Lifetime Risk Of Ovarian Cancer Research Articles

Commentary on Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-Oophorectomy

BRCA mutation carriers have a significantly increased lifetime risk of ovarian cancer compared to the general population. Risk-Reducing Salpingo-Oophorectomy (RRSO) is the primary evidence-based treatment to decrease that risk. The National Comprehensive Care Network (NCCN) and American College of Obstetricians and Gynecologists (ACOG) endorse a set of surgical guidelines to be completed at the time of RRSO. In the study “Provider Adherence to Surgical Guidelines for Risk Reducing Salpingo-oophorectomy”, we found that only two-thirds of all surgical providers were fully adherent to these guidelines. Gynecologic oncologists were more likely to follow surgical guidelines compared to general Obstetrician Gynecologists, and more likely to diagnose occult neoplasia despite similar patient populations. Here we discuss the reason for the surgical protocol, the clinical implications of noncompliance, and practical ways that providers can ensure full adherence to the protocol.

No signs of subclinical atherosclerosis after risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers

BackgroundBRCA1/2 mutation carriers are generally exposed to early menopause due to risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 years. This risk-reducing intervention is based on a 10–40% life-time risk of ovarian cancer in this population. Although effective, premature and acute menopause induces non-cancer related morbidity in both the short and long term. Little is known about the impact of RRSO on the cardiovascular system. MethodsThis cross-sectional study explored the relationship between time since RRSO and signs of subclinical atherosclerosis, as measured by carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), in 165 BRCA1/2 mutation carriers. All participants, aged 40 to 63 years, underwent RRSO before the age of 45 years, and at least 5 years ago. Cardiovascular risk factors were assessed by questionnaires and a single screening visit. Data were analyzed using linear regression models. ResultsMean CIMT was 692.7 μm (SD 87.0), and mean central PWV 6.40 m/s (SD 1.42). After adjustment for age and several relevant cardiovascular risk factors, time since RRSO was not associated with CIMT (β=0.68 μm; 95% CI –4.02, 5.38) and PWV (β=44 mm/s; 95% CI –32, 120). Compared to women of a reference group from the general population, lower systolic blood pressure [mean difference 12 mmHg; 95% confidence interval (CI) 10, 14] was found in BRCA1/2 mutation carriers. ConclusionsWe found that, in BRCA1/2 mutation carriers, at 5 to 24 years follow-up, time since RRSO is not related to development of subclinical atherosclerosis. However, the follow-up period in these relatively young women might have been too short.

Histopathological characterization of the tubal fimbria reveals a subgroup of BRCA1 mutation carriers with tumor-promoting gene-set enrichment

Objective: Fallopian tube secretory epithelial cells have been implicated as the origin of high-grade serous ovarian cancer (HGSOC). Most ovarian cancers are diagnosed in postmenopausal women, although it is unclear how postmenopausal conditions contribute to cancer formation. Germline BRCA1 mutations are associated with a 40% lifetime risk of ovarian cancer. This high-risk population is characterized by early onset of disease and predominant serous histology. The events that lead to secretory cell transformation are unknown.

Uptake of oophorectomy in women with findings on multigene panel testing: Results from the Prospective Registry of Multiplex Testing (PROMPT).

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]

Population Study of Ovarian Cancer Risk Prediction for Targeted Screening and Prevention

