Ovarian Cancer Risk Reduction Research Articles

Physician variation in adopting prophylactic salpingectomy at the time of postpartum sterilization for ovarian cancer risk reduction

Physician variation in adopting prophylactic salpingectomy at the time of postpartum sterilization for ovarian cancer risk reduction

Antidepressant use and ovarian cancer risk: Evidence from nationwide studies with >14,000 cases from Denmark and Sweden

ObjectiveGiven that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. MethodsAltogether, 14,121 women with epithelial ovarian cancer (30–84 years old) (Denmark: 8976 diagnosed 2000–2019, Sweden: 5145 diagnosed 2010–2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. ResultsAntidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88–0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86–0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82–0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. ConclusionsUse of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically.

Ovarian Cancer Risk-Reduction and Screening in BRCA1/2 Mutation Carriers.

Objective: To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female BRCA1/2 carriers. Methods: This study was a sub-analysis of female participants from a larger multicenter, cross-sectional survey of BRCA1/2 mutation carriers unaffected by cancer. The questionnaire was administered electronically via email at four institutions located in the northeast United States. Data were analyzed with Fisher's exact test. Results: The survey was completed by 104 female BRCA mutation carriers. BRCA subtypes included 54.3% BRCA2, 41.0% BRCA1, and 2.9% both. The age at which patients underwent genetic testing varied 21.2% were 18-24 years, 25.0% were 25-34 years, 29.8% were 35-44 years, and 24.0% were 45 years or older. Nearly, all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Of the 79 females who underwent genetic testing before 45 years of age, 53.2% reported that a health care provider recommended taking combined oral contraceptive pills (COCs) to reduce their risk of ovarian cancer, and, of these women, 88.1% chose to use them. COCs were offered at higher rates among women who were younger at the age of genetic testing (18-24: 86%, 25-34: 62%, 35-44: 23%; p < 0.0001). Approximately half (55.8%) of the respondents reported having been offered increased screening for possible early detection of ovarian cancer, of which 81.0% chose to undergo screening. The majority utilized a combination of transvaginal ultrasound and serum CA125 measurements. There were no differences observed in screening utilization based on BRCA mutation type. Conclusion: In our cohort of female BRCA mutation carriers, risk-reducing surgery was offered to almost all women, whereas only half were offered risk-reducing medication and/or increased screening. Further investigation is needed to identify barriers to the utilization of risk-reducing strategies among this high-risk population.

Screening and prevention of ovarian cancer.

Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Complications after opportunistic salpingectomy compared with tubal ligation at cesarean section: a retrospective cohort study

To compare perioperative and postoperative complications in patients who underwent opportunistic salpingectomy (OS) (removal of the fallopian tubes for ovarian cancer risk reduction during another surgery) at the time of cesarean section (C-section) with those in patients who underwent tubal ligation. A population-based, retrospective cohort study. British Columbia, Canada. A total of 18,184 patients were included in this study, of whom 8,440 and 9,744 underwent OS and tubal ligation, respectively. Patients who underwent OS during a C-section were compared with those who underwent tubal ligation during a C-section. We examined the perioperative outcomes, including operating room time, length of hospital stay, surgical complications such as infections, anemia, incision complications, injury to a pelvic organ, or operating room return; postoperative complications, including physician visits for a postoperative infection or visits that resulted in ultrasound or laboratory examinations and hospital readmissions in the 6 weeks after discharge; and likelihood to fill a prescription for antibiotics or analgesics. The OS group had decreased odds of perioperative complications compared with the tubal ligation group (adjusted odds ratio [aOR], 0.77; 95% confidence interval [CI], 0.61-0.99). Patients who underwent OS did not have increased risks of physician visits for surgical complications, such as infection, or hospital readmissions in the 6 weeks after hospital discharge. In addition, these patients had 18% and 23% increased odds of filling prescriptions for nonsteroidal anti-inflammatory drugs (aOR, 1.18; 95% CI, 1.07-1.28) and opioids (aOR, 1.23%; 95% CI, 1.12-1.35), respectively. In this population-based, real-world study of OS at C-section, we report decreased perioperative complications and no difference in postoperative complications between patients who underwent OS and those who underwent tubal ligation. Patients who underwent OS had an increased likelihood of filling a prescription for nonsteroidal anti-inflammatory drugs and opioids in the 6 weeks after hospital discharge. This result should be interpreted with caution because we did not have data on over-the-counter medication use and, thus, not all prescription analgesics were captured in our data. Our data suggest that OS after C-section is a safe way to provide effective contraception and ovarian cancer risk reduction.

