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Background: Identifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing., Primary Objective: Our primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing., Study Hypothesis: We hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care., Trial Design: The FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services., Major Inclusion/exclusion Criteria: Adult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included., Primary Endpoint: Analyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm., Sample Size: One hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants., Estimated Dates for Completing Accrual and Presenting Results: January 2024., Trial Registration: NCT04613440., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment., Methods: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response., Results: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response., Conclusion: Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In response to the critical shortage of liposomal doxorubicin (Doxil®) in the United States, the Food and Drug Administration (FDA) approved temporary importation of doxorubicin hydrochloride liposome (Lipodox®). The objective was to compare toxicity and clinical activity of Lipodox® with Doxil®., Methods: Recurrent ovarian cancer patients who received Lipodox® were compared 3:1 to matched control Doxil® patients who had received Doxil®. Patients were matched based on age, stage, dose, platinum sensitivity, and prior treatments from an existing de-identified database. Patients receiving combination regimens were excluded., Results: The data from 40 Lipodox® patients was compared to 120 matched control Doxil® patients. In this study, 17 (42.5%) of the Lipodox® patients were switched to Doxil®. The overall response rate Lipodox® was 4.3% (1/23) compared to 18% (20/111) in matched control Doxil® patients. In the platinum-sensitive patients, 100% progressed in the Lipodox® group compared to 78.4% in matched control Doxil® patients. The mean time to progression was 4.1 ± 2.8 months for Lipodox® and 6.2 ± 7.2 months in control Doxil®s (p = 0·25). Toxicity was similar in the Lipodox® group and control Doxil® group., Conclusion: Lipodox® for treatment of recurrent ovarian cancer did not appear to have equivalent efficacy compared to Doxil®. A prospective clinical study is warranted before Lipodox® can be deemed equivalent substitution for Doxil®., (© The Author(s) 2015.)

Ovarian high-grade serous carcinoma is an aggressive malignancy with poor prognosis. Optimal surgical debulking and tumor sensitivity to platinum-based chemotherapy are 2 well-established prognostics for this tumor type. Molecular markers that identify more clinically aggressive tumors would potentially allow for the development of individualized treatment options. PTEN is a key negative regulator of the PI3K signaling pathway. Loss of PTEN expression in endometrial carcinoma is associated with endometrioid histology; women with endometrioid tumors have a better prognosis than those with nonendometrioid tumors. The prognostic and predictive value for PTEN has not been effectively explored in ovarian/peritoneal high-grade serous carcinoma. PTEN immunohistochemistry was assessed in 126 women with Stage III, high-grade serous carcinoma of the ovary/peritoneum treated with surgery and then a platinum-based regimen. Compared with PTEN-negative or PTEN-reduced tumors, positive PTEN immunohistochemistry, detected in 58% of tumors, was associated with decreased pS6 and increased PTEN mRNA levels. Positive PTEN expression was independent of surgical debulking status or platinum sensitivity. PTEN-positive tumors were associated with significantly decreased recurrence-free survival. Importantly, the devised PTEN immunohistochemistry scoring system was reproducible among pathologists.

Background: Preclinical evidence has suggested that sustained adrenergic activation can promote ovarian cancer growth and metastasis. The authors examined the impact of beta-adrenergic blockade on the clinical outcome of women with epithelial ovarian, primary peritoneal, or fallopian tube cancers (collectively, epithelial ovarian cancer [EOC])., Methods: A multicenter review of 1425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta-blocker use during chemotherapy and those without beta-blocker use., Results: The median age of patients in the current study was 63 years (range, 21-93 years). The sample included 269 patients who received beta-blockers. Of those, 193 (71.7%) were receiving beta-1-adrenergic receptor selective agents, and the remaining patients were receiving nonselective beta antagonists. The primary indication for beta-blocker use was hypertension but also included arrhythmia and postmyocardial infarction management. For patients receiving any beta-blocker, the median overall survival (OS) was 47.8 months versus 42 months for nonusers (P =.04). The median OS based on beta-blocker receptor selectivity was 94.9 months for those receiving nonselective beta-blockers versus 38 months for those receiving beta-1-adrenergic receptor selective agents (P<.001). Hypertension was associated with decreased OS compared with no hypertension across all groups. However, even among patients with hypertension, a longer median OS was observed among users of a nonselective beta-blocker compared with nonusers (38.2 months vs 90 months; P<.001)., Conclusions: Use of nonselective beta-blockers in patients with EOC was associated with longer OS. These findings may have implications for new therapeutic approaches. Cancer 2015;121:3435-43. © 2015 American Cancer Society., (© 2015 American Cancer Society.)