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks. Inclusion criteria: women ≥18 years. Exclusion criteria: prior ovarian/tubal/peritoneal cancer, previous genetic testing for OC genes. Participants accessed an online/web-based decision aid along with optional telephone helpline use. Consenting individuals completed risk assessment and underwent genetic testing (BRCA1/BRCA2/RAD51C/RAD51D/BRIP1, OC susceptibility single-nucleotide polymorphisms). A validated OC risk prediction algorithm provided a personalised OC risk estimate using genetic/lifestyle/hormonal OC risk factors. Population genetic testing (PGT)/OC risk stratification uptake/acceptability, satisfaction, decision aid/telephone helpline use, psychological health and quality of life were assessed using validated/customised questionnaires over six months. Linear-mixed models/contrast tests analysed impact on study outcomes. Main outcomes: feasibility/acceptability, uptake, decision aid/telephone helpline use, satisfaction/regret, and impact on psychological health/quality of life. In total, 123 volunteers (mean age = 48.5 (SD = 15.4) years) used the decision aid, 105 (85%) consented. None fulfilled NHS genetic testing clinical criteria. OC risk stratification revealed 1/103 at ≥10% (high), 0/103 at ≥5%–<10% (intermediate), and 100/103 at <5% (low) lifetime OC risk. Decision aid satisfaction was 92.2%. The telephone helpline use rate was 13% and the questionnaire response rate at six months was 75%. Contrast tests indicated that overall depression (p = 0.30), anxiety (p = 0.10), quality-of-life (p = 0.99), and distress (p = 0.25) levels did not jointly change, while OC worry (p = 0.021) and general cancer risk perception (p = 0.015) decreased over six months. In total, 85.5–98.7% were satisfied with their decision. Findings suggest population-based personalised OC risk stratification is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life.

Prophylactic salpingectomy for the prevention of ovarian cancer: Who should we target?

Ovarian cancer is the most fatal gynecologic malignancy (50% 5-year survival) due to a typically advanced stage at diagnosis and a high rate of recurrence. Chemoprevention options are limited, and few interventions have been shown to reduce cancer risk or mortality. Emerging data support the model that fallopian tubes are the site of origin for a proportion of high-grade serous cancers. This implies that a subset of cancers may be prevented by removing the fallopian tubes while leaving the ovaries intact. Accordingly, there has been shift in clinical practice for average risk women; some now recommend removal of both the fallopian tubes only instead of tubal ligation for sterilization or at the time of benign gynecologic surgery. This has been termed opportunistic salpingectomy and represents a means of decreasing the burden of ovarian cancer by preventing cancers that arise in the fallopian tubes. There have been no detailed, prospective reports that have estimated ovarian cancer risk reduction with opportunistic salpingectomy, neither among women at baseline population risk nor among women at a high risk of developing the disease. The situation is complicated for women with a BRCA mutation-bilateral salpingo-oophorectomy is a proven means of risk reduction and salpingectomy alone is not the standard of care. Based on the existing data, salpingectomy alone should only be reserved for women with a lifetime risk of ovarian cancer of less than 5%.

Perceptions of risk and reward in BRCA1 and BRCA2 mutation carriers choosing salpingectomy for ovarian cancer prevention.

Salpingectomy with interval oophorectomy has gained traction as an ovarian cancer prevention strategy, but is not currently recommended for high risk women. Nevertheless, some choose this approach. We aimed to understand risk perception and plans for oophorectomy in BRCA1 and BRCA2 (BRCA) mutation carriers choosing salpingectomy for ovarian cancer prevention. This was a longitudinal survey study of BRCA mutation carriers who underwent bilateral salpingectomy to reduce ovarian cancer risk. An initial written questionnaire and telephone interview was followed by annual phone interviews. 22 women with BRCA mutations were enrolled. Median follow-up was three years. The median age at salpingectomy was 39.5 years (range 27-49). Perceived lifetime ovarian cancer risk decreased by half after salpingectomy (median risk reduction 25%, range 0-40%). At final follow-up, five (22.7%) had undergone oophorectomy and five women (22.7%) were not planning to undergo completion oophorectomy. BRCA mutation carriers who had salpingectomy after the recommended age of prophylactic surgery (vs. before the recommended age) were less likely to plan for future oophorectomy (28.6% vs. 66.7%, p = 0.037). All women were satisfied with their decision to undergo salpingectomy with eighteen (81.8%) expressing decreased cancer-related worry. There were no diagnoses of ovarian cancer during our study period. In conclusion, most BRCA mutation carriers undergoing risk-reducing salpingectomy are satisfied with their decision and have lower risk perception after salpingectomy, though some older mutation carriers did not plan on future oophorectomy. Salpingectomy with delayed oophorectomy in BRCA mutation carriers remains investigational and should preferably be performed within a clinical trial to prevent introduction of an innovation before safety has been proven.