Postpartum Complete Salpingectomy as an Alternative to Traditional Partial Salpingectomy.

In this narrative review, we describe evidence regarding the associated risks, benefits, and cost effectiveness of postpartum complete salpingectomy compared with partial salpingectomy. Permanent contraception can be performed via several methods, but complete salpingectomy is becoming more common secondary to its coincident benefit of ovarian cancer risk reduction. Small prospective studies and larger retrospective cohort studies have demonstrated the feasibility and safety of complete salpingectomy in the postpartum period. Additionally, multiple cost-effectiveness analyses have demonstrated the cost effectiveness of this method secondary to ovarian cancer reduction over the life span. Although future larger cohort studies will allow for more precise estimates of the effect of complete salpingectomy on ovarian cancer risk and incidence of rare complications, current data suggest that complete salpingectomy should be offered to patients as a method of permanent contraception in the postpartum period.

Decision-making regarding ovarian cancer risk-reduction among women of color who carry a BRCA mutation (2163)

Decision-making regarding ovarian cancer risk-reduction among women of color who carry a BRCA mutation (2163)

52 Decision-making regarding ovarian cancer risk-reduction among women of color who carry a BRCA mutation

52 Decision-making regarding ovarian cancer risk-reduction among women of color who carry a BRCA mutation

Risk-Reducing Salpingectomy And Other Strategies For Prevention Of Ovarian And Tubal Carcinoma

Objective: To provide a review of most current evidence and data for risk-reducing strategies used in prevention of ovarian cancer. Methods of study selection: PubMed was used as a search tool for articles with key words focusing on current strategies on prevention of ovarian cancer such as “risk-reducing salpingectomy, “risk-reducing salpingo-oophorectomy, “salpingectomy with delayed oophorectomy”. General consensus and society guidelines from leading organizations such as Society of Gynecologic Oncology, American Cancer Society, and American College of Obstetricians and Gynecologists were reviewed and summarized in this review article with supporting evidence and research studies on most current riskreduction strategies for prevention of ovarian and tubal carcinoma. Result: There is growing evidence that high-grade serous ovarian carcinoma arises in the fallopian tube in the form of serous tubal intraepithelial carcinoma (STIC). Therefore, opportunistic salpingectomy has been increasingly offered at the time of routine benign gynecologic surgery. Risk-reducing bilateral salpingo-oophorectomy has been shown to reduce risk of ovarian cancer up to 90% and offered to women with high hereditary predisposition for ovarian cancer. Riskreducing salpingectomy with delayed oophorectomy (SDO) has been suggested in younger women to balance the effects of infertility and surgically induced menopause resulting from oophorectomy. Conclusion: Combined oral Contraceptive COCs confer long-term protection against ovarian cancer with reported 20% reduction for every 5 years of use, which have been cited as a confounding factor in most of the published studies. Women who used HRT (estrogen alone or combined estrogen and progesterone) carry 20% higher risk of ovarian cancer compared to never-users. The associated increased risk of cervical and breast cancer with COCs/HTR use, have recently let women prefer the RRSO over COCs for prevention of ovarian cancer. Bilateral risk reducing Salpingo-oophorectomy (RRSO) at the age of 40–45 in BRCA1 and 45–50 in BRCA2 mutation carriers is recommended to be the primary approach for risk reduction of ovarian cancer. There is well-supported evidence of lowering the risk of ovarian cancer in high-risk population by 90%. The American college of obstetrics and gynecology committee opinion, recommended opportunistic salpingectomy for the primary prevention of ovarian cancer in a woman already undergoing pelvic surgery for another indication. Bilateral salpingectomy at the time of cesarean delivery is recommended to replace the tubal ligation as the method of choice for sterilization performed with cesarean delivery. The novel alternative procedure of Risk-reducing Salpingectomy with delayed risk-reducing oophorectomy (RRSO-RRO) have growing attention as a better alternative to improve the menopause-related morbidity and quality of life.

