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Epithelial ovarian cancer (EOC) is widely recognized as the most lethal gynecological malignancy; however, its early-stage detection remains a considerable clinical challenge. To address this, we have introduced a new method, named Comprehensive Serum Glycopeptide Spectral Analysis (CSGSA), which detects early-stage cancer by combining glycan alterations in serum glycoproteins with tumor markers. We detected 1712 glycopeptides using liquid chromatography-mass spectrometry from the sera obtained from 564 patients with EOC and 1149 controls across 13 institutions. Furthermore, we used a convolutional neural network to analyze the expression patterns of the glycopeptides and tumor markers. Using this approach, we successfully differentiated early-stage EOC (Stage I) from non-EOC, with an area under the curve (AUC) of 0.924 in receiver operating characteristic (ROC) analysis. This method markedly outperforms conventional tumor markers, including cancer antigen 125 (CA125, 0.842) and human epididymis protein 4 (HE4, 0.717). Notably, our method exhibited remarkable efficacy in differentiating early-stage ovarian clear cell carcinoma from endometrioma, achieving a ROC-AUC of 0.808, outperforming CA125 (0.538) and HE4 (0.557). Our study presents a promising breakthrough in the early detection of EOC through the innovative CSGSA method. The integration of glycan alterations with cancer-related tumor markers has demonstrated exceptional diagnostic potential., (© 2024. The Author(s).)

Objective: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD)., Methods: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity., Results: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23)., Conclusions: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To describe population-level utilization of fertility-sparing surgery and outcome of reproductive-aged patients with early epithelial ovarian cancer who underwent fertility-sparing surgery in the United States., Methods: This retrospective study queried the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study included 3,027 patients younger than age 50 years with stage I epithelial ovarian cancer receiving primary surgical therapy from 2007 to 2020. Fertility-sparing surgery was defined as preservation of one ovary and the uterus for unilateral lesion and preservation of the uterus for bilateral lesions. Temporal trend of fertility-sparing surgery was assessed with linear segmented regression with log-transformation. Overall survival associated with fertility-sparing surgery was assessed with Cox proportional hazard regression model., Results: A total of 534 patients (17.6%) underwent fertility-sparing surgery. At the cohort level, the utilization of fertility-sparing surgery was 13.4% in 2007 and 21.8% in 2020 ( P for trend=.009). Non-Hispanic White individuals (2.8-fold), those with high-grade serous histology (2.2-fold), and individuals with stage IC disease (2.3-fold) had a more than twofold increase in fertility-sparing surgery utilization during the study period (all P for trend<.05). After controlling for the measured clinicopathologic characteristics, patients who received fertility-sparing surgery had overall survival comparable with that of patients who had nonsparing surgery (5-year rates 93.6% vs 92.1%, adjusted hazard ratio 0.87, 95% CI, 0.57-1.35). This survival association was consistent in high-grade serous (5-year rates 92.9% vs 92.4%), low-grade serous (100% vs 92.2%), clear cell (97.5% vs 86.1%), mucinous (92.1% vs 86.6%), low-grade endometrioid (95.7% vs 97.7%), and mixed (93.3% vs 83.7%) histology (all P >.05). In high-grade endometrioid tumor, fertility-sparing surgery was associated with decreased overall survival (5-year rates 71.9% vs 93.8%, adjusted hazard ratio 2.90, 95% CI, 1.09-7.67). Among bilateral ovarian lesions, fertility-sparing surgery was not associated with overall survival (5-year rates 95.8% vs 92.5%, P =.364). Among 41,914 patients who had epithelial ovarian cancer with any age and stage, those younger than age 50 years with stage I disease increased from 8.6% to 10.9% during the study period ( P for trend=.002)., Conclusion: Nearly one in five reproductive-aged patients with stage I epithelial ovarian cancer underwent fertility-sparing surgery in recent years in the United States. More than 90% of reproductive-aged patients with stage I epithelial ovarian cancer who underwent fertility-sparing surgery were alive at the 5-year timepoint, except for those with high-grade endometrioid tumors., Competing Interests: Financial Disclosure Maximilian Klar reports being a consultant for AstraZeneca, CooperSurgical, and KLS Martin. Lynda D. Roman reports being a consultant for Cardiff Oncology and Nutcracker, and she has participated in the Steering Committee for the Global Coalition of Adaptive Research. Jason D. Wright reports being a consultant and receiving a research grant from Merck and royalties from UpToDate. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10 -8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10 -5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To assess population-level trends, characteristics, and outcomes of high-grade serous tubo-ovarian carcinoma in the United States., Methods: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 27,811 patients diagnosed with high-grade serous tubo-ovarian carcinoma from 2004 to 2020. The exposure was the primary cancer site (ovary or fallopian tube). Main outcome measures were temporal trends, clinical characteristics, and overall survival associated with primary cancer site assessed in multivariable analysis., Results: The study population comprised 23,967 diagnoses of high-grade serous ovarian carcinoma and 3,844 diagnoses of high-grade serous fallopian tubal carcinoma. The proportion of diagnoses of high-grade serous fallopian tubal carcinoma increased from 365 of 7,305 (5.0%) in 2004-2008 to 1,742 of 6,663 (26.1%) in 2017-2020. This increase was independent in a multivariable analysis (adjusted odds ratio [aOR] vs 2004-2008, 2.28 [95% CI, 1.98-2.62], 3.27 [95% CI, 2.86-3.74], and 6.65 [95% CI, 5.84-7.57] for 2009-2012, 2013-2016, and 2017-2020, respectively). This increase in high-grade serous fallopian tubal carcinoma was seen across age groups (4.3-5.8% to 22.7-28.3%) and across racial and ethnic groups (4.1-6.0% to 21.9-27.5%) (all P for trend <.001). Among the cases of tumors smaller than 1.5 cm, the increase was particularly high (16.9-67.6%, P for trend <.001). Primary-site tumors in the high-grade serous fallopian tubal carcinoma group were more likely to be smaller than 1.5 cm (aOR 8.26, 95% CI, 7.35-9.28) and unilateral (aOR 7.22, 95% CI, 6.54-7.96) compared with those in high-grade serous ovarian carcinoma. At the cohort level, the diagnosis shift to high-grade serous fallopian tubal carcinoma was associated with narrowing differences in survival over time between the two malignancy groups: adjusted hazard ratio 0.84 (95% CI, 0.74-0.96), 0.91 (95% CI, 0.82-1.01), 1.01 (95% CI, 0.92-1.12), and 1.12 (95% CI, 0.98-1.29) for 2004-2008, 2009-2012, 2013-2016, and 2017-2020, respectively., Conclusion: This population-based assessment suggests that diagnoses of high-grade serous tubo-ovarian carcinoma in the United States have been rapidly shifting from high-grade serous ovarian to fallopian tubal carcinoma in recent years, particularly in cases of smaller, unilateral tumors., Competing Interests: Financial Disclosure Jason D. Wright has been a consultant and received a research grant from Merck and royalties from UpToDate. Lynda D. Roman has been a consultant for Cardiff Oncology and Nutcracker. She participates in the Steering Committee for the Global Coalition of Adaptive Research. Maximilian Klar has been a consultant for AstraZeneca, CooperSurgical, and KLS Martin. Anil K. Sood has been a consultant for AstraZeneca, Kiyatec, Merck, GlaxoSmithKline, ImmunoGen, Iylon, and Onxeo, and is a shareholder in BioPath. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

In this cross-sectional study including 1,722,479 women who underwent laparoscopic cholecystectomy between January 2016 and December 2019 identified in the Healthcare Cost and Utilization Project's Nationwide Ambulatory Surgery Sample, the prevalence rate of gynecologic diagnoses was 11.3 per 1,000. Among presumed elective laparoscopic cholecystectomy, the highest performance rate of concurrent gynecologic procedure per gynecologic diagnosis was laparoscopic adnexectomy among patients with benign ovarian tumor (652/1,000 diagnoses), followed by laparoscopic adnexectomy for endometrioma (386/1,000 diagnoses) and cervical conization for cervical carcinoma in situ (304/1,000 diagnoses). The measured surgical morbidity rates for patients who had concurrent gynecologic surgery and those who did not were 2.8 per 1,000 and 1.9 per 1,000, respectively (adjusted odds ratio 1.39, 95% CI 0.75-2.59). These results suggest that minimally invasive gynecologic surgeries are being performed at the time of outpatient laparoscopic cholecystectomy in the United States., Competing Interests: Financial Disclosure Jason D. Wright reports his institution received a research grant from Merck, he received royalties from UpToDate, and he received payment from the American College of Obstetricians and Gynecologists. Maximilian Klar has been a consultant for CooperSurgical and KLS Martin; Lynda D. Roman has been a consultant for Cardiff Oncology and received payment from Nutcracker Therapeutics and participates in the Steering Committee for the Global Coalition of Adaptive Research. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC., Methods: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves., Results: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage., Conclusion: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice., Competing Interests: Competing interests: Stephanie Lheureux reports study grants from AstraZeneca, GSK and Roche, consulting fees from AstraZeneca, GSK, Roche, Novartis, Merck, Eisai Co. and Shattuck Labs, and speaker’s honororia from AstraZeneca, GSK, Eisai Co. and Merck. Line Bjørge is president of the Nordic Society of Gynaecological Oncology executive board. Anna deFazio sits on the Australia New Zealand Gynaecological Oncology Group (ANZGOG) Research Advisory Committee, the Clinical and Scientific Expert Advisory Panel of Ovarian Cancer Australia and the Scientific Advisory Committee of the Australian Gynaecological Cancer Foundation. She is chair of the Translational ANZGOG (TRANZGOG) Steering Committee, chair of the International Consortium for