Recommendations for Preventive Care for Women with Rare Genetic Cause of Breast and Ovarian Cancer.

An inherited predisposition to breast cancer underlies 5-10% of breast tumors. High-risk BRCA1 and BRCA2 genes result in an 85% lifetime risk of breast cancer and a 20-60% lifetime risk of ovarian cancer. Next-generation sequencing or massive parallel sequencing are now established testing methods that enable screening for many genes that predispose to heterogeneous hereditary cancer syndromes (22 genes are required by the health insurance companies). In addition to BRCA1 and BRCA2, inherited mutations in other genes predispose to breast and/or ovarian cancer. High-risk breast cancer genes include TP53, STK11, CDH1, PTEN, PALB2, and NF1, while moderate-risk (2-4 times increased risk) breast cancer genes include ATM, CHEK2, and NBN. Moderate risk is also suggested for Lynch syndrome, MUTYH, BRIP1, RAD51C, RAD51D, BARD1, FANCA, FANCC, FANCM, BLM, WRN genes. In heterozygotes for other recessive syndromes the risk of developing breast cancer is subject to current research. Low-risk genes are (mostly) irrelevant from a clinical perspective. Other genes that increase the risk of ovarian cancer include the genes for Lynch syndrome, the BRIP1, RAD51C and RAD51D genes. Preventive care should be proposed based on assumed cumulative breast cancer risk (see http: //www.mamo.cz): a risk of &gt;20% for BRCA1/2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, and NF1; and a risk of 10-20% for BRIP1, RAD51C, RAD51B, BARD1, FANCA, FANCC, FANCM, NBN, BLM, and WRN. The genetic risk should be assessed by a geneticist and be based on inherited mutations and empirical risk according to family history. Prophylactic mastectomy is considered for high-risk gene carriers but not for moderate-risk gene carriers; however, it may be considered if there is an underlying family history, a risk of parenchyma of the mammary gland, or other risk factors. Ovarian cancer risk increases significantly in carriers of the BRIP1, RAD51C, and RAD51D genes. For prevention of ovarian cancer, prophylactic salpingo-oophorectomy is an important component of preventive care. In ovarian cancer families with no identified risk germline mutation, preventive salpingo-oophorectomy is not routinely recommended but may be considered as the only efficient method of prevention due to the increased empirical risk (4 times) of ovarian cancer in first-degree relatives. Supported by the grant project MH CZ - RVO (MMCI, 00209805), AZV 15-27695A and AZV 16-29959A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 5. 2019 Accepted: 31. 5. 2019.

Modified panel-based genetic counseling for ovarian cancer susceptibility: A randomized non-inferiority study

ObjectiveGenetic testing identifies cancer patients who may benefit from targeted treatment and allows for enhanced cancer screening and risk-reduction in their at-risk relatives. Traditional models of genetic counseling (GC) cannot meet the increasing demand and urgency for genetic testing. The objective of this study was to evaluate a new model of service delivery to improve the efficiency of pre-test GC for panel-based genetic testing. MethodsA parallel, two-armed, randomized non-inferiority study compared traditional and modified pre-test GC models (1:2) prior to panel-based genetic testing. Participants were adult females, whose first-degree relative died of serous ovarian cancer. In the modified group, participants were emailed a 20-minute presentation prior to a scheduled pre-test GC telephone call. Psychosocial and knowledge questionnaires were provided at baseline (P1) and one week after pre-test GC (P2). Results382 women completed pre-test GC (256 modified, 126 traditional). There were no differences in marital status, education level or household income. Pre-test GC time was shorter in the modified group (average 19 vs. 46 min, p < 0.001), with no difference in post-test GC time (average 16 min each, p = 0.78). The modified pre-test GC model was found to be non-inferior to traditional GC on measures of cancer-specific distress, depression, anxiety, decisional conflict, ovarian cancer knowledge and satisfaction. Perceived lifetime risk for ovarian cancer decreased to a lesser extent from baseline in women who received modified pre-test GC. ConclusionsA 20-minute presentation prior to pre-test telephone GC is non-inferior to traditional in-person GC on all variables tested, except for perceived ovarian cancer risk. This modified model improved GC efficiency without negatively affecting psychosocial outcomes, providing an alternative strategy to meet the growing demand for genetic testing.