MP22-05 RATES OF OVARIAN CANCER AFTER RADICAL CYSTECTOMY FOR BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP22-05 RATES OF OVARIAN CANCER AFTER RADICAL CYSTECTOMY FOR BLADDER CANCER Pranjal Agrawal, Dipak Subramaniam, Rebecca Stone, Sunil Patel, and Max Kates Pranjal AgrawalPranjal Agrawal More articles by this author , Dipak SubramaniamDipak Subramaniam More articles by this author , Rebecca StoneRebecca Stone More articles by this author , Sunil PatelSunil Patel More articles by this author , and Max KatesMax Kates More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003247.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: AUA guidelines for radical cystectomy (RC) in women recommend removing adjacent reproductive organs including ovaries to reduce subsequent ovarian cancer (OC) risk. However, the most common histologic type of OC, high grade serous cancer, is now thought to originate from the fallopian tubes and many national level organizations now recommend bilateral salpingectomy (BS) for OC risk reduction at the time of abdominal surgery. Recent data also suggest that retention of post-menopausal ovaries is health beneficial. In the setting of ongoing debate regarding oophorectomy at the time of RC, rates of OC in a female population undergoing RC for bladder cancer need to be defined. Our objectives were: 1. To determine rates of OC in a female population undergoing RC for bladder cancer. 2. To determine rates of adverse effects associated with oophorectomy in this population. METHODS: Retrospective cohort study conducted via TriNetX Research Network after IRB approval; final cohort contained 1,286 patients. Baseline demographic and clinical data were determined among patients undergoing RC and RC with concurrent bilateral salpingo-oophorectomy (BSO). Logistic regression analysis was used to evaluate associations between surgery performed and downstream co-morbid diseases. All statistical analysis conducted via Stata. RESULTS: 1,133 patients underwent RC; 3 underwent RC and BS, and 150 underwent RC+BSO. At baseline, groups did not differ in age, race, ethnicity, or oncologic family or personal history; significant differences were noted in BMI, HTN, HLD, and overweight/obesity. Among those with RC, 1.3% developed OC and 0.5% developed peritoneal cancer. No significant differences were noted in development of adverse effects between the RC and RC+BSO groups (Table 1). No significant difference in all-cause mortality observed between RC and RC+BSO group (HR = 0.997 [0.827 – 1.203], log-rank p=0.979). CONCLUSIONS: Our study shows that 1.8% of females undergoing RC for bladder cancer develop ovarian or peritoneal cancer. This is consistent with the lifetime OC risk for the general population. Current performance of BS in lieu of BSO at RC is less than 1%. Whether BS can replace BSO for ovarian cancer risk reduction at the time of RC in patients with no known or suspected genetic risk for OC warrants further study. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e297 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pranjal Agrawal More articles by this author Dipak Subramaniam More articles by this author Rebecca Stone More articles by this author Sunil Patel More articles by this author Max Kates More articles by this author Expand All Advertisement PDF downloadLoading ...

Postpartum Opportunistic Salpingectomy Compared With Bilateral Tubal Ligation After Vaginal Delivery for Ovarian Cancer Risk Reduction: A Cost-Effectiveness Analysis.