Purpose: To evaluate if an individual's locus of control (LOC) predicts various quality of life (QOL) and mental well-being measures. To identify targets that might enhance the overall spiritual well-being and QOL of ovarian cancer patients., Methods: Multi-site analysis of women with newly diagnosed stages II-IV ovarian, primary peritoneal or fallopian tube cancer. Patients completed the following surveys: Locus of Control Scale (LOC), Functional Assessment of Chronic Illness Therapy-Ovarian (FACT-O), Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp), Edmonton Symptom Assessment score (ESAS), Hospital Anxiety Depression Scale (HADS), Templer's Death Anxiety Scale (DAS), and Herth Hope Index (HHI). Regression models were created to examine the effect of LOC upon QOL, symptoms, and other measures of mental well-being. These models adjusted for the effect of site of care, race, and partnership status as potential confounders., Results: This study enrolled 104 patients from three separate treatment facilities. After adjusting for site, race and partnership status, higher levels of external LOC predicted decreased QOL (FACT-O) (p<0.05). Higher levels of external LOC also correlated with increased death anxiety and general anxiety (p≤0.05). Additionally, higher levels of external LOC predicted decreased hope (HHI) (p≤0.01)., Discussion: Ovarian cancer patients with a high external LOC may be at risk for decreased QOL at the time of their cancer diagnosis. They may also experience higher levels of anxiety and decreased feelings of hope. Identification of these women and interventions designed to increase a woman's sense of control over her situation may improve QOL and overall mental well-being., (Copyright © 2015. Published by Elsevier Inc.)

Purpose: Identification of the 10% to 15% of patients with ovarian cancer who have germline BRCA1 or BRCA2 mutations is important for management of both patients and relatives. The BRCAPRO model, which estimates mutation likelihood based on personal and family cancer history, can inform genetic testing decisions. This study's purpose was to assess the accuracy of BRCAPRO in women with ovarian cancer., Methods: BRCAPRO scores were calculated for 589 patients with ovarian cancer referred for genetic counseling at three institutions. Observed mutations were compared with those predicted by BRCAPRO. Analysis of variance was used to assess factors impacting BRCAPRO accuracy., Results: One hundred eighty (31%) of 589 patients with ovarian cancer tested positive. At BRCAPRO scores less than 40%, more mutations were observed than expected (93 mutations observed v 34.1 mutations expected; P < .001). If patients with BRCAPRO scores less than 10% had not been tested, 51 (28%) of 180 mutations would have been missed. BRCAPRO underestimated the risk for high-grade serous ovarian cancers but overestimated the risk for other histologies (P < .001), underestimation increased as age at diagnosis decreased (P = .02), and model performance varied by institution (P = .02)., Conclusion: Patients with ovarian cancer classified as low risk by BRCAPRO are more likely to test positive than predicted. The risk of a mutation in patients with low BRCAPRO scores is high enough to warrant genetic testing. This study demonstrates that assessment of family history by a validated model cannot effectively target testing to a high-risk ovarian cancer patient population, which strongly supports the recommendation to offer BRCA1/BRCA2 genetic testing to all patients with high-grade serous ovarian cancer regardless of family history.

Background: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer., Methods: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival., Results: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8-5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9-18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01-1.04) were related to decreased survival., Conclusion: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer., Impact: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy., (©2013 AACR.)

Objectives: Previous studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for "survival bias" by minimizing lead time that may exist between diagnosis and genetic testing., Methods: Patients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi-square were also used for analysis., Results: Ninety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43-0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27-0.68]). BRCA status was an independent predictor of PFS and OS., Conclusions: This multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the "survival bias" that coincides with genetic testing., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Assessment of estrogen receptor (ER) expression by immunohistochemistry has yielded inconsistent results as a prognostic indicator in ovarian carcinoma. In breast and endometrial carcinomas, panels of estrogen-induced genes have shown improved prognostic capability over the use of ER immunohistochemistry alone. For both breast and endometrial cancers, overexpression of estrogen-induced genes is associated with better prognosis. We hypothesized that analysis of a panel of estrogen-induced genes can predict the outcome in ovarian carcinoma and potentially differentiate between tumors of varying hormonal responsiveness. From a cohort of 219 women undergoing ovarian cancer surgery from 2004 to 2007, 83 patients were selected for inclusion. All patients had advanced stage ovarian/primary peritoneal high-grade serous carcinoma and underwent primary surgical debulking, followed by adjuvant treatment with platinum and taxane agents. The expression of ERα and six genes known to be induced by estrogen in the female reproductive tract (namely EIG121, sFRP1, sFRP4, RALDH2, PR, and IGF-1) was measured using quantitative RT-PCR. Unsupervised cluster analyses were used to categorize patients as high or low gene expressors. Gene expression results were then compared with those for ER immunohistochemistry. Clusters were compared using χ(2) analyses, and Cox proportional hazards models were used to evaluate survival outcomes. The median follow-up time was 38.7 months (range: 1-68). A cluster defined by EIG121 and ERα segregated tumors into distinct groups of high and low gene expressors. Shorter overall survival (OS) was associated with high gene expression (HR 2.84 (1.11-7.30), P=0.03), even after adjustment for other covariates. No difference in ER immunohistochemistry expression was noted between gene clusters. In contrast to other hormonally driven cancers, high expression of ERα and the estrogen-induced gene EIG121 predicts shorter OS in patients with high-grade serous ovarian carcinoma. Such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population.