Salpingectomy During Vaginal Hysterectomy: A Surgical Technique to Make It Easier.

Opportunistic salpingectomy at the time of hysterectomy is currently recommended to reduce the lifetime risk of ovarian cancer. The vaginal route is least invasive, but surgeons sometimes may choose to perform this procedure laparoscopically or robotically when anticipating adnexal surgery as a result of limited visibility. We describe a surgical technique to make salpingectomy by the vaginal route easier and more feasible. Posterior rotation of the uterus provides excellent access to the tube, which can easily be removed before separation of the adnexa. We have performed more than 60 vaginal hysterectomies using this technique. Salpingectomy was always feasible. We demonstrate a simple technique to safely perform opportunistic salpingectomy during a vaginal hysterectomy.

Changes in Hysterectomy Route and Adnexal Removal for Benign Disease in Australia 2001-2015: A National Population-Based Study.

Objective Hysterectomy rates have fallen over recent years and there remains debate whether salpingectomy should be performed to reduce the lifetime risk of ovarian cancer. We examined trends in adnexal removal and route of hysterectomy in Australia between 2001 and 2015. Methods Data were obtained from the national procedural dataset for hysterectomy approach (vaginal, VH; abdominal, AH; and, laparoscopic, LH) and rates of adnexal removal, as well as endometrial ablation. The total female population in two age groups (“younger age group,” 35 to 54 years, and “older age group,” 55 to 74 years) was obtained from the Australian Bureau of Statistics. Results The rate of hysterectomy fell in both younger (61.7 versus 45.2/10000/year, p < 0.005) and older (38.8 versus 33.2/10000/year, p < 0.005) age groups. In both age groups there were significant decreases in the incidence rates for VH (by 53% in the younger age group and 29% in the older age group) and AH (by 53% and 55%, respectively). The rates of LH increased by 153% in the younger age group and 307% in the older age group. Overall, the proportion of hysterectomies involving adnexal removal increased (31% versus 65% in the younger age group, p < 0.005; 44% versus 58% in the older age group, p < 0.005). The increase occurred almost entirely after 2011. Conclusion Hysterectomy is becoming less common, and both vaginal and abdominal hysterectomy are being replaced by laparoscopic hysterectomy. Removal of the adnexae is now more common in younger women.

Impact of prophylactic bilateral salpingo-oophorectomy on bone health in BRCA mutation carriers: A prospective cohort study.

1566Background: Women who inherit a deleterious mutation in BRCA1 or BRCA2 face a high lifetime risk of ovarian cancer. Prophylactic bilateral-salpingo oophorectomy (PBSO) is recommended prior to n...

Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer.

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.

Factors associated with deciding between risk-reducing salpingo-oophorectomy and ovarian cancer screening among high-risk women enrolled in GOG-0199: An NRG Oncology/Gynecologic Oncology Group study