To compare the cost effectiveness of opportunistic salpingectomy and bilateral tubal ligation for sterilization immediately after vaginal delivery. A cost-effectiveness analytic decision model was used to compare opportunistic salpingectomy with bilateral tubal ligation during vaginal delivery admission. Probability and cost inputs were derived from local data and available literature. Salpingectomy was assumed to be performed with a handheld bipolar energy device. The primary outcome was the incremental cost-effectiveness ratio (ICER) in 2019 U.S. dollars per quality-adjusted life-year (QALY) at a cost-effectiveness threshold of $100,000/QALY. Sensitivity analyses were performed to determine the proportion of simulations in which salpingectomy would be cost effective. Opportunistic salpingectomy was more cost effective than bilateral tubal ligation with an ICER of $26,150/QALY. In 10,000 patients desiring sterilization after vaginal delivery, opportunistic salpingectomy would result in 25 fewer ovarian cancer cases, 19 fewer ovarian cancer deaths, and 116 fewer unintended pregnancies than bilateral tubal ligation. In sensitivity analysis, salpingectomy was cost effective in 89.8% of simulations and cost saving in 13% of simulations. In patients undergoing sterilization immediately after vaginal deliveries, opportunistic salpingectomy is more cost effective and may be more cost saving than bilateral tubal ligation for reducing ovarian cancer risk.

Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers: A Systematic Review and Meta-Analysis

Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59-1.21) or CBC risk (RR = 0.95, 95%CI: 0.65-1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18-0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68-1.17) or CBC risk (RR = 0.85, 95%CI: 0.59-1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07-1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41-0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30-0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers.

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility

Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

Combining TNFR2-Expressing Tregs and IL-6 as Superior Diagnostic Biomarkers for High-Grade Serous Ovarian Cancer Masses.

We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood samples from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2+ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2+ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2+ Treg is likely to be mediated via the STAT3 signalling pathway.

Management of ovarian and breast cancer risk in non-BRCA HBOC pathogenic variant carriers in a large California health care system

PurposeTo describe breast and ovarian cancer risk reduction strategies in the clinical management of women who test positive for non-BRCA hereditary breast and ovarian cancer (HBOC) pathogenic variants compared to those who test positive for pathogenic BRCA variants or have negative germline panel testing. MethodsExamination of imaging and preventive surgeries in women undergoing HBOC genetic testing from 1/1/2015 to 12/31/2018, with follow up to 03/31/2020 in Kaiser Permanente Northern California. ResultsA total of 13,271 tests which included HBOC genes were identified. Rate of bilateral salpingo-oophorectomy after genetic testing were similar for BRCA and the non-BRCA moderate risk ovarian pathogenic variants (PVs) (47.4% vs 54%, p = 0.25). Rates were lower for low risk or unknownrisk non-BRCA PVs (12.8%, p < 0.001, 5.3% (p < 0.001). Rates of surveillance for ovarian cancer with ultrasound and CA 125 in the first year was 63.3% and 64.7% for BRCA PV, 37.5% and 27.1%, for non-BRCA moderate risk PVs and 13.7% and 4.6%, for low-risk PVs. Bilateral mastectomy rates were 19.7% for BRCA PV, 10.1% (p = 0.028) for non-BRCA breast high risk PVs, for moderate risk PVs 7.7% (p < 0.001) and for unknown risk 0.4% (p < 0.001). MRI surveillance rates in the first year similarly were 47.4% for non-BRCA BRCA PV, 43% for breast high risk PV, 39.4% for moderate risk and 4.9% for unknown risk PV. ConclusionSurgical and surveillance strategies are underutilized for HBOC PV, however there is concordance of uptake of preventive strategies with specific risk associated with non-BRCA PVs.

