilateral oophorectomy, a common surgical procedure that has more than doubled in frequency since the 1960s. Literature review of the published data on the consequences of prophylactic bilateral oophorectomy. Special emphasis was given to the Mayo Clinic Cohort Study of Oophorectomy and Aging. Main outcome measures Overall mortality, cardiovascular disease, cognitive impairment and dementia, parkinsonism, osteoporosis, psychological wellbeing and sexual function. There is a growing body of evidence suggesting that the premature loss of ovarian function caused by bilateral oophorectomy performed before natural menopause is associated with several negative outcomes. In particular, studies have revealed an increased risk of premature death, cardiovascular disease, cognitive impairment or dementia, parkinsonism, osteoporosis and bone fractures, decline in psychological wellbeing and decline in sexual function. The effects involve different organs (e.g. heart, bone, or brain), and different functions within organs (e.g. cognitive, motor, or emotional brain functions). Estrogen treatment may prevent some but not all of these negative outcomes. The potential adverse effects of prophylactic bilateral oophorectomy on heart health, neurological health, bone health and quality of life should be carefully weighed against its potential benefits for cancer risk reduction in women at average risk of ovarian cancer.

How Do You Distinguish a Malignant Pelvic Mass From a Benign Pelvic Mass? Imaging, Biomarkers, or None of the Above

The 125th attempt to develop a monoclonal antibody against ovarian cancer in a laboratory at the Dana-Farber Cancer Institute (Boston, MA) led to the discovery of one of the most widely used tumor markers, CA-125. Over the past two decades, the value of CA-125 has been tested in monitoring response to treatment, detecting recurrent disease, and screening for early-stage ovarian cancer. CA-125 has proven useful in determining prognosis and response to treatment for women undergoing chemotherapy. Persistent elevation of CA-125 has detected residual disease after primary treatment with high specificity. A rise in serum CA-125 levels often precedes clinical symptoms or imaging detection of recurrent disease by 3 to 6 months. While the use of a “good marker” to track a “bad disease” in these settings has been questioned, information provided by CA-125 provides additional time for patients to receive and to benefit from the many currently active drugs. As treatment of persistent and recurrent disease becomes more effective in the era of targeted therapy, CA-125 and other biomarkers should become of even greater value in patient management. While a single value of CA-125 lacks the specificity and sensitivity required for early detection, greater specificity has been attained by measuring CA-125 over time and by combining CA125 with ultrasonography. Statistical analysis, such as the Risk of Ovarian Cancer Algorithm (ROCA model) developed by Skates et al, can examine changes in CA-125 levels over time. The United Kingdom Collaborative Trial on Ovarian Cancer Screening has completed accrual of 200,000 women, testing the value of a rising CA-125 to trigger transvaginal sonography in postmenopausal women at average risk for ovarian cancer. If this trial succeeds, there is clearly room for improvement, as 20% of ovarian cancers fail to express significant amounts of CA-125. A greater fraction of patients with early-stage disease might be detected with a panel of biomarkers that complement or replace CA-125. CA-125 has also been tested for the ability to distinguish malignant from benign pelvic masses. The ability to predict whether a tumor is malignant or benign before surgery is important. Approximately 20% of women will develop an ovarian cyst or pelvic mass in their lifetime and many of these women will undergo unnecessary surgery. Conversely, if surgery is indicated, the location in which the surgery is performed is critical. Despite modest gains in the fraction of women cured, optimal management of malignant ovarian cancers has significantly improved survival over the past 30 years. With the development and application of cytoreductive surgery, primary platinum-taxane chemotherapy and active second-line agents, the 5-year survival rate for ovarian cancer patients has improved from 20% to 50%. Several different reports have shown that patients treated by gynecologic oncologists will more often undergo full surgical staging or an optimal cytoreductive operation. More recently, multiple studies have shown ovarian cancer patients treated in tertiary care centers with multidisciplinary teams specializing in the management of ovarian cancer have fewer complications and longer survival rates. The triage of women to centers of excellence in the management of ovarian malignancy is critical for optimal treatment. Tests that permit the identification of women at high risk for the presence of a malignancy will be instrumental for the triage of patients to appropriate centers. Despite a number of trials examining CA-125, with or without the use of sonography, in women with a pelvic mass, it has become increasingly clear that no one modality will be sufficient to predict accurately the presence of an ovarian malignancy. Many different tumor markers have been analyzed, but none has achieved the sensitivity or specificity to be clinically useful as an individual test. Recently, the addition of HE-4 to CA-125, without the use of ultrasound, has increased the sensitivity of CA-125 by 22% at a specificity of 90%. Jacobs et al have used the combination of ultrasound, CA-125, and menopausal status to create a risk of malignancy index (RMI), achieving a sensitivity of 85% with a specificity of 97% for predicting the presence of ovarian cancers in women with pelvic masses. The contribution of CA-125 to the RMI was critical for assigning masses to the malignant category, whereas sonography was particularly important in identifying benign disease. One of the advantages of the RMI is its simplicity, making it appropriate for everyday clinical use. DePriest et al developed a morphology index utilizing the architectural features of ovarian neoplasms on pelvic ultrasound to predict a probability of malignancy without the use of CA-125. The morphology index achieved a positive predictive value of up to 0.45. Although JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 27 SEPTEMBER 2

Elective oophorectomy in the gynecological patient: when is it desirable?