ObjectivesWomen at increased genetic risk of ovarian cancer (OC) are recommended to have risk-reducing salpingo-oophorectomy (RRSO) after completion of reproductive planning. Effective screening has not been established, and novel screening modalities are being evaluated. MethodsParticipants chose either RRSO or a novel OC screening regimen (OCS) as their risk management option, and provided demographic and other data on BRCA mutation status, cancer worry, perceived intervention risks/benefits, perceived cancer risk, and quality-of-life at enrollment. We performed univariate and multivariate analyses to evaluate factors influencing decision between RRSO and OCS. ResultsOf 2287 participants enrolled, 904 (40%) chose RRSO and 1383 (60%) chose OCS. Compared with participants choosing OCS, participants choosing RRSO were older (p<0.0001), more likely to carry deleterious BRCA1/2 mutations (p<0.0001), perceive RRSO as effective, be more concerned about surgical harms and OCS limitations, and report higher perceived OC risk and OC-related worry. OCS participants were more likely to perceive screening as effective, be more concerned about menopausal symptoms, infertility, and loss of femininity, and report better overall quality-of-life. Twenty-four percent of participants believed they would definitely develop OC, and half estimated their lifetime OC risk as >50%, both higher than objective risk estimates. ConclusionsCancer worry, BRCA1/2 mutation status, and perceived intervention-related risks and benefits were associated with choosing between RRSO and OCS. Efforts to promote individualized, evidence-based, shared medical decision-making among high-risk women facing management choices should focus on conveying accurate OC risk estimates, clarifying the current understanding of intervention-related benefits and limitations, and addressing OC worry.

Physicians' Perspectives and Practice Patterns Toward Opportunistic Salpingectomy in High- and Low-Risk Women

ABSTRACTBackground: Opportunistic bilateral salpingectomy (OBS) has been proposed as an ovarian cancer risk-reducing strategy. Methods: A survey was emailed to 300 members of the American College of Obstetricians and Gynecologists. Results: 125 (42%) surveys were returned: 60% female, 88% generalists, 67% private practice. Only 36% correctly identified the lifetime risk of ovarian cancer, only 23% understood the risk-reducing benefit of bilateral salpingo-oophorectomy. 75% perform salpingectomy during hysterectomy, 26–53% use for sterilization depending on approach. Concerns were increased operative time and complications. For BRCA mutations, 64% recommend BSO, 12% recommend a two-step risk-reducing strategy, and 14% refer to gynecologic oncology. Conclusions: We identified broad support and factors limiting willingness to perform OBS.

Lifestyle intervention in BRCA1/2 mutation carriers: study protocol for a prospective, randomized, controlled clinical feasibility trial (LIBRE-1 study).

BackgroundWomen with highly penetrant BRCA mutations have a 55–60% lifetime risk for breast cancer and a 16–59% lifetime risk for ovarian cancer. However, penetrance differs interindividually, indicating that environmental and behavioral factors may modify this risk. These include lifestyle factors such as physical activity status, dietary habits, and body weight. The modification of penetrance by changing lifestyle factors has not thus far been investigated in a randomized trial in BRCA mutation carriers.MethodsTherefore, we intend to enroll 60 BRCA1/2 mutation carriers in a pilot feasibility study (Lifestyle Intervention Study in Women with Hereditary Breast and Ovarian Cancer (LIBRE) pilot). This multi-center, prospective, controlled trial aims to randomize (1:1) participants into a (1) multi-factorial lifestyle intervention group (IG) versus (2) the control group with usual care (CG). The primary endpoint is feasibility and acceptance of a structured interdisciplinary lifestyle intervention program over 12 months (at least 70% of the patients to complete the 1-year intervention). Furthermore, the effects on physical fitness, BMI, quality of life, and stress coping capacity will be investigated.During the first 3 months, women in the IG will receive structured, individualized and mainly supervised endurance training of ≥18 MET*h/week (MET = metabolic equivalent task) and personal nutritional counseling based on the Mediterranean diet. During the subsequent 9 months, the IG will receive monthly group training sessions and regular telephone contacts for motivation, whereas the CG will only receive usual care (one general counseling on healthy nutrition and benefits of regular physical activity on health status). At randomization and subsequent time points (3, 6, 12 months), cardiopulmonary fitness will be assessed by spiroergometry and nutritional and psychological status by validated questionnaires.DiscussionThis pilot study will investigate the optimal strategy to improve physical fitness, nutritional habits, and psychological factors in women at high risk for developing breast or ovarian cancer. The results of this pilot feasibility study will be the basis for a larger prospective randomized trial including clinical events (LIBRE).Trial registrationClinicalTrials.gov, NCT02087592

Specifying the ovarian cancer risk threshold of ‘premenopausal risk-reducing salpingo-oophorectomy’ for ovarian cancer prevention: a cost-effectiveness analysis

BackgroundRisk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been...