Editors' Selections from Relevant Scientific Publications

Editors' Selections from Relevant Scientific Publications

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Ovarian cancer risk-reduction and screening in BRCA 1/2 mutation carriers (383)

<b>Objectives:</b> To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female <i>BRCA1/2</i> carriers. <b>Methods:</b> A multi-center, cross-sectional survey was conducted among <i>BRCA1/2</i> mutation carriers unaffected by cancer. The questionnaire was administered electronically via email using REDCap with two reminder emails. There were 2-23 fixed-response questions, including questions on genetic testing and risk-reducing decisions. Data were analyzed with Fisher's exact test. <b>Results:</b> The survey was completed by 105 female <i>BRCA</i> mutation carriers (34% response rate). <i>BRCA</i> subtypes included 54.3% <i>BRCA 2,</i> 41.0% <i>BRCA 1</i> and 2.9% of both. The age at which patients underwent genetic testing varied, with 21.0% within the age range of 18-24 years (yr), 24.8% within 25-34 yr, 30.5% 35-44 yr, 17.1% were 45-54 yr and 6.7% were >55 years. The majority of ordering providers were genetic counselors (57.1%), with fewer tests ordered by OBGYNs (18.1%), primary care providers (4.8%), gynecologic oncologists (4.8%), and breast surgeons (3.8%). Approximately half (55.8%) of respondents reported having been offered increased screening for possible early detection of ovarian cancer. Of the 79 women who performed their genetic testing before 45 years, 41.8% underwent increased ovarian cancer screening with either transvaginal ultrasound alone (21.2%), CA-125 alone (12.1%), or combined (63.6%). There were no differences seen in screening utilization based on <i>BRCA</i> mutation type <i>(BRCA1</i> 40.0% vs <i>BRCA2</i> 42.5%; p=0.93). Nearly all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Sixty women underwent a risk-reducing bilateral salpingo-oophorectomy, which was recommended in similar proportions by gynecologic oncologists (58.3%), OBGYNs (48.3%), and genetic counselors (46.7%). Overall, 43.3% of respondents reported that a healthcare provider recommended taking combined oral contraceptive pills to reduce their risk of ovarian cancer, and of these women, 86.7% chose to use them. Combined oral contraceptive pills were offered at higher rates among women who were younger at age of genetic testing (18-24 yr: 86%, 25-34 yr: 62%, 35-44 yr: 23%; p<0.0001) as well as women with <i>BRCA1</i> mutations <i>(BRCA1:</i> 60%, <i>BRCA2:</i> 43%; p=0.048). <b>Conclusions:</b> In our cohort of female <i>BRCA</i> mutation carriers, ovarian cancer screening was offered to only half of the women. While the majority had discussed surgical options, less than half of women received recommendations to use medication-based risk-reduction. Further investigation is needed to identify barriers to utilization of ovarian cancer screening and nonsurgical risk-reduction among this high-risk population.

Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia.

Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

Pregnancy duration and ovarian cancer risk: A 50-year nationwide cohort study.

A woman's reproductive history is strongly associated with her risk of ovarian cancer. However, it is unclear how pregnancies of different duration impact a woman's ovarian cancer risk, and therefore, what part of a pregnancy explains the protective effect. Using a cohort of all Danish women followed from 1968 to 2018, with prospectively registered information on reproductive history (eg, gestational duration of pregnancies, tubal ligation and resection and hormonal pharmaceutical use), we investigated the effect of pregnancy duration on ovarian cancer risk. We adjusted for potential confounders, such as age at pregnancy and time since pregnancy, using log-linear Poisson regression to isolate the effect of pregnancy duration on ovarian cancer risk. Among 2.5 million Danish women with 4.4 million pregnancies, a pregnancy was associated with a reduction of ovarian cancer risk of 21% (95% CI, 14%-28%), 26% (95% CI, 21%-31%), 12% (95% CI, 7%-17%) and 3% (95% CI, -5% to 11%) compared to one less, for the first, second, third and fourth pregnancy, respectively (P < .001 for heterogeneity), with similar effects of induced abortions, spontaneous abortions and childbirths. Sensitivity analysis of age at pregnancy, time since pregnancy and other potential confounders did not change these findings. The reduced ovarian cancer risk associated with pregnancy is primarily driven by the first three pregnancies, with similar effects of induced abortion, spontaneous abortions and childbirth, suggesting that mainly exposure to early pregnancy factors, and not pregnancy duration, protect against ovarian cancer.