Oophorectomy is electively performed in approximately 300,000 US women per year who are having hysterectomy for benign disease. New studies have suggested that elective oophorectomy may not be advisable for the majority of women, as it may lead to a higher risk of death from cardiovascular disease and hip fracture, and may result in a higher incidence of dementia and Parkinson's disease. Women with known BRCA 1/2 germ-line mutations clearly benefit from oophorectomy after childbearing. Prophylactic oophorectomy should be undertaken with caution in the majority of women with an average risk of ovarian cancer who are having a hysterectomy for benign disease.

Elective oophorectomy for benign gynecological disorders

To review the risks and benefits of elective oophorectomy and to make a clinical recommendation for an appropriate age when benefits of this procedure outweigh the risks. The risks and benefits of oophorectomy as detailed in published articles are reviewed with regard to quality-of-life issues and mortality outcomes in oophorectomized versus non-oophorectomized women from five diseases linked to ovarian hormones (coronary heart disease, ovarian cancer, breast cancer, stroke, and hip fracture). Numerous reports link oophorectomy to higher rates of cardiovascular disease, osteoporosis, hip fractures, dementia, short-term memory impairment, decline in sexual function, decreased positive psychological well-being, adverse skin and body composition changes, and adverse ocular changes, as well as more severe hot flushes and urogenital atrophy. The potential benefits associated with oophorectomy include prevention of ovarian cancer, a decline in breast cancer risk, and a reduced risk of pelvic pain and subsequent ovarian surgery. In our study of long-term mortality after oophorectomy using Markov modeling, preservation of ovaries until women are at least aged 65 years was associated with higher survival rates. For women between ages 50 and 54 with hysterectomy and ovarian preservation, the probability of surviving to age 80 was 62% versus 54% if oophorectomy was performed. This 8% difference in survival is primarily due to fewer women dying from cardiovascular heart disease and/or hip fracture. This survival advantage far outweighs the 0.47% increased mortality rate from ovarian cancer prevented by oophorectomy. If surgery occurred between ages 55 and 59, the survival advantage was 4%. After age 64 there were no significant differences in survival rates. Prior literature supports our conclusion of a benefit over risk for ovarian conservation. Elective oophorectomy is associated with short-and long-term health consequences that merit serious consideration. For women with an average risk of ovarian cancer, ovarian conservation until at least age 65 seems to benefit long-term survival.

Does retention of the ovaries improve long-term survival after hysterectomy? The validity of the epidemiological evidence

Based on a decision analysis of multiple epidemiological studies, it has been claimed that, among women hysterectomized for benign disease, removal of the ovaries before the age of 65 years decreases long-term survival, and that the benefit conferred by retaining the ovaries outweighs any reduction in ovarian cancer mortality among oophorectomized women who are at average risk of ovarian cancer. The decision analysis failed to allow for the inevitable complexity involved in an overarching quantitative analysis of multiple outcomes, and to do so would not have been feasible; it made multiple assumptions, some of which could not be defended; a definition of ‘average risk’ of ovarian cancer was not provided, and the validity of the concept of ‘average risk’ was not considered; sensitivity analyses designed to test the robustness of the data were inadequate. The findings from decision analysis cannot be used as evidence to determine whether bilateral oophorectomy poses a public health problem in terms of long-term survival.

Ovarian Conservation at the Time of Hysterectomy for Benign Disease

Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.

449 BRCA1 gene mutation carrier analysis in familial breast cancer patients

BRCA1, the predisposing gene for familial breast and ovarian cancer localized on chromosome 17q21.3 has been recently cloned. The gene comprises 22 coding exons which span 100 kB of genomic sequence. The protein predicted is 1863 aminoacids long. 31 mutations have been identified in constitutional DNA of affected member from various family of which 22 were distinct. Not one of 22 transcribed exons seems to be a preferential target site for mutations. Overall germline BRCA1 mutations account for 1–2% of all breast cancers and about 3% of ovarian cancers. The lifetime risk of breast and ovarian cancer in BRCA1 mutation carriers is high: the risk of breast cancer is about 50% by age 50 and 70% by age 70. The average risk of ovarian cancer is 40% by age 70. BRCA1 has never been found mutated in sporadic carcinomas, however, loss of heterozigosity in the region of BRCA1 has been observed in 40% of breast and about 60% of ovarian cancers. The lifetime risk to develop the familial form of the disease may be calculated by identifying mutations in BRCA1 or BRCA2 genes. From the screening of 1100 medical records of patients subjected to mastectomy in S. Chiara Hospital in Pisa during the period 1990–1994, the patients with a referred familial recurrence of breast or ovarian cancer were selected for interview. 81 patients belonging to 75 families fitted the BRCA1 eligibility criteria. 37 patients belonging to different families were analyzed for BRCA1 germline mutation. All 37 families are Caucasian and principally reside in Tuscany. Mutation screening was done by ASO (allelic specific oligo hybridization) for three common mutations and by direct sequencing of each of the coding exons. The analysis is under way and approximately 50% ofthe coding region has been screened up to now. We have so far identified 7 mutations of which 5 are different. Three are frameshift and 2 missense. Only one of the mutations found has been reported previously (5382insC). The insertion of an A has been reported in three different families, the aplotype analysis has been performed to ascertain if a common ancestor exist for those three families. No evident correlation between phenotype and genotype has been detected. CG and GC are fellows of the Italian Association for Cancer Research. This work was supported by AIRC and CNR PF ACRO grants.