A model for estimating ovarian cancer risk: Application for preventive oophorectomy

ObjectiveIt is important to identify women in the population who have a high risk of ovarian cancer and who might benefit from prophylactic bilateral salpingo-oophorectomy. The probability that a woman will develop ovarian cancer depends on her current age, her reproductive history and her genetic status. MethodsWe simulated the distribution of ovarian cancer risk for the 2011 Ontario female population. We generated (at random) individual risks of ovarian cancer to age 80 for 6,301,340 women, based on the published risk factors, mutation frequencies and population age-specific incidence rates (SEER database). Risk factors included parity, breastfeeding, oral contraceptives, tubal ligation and family history. Genetic factors included 11 single nucleotide polymorphisms (SNPs) and BRCA1/2 mutations. ResultsOf the 6,301,340 women simulated as the general population of Ontario, the (complete) model predicts that 65,805 women (1.0%) will develop ovarian cancer by age 80. There were 46,069 women (0.7%) with a risk of ovarian cancer above 5%. BRCA1/2 mutation carriers accounted for 67.4% of the women at greater than 5% risk (31,028 women). Among ovarian cancer patients at greater than 5% risk, a BRCA1/2 mutation was present in 89.2%. In contrast, SNPs contribute to a very small proportion of the ovarian cancer patients who were at greater than 5% risk. ConclusionsApproximately 12.9% of all ovarian cancers in Ontario occur in the 0.7% of women in the general population who have a lifetime ovarian cancer risk in excess of 5%, the majority of whom carry a mutation in BRCA1 or BRCA2.

Population-Wide Screening for Germline BRCA1 and BRCA2 Mutations: Too Much of a Good Thing?

Germline testing for highly penetrant mutations in cancer susceptibility genes such as BRCA1 and BRCA2 (BRCA1/2) can prevent cancer and save lives. Inherited BRCA1/2 mutations confer a 39% to 85% lifetime risk of female breast cancer and an 11% to 62% lifetime risk of ovarian cancer. Identifying BRCA1/2 mutation carriers thus allows for prophylactic surgeries, which can markedly decrease cancer incidence, morbidity, and mortality. Despite these benefits and increasing public awareness, a low fraction (35% in a recent Israeli study) of women with high-risk histories have undergone BRCA1/2 testing. Moreover, women from families with few female relatives are unlikely to recognize their risk of carrying a BRCA1/2 mutation until they themselves develop cancer. Recently, citing the impact of riskreducing surgeries, King et al published a high-profile appeal for BRCA1/2 mutation screening to be offered to all US women at age 30 years. King is to be commended for stimulating a serious discussion on the potential impact of bringing modern genetic medicine to the general population in a compelling circumstance. However, because testing all women for BRCA1/2 mutations would represent the first population-based screening for a hereditary cancer syndrome, careful consideration of the potential limitations, risks, and benefits of population-wide BRCA1/2 testing is essential. Currently, genetic screening efforts in the general population examine newborns for rare recessive disorders (eg, phenylketonuria, beta thalassemia) or screen prenatally for carriers of populationdependent recessive conditions (eg, Tay-Sachs, cystic fibrosis), seeking to prevent morbidity and mortality from childhood-onset diseases. In the case of autosomal dominantly inherited BRCA1/2 mutations, the goal is to reduce suffering and mortality from associated adult-onset malignancies, particularly in individuals who would not otherwise be aware of their cancer risk. Demonstration studies in the Ashkenazi Jewish population have shown that screening for its three BRCA1/2 founder mutations (with a combined 1-in-40 prevalence among unselected Ashkenazi Jews) is cost-effective and identifies carriers who would not have been suspected on the basis of their family cancer history. Citing a recent study of population-wide screening for the Ashkenazi founder mutations in Israel, King et al claim that the high penetrance of BRCA1/2 mutations is independent of whether patients who carry the mutations are ascertained on the basis of family history. However, all such studies examined Ashkenazi founder mutations only, which constitute more than 90% of mutations in the Ashkenazi population, thereby limiting generalizability to other populations. In the general US population, in which combined prevalence of a diverse array of BRCA1/2 mutations is 10-fold lower, widespread screening would have different performance characteristics than in the Ashkenazim. Whether the assortment of BRCA1/2 mutations found in non-Ashkenazi populations would have the same penetrance in population-based ascertainment as they do in clinicbased patients is unknown.