Objective: To determine whether women with low-grade serous ovarian cancer (LGSOC) have personal and family histories of breast and ovarian cancer that are less suggestive of Hereditary Breast and Ovarian Cancer (HBOC), as compared to women with high-grade serous ovarian cancer (HGSOC)., Methods: A single institution, case-control retrospective review of medical records was conducted. Personal demographics, personal cancer history, and family history of breast and ovarian cancer of women with LGSOC were collected and compared to controls with HGSOC, which is known to be associated with HBOC., Results: 195 cases of LGSOC and 386 controls with HGSOC were included in the analysis. Women with LGSOC were significantly less likely to have a first- or second-degree relative with breast or ovarian cancer (p=0.0016). Additionally, when the personal and family histories were quantified using the AMyriad BRC mutation prevalence tables, women with LGSOC had lower scores indicative of a less suggestive family history for HBOC (p=0.027)., Conclusions: In this study, women with LGSOC had family histories that were less suggestive of HBOC compared to women with HGSOC, especially when the degree of relatedness of affected relatives was taken into account. By beginning to determine if LGSOC is part of the tumor spectrum seen in HBOC, this study is an important step towards refining hereditary cancer risk assessment for women with ovarian cancer., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To estimate the incidence of genetic counseling referral for ovarian cancer patients who are at substantial risk for a BRCA1 or BRCA2 mutation., Methods: An analysis was performed of new ovarian cancer patients who were seen at a comprehensive cancer center from January 1, 1999, through December 31, 2007. Patients at substantial (more than 20-25%) risk for a BRCA1 or BRCA2 mutation were identified and records reviewed for referral to genetic counseling. Time to referral was estimated using the Kaplan-Meier method., Results: A total of 3,765 epithelial ovarian cancer patients were seen during the 9-year period. On average, 23.8% of patients met substantial-risk criteria for BRCA mutations. In 1999, only 12% of patients at substantial-risk were referred. Referral improved over time with 48% referred in 2007 (P<.001). Newly diagnosed patients were more often referred for genetic counseling than new patients with recurrent disease or those seen as second opinions. African-American women meeting substantial-risk criteria were less likely to be referred than were white or Hispanic women (P=.009)., Conclusion: Although dictated family history was accurate, interpretation of risk for BRCA1 or BRCA2 mutations and subsequent referral to genetic counseling was poor. Although there was significant improvement over time, 50% of substantial-risk patients still were missed. Systematic efforts to identify those ovarian cancer patients at substantial risk for a BRCA1 or BRCA2 are necessary.

Purpose: To determine when, in reference to the course of their treatment, women with ovarian cancer are seen for genetic counseling, as well as to determine what factors influence this timing., Methods: : Single institution retrospective chart review of patients with ovarian cancer who underwent BRCA1/BRCA2 genetic testing., Results: Thirty-three percent of our sample (n = 100) were seen for genetic counseling after ovarian cancer recurrence. In four cases, genetic test results were disclosed to next of kin. Thirty percent of women seen for genetic counseling after recurrence received their initial treatment elsewhere. Women with a history of breast cancer were significantly more likely to be seen for genetic counseling at an earlier phase of their treatment than women with no history of breast cancer., Conclusion: We found that one third of patients with ovarian cancer who underwent genetic testing were seen for initial genetic counseling after disease recurrence. In some cases, genetic counseling took place during the end of life care, with genetic test results disclosed to next of kin. Given the poor prognosis of women with recurrent ovarian cancer, we advocate providing genetic counseling at the time of initial ovarian cancer treatment both in comprehensive cancer centers and in community oncology settings.

Purpose: Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma., Experimental Design: After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), beta 2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry., Results: The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and beta 2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P < 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P < 0.001) were independent prognostic markers for death from ovarian carcinoma., Conclusion: The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.

Background: EphA2 is overexpressed in the majority of ovarian cancers and predicts poor clinical outcome. Based on EphA2's emerging role in angiogenesis, we hypothesized that tumors overexpressing EphA2 demonstrate greater microvessel density (MVD) and matrix metalloproteinase (MMP) expression., Methods: After Institutional Review Board (IRB) approval, 77 invasive epithelial ovarian tumors were analyzed for CD31, EphA2, MMP-2, MMP-9, and MT1-MMP expression., Results: The median age of the patients was 59 years (range, 34-83). EphA2 was overexpressed in 76% of tumors and was associated with advanced-stage disease (P < .001) and high-grade histology (P = .04). MVD was stratified into high (>12.7 vessels/high-power field [HPF]) versus low (