Abstract POSTER-BIOL-1311: Mechanisms of differential activities of progesterone receptor (PR) isoforms in ovarian cancer models

Abstract Progesterone is proliferative in the breast, but inhibitory in the reproductive tract and ovaries. Elevated circulating progesterone levels observed during pregnancy or through the use of progestin-containing oral contraceptives are associated with decreased lifetime risk of ovarian cancer (OC). In contrast, low progesterone or the functional loss of PR are associated with increased risk. The detailed mechanisms of progesterone’s protective role in OC are not well understood. The actions of progesterone are mediated through two nuclear receptors, the full-length PR-B and the N-terminally truncated PRA. While PR-A and PR-B share the same amino acid sequence downstream of the extreme N-terminus (B-upstream segment or BUS) that is missing in PR-A, they are functionally distinct transcriptional regulators. While PR-isoform specificity has been extensively studied in the breast (PR-B is required for mammary gland development and proliferative in breast cancer models), little is understood about the specific actions of PR isoforms in the ovary. It has been suggested that PR-A is primarily an inhibitory isoform that acts to suppress transcriptional actions of ER-alpha and PR-B. Further complexity is conferred by compartmentalized PR. For example, in the reproductive track, progestins may act primarily through stromal PR-A as potent antagonists of estrogen-induced epithelial hyperplasia. More recently, we have demonstrated that PRB is an OC tumor suppressor that exhibits anti-proliferative properties by inducing cellular senescence. In OC cells, in the presence of progestins, PR-B induces cellular senescence through a mechanism that involves FOXO1-dependent induction of p21 expression. In contrast to PR-B, progestin stimulation of PR-A failed to upregulate p21 and FOXO1 mRNA and thus did not induce a cellular senescence phenotype. However, we detected either PR-B or PR-A and FOXO1 within the same PRE-containing region of the p21 upstream promoter, suggesting that PR-A may actively suppress the expression of this gene, while PR-B forms an active transcriptional complex. PR isoforms differentially associate with protein kinases that in turn alter their transcriptional activity at selected target genes. We speculated that PR isoforms directly associated with FOXO1 in transcriptional complexes alter the phosphorylation state of FOXO1 to dictate the degree of isoform-specific PR target gene expression, thereby determining cell fate. Future studies will define how the PR isoforms differentially cooperate with FOXO1 as either regulated (i.e. phosphorylated) activating or repressive transcription complexes on target genes that control cell fate. Overall, identifying the mechanisms governing PRA versus PR-B specific gene regulation may provide a means to therapeutically induce the protective actions of progesterone in hormone-driven cancers towards specific cell fates (e.g. senescence relative to proliferation). (Studies supported by NIH R01 CA159712, T32 CA009138, CTSA UL1TR000114, MN Ovarian Cancer Alliance, and Doctoral Dissertation Fellowship.) Citation Format: Caroline H. Diep, Carol A. Lange. Mechanisms of differential activities of progesterone receptor (PR) isoforms in ovarian cancer models [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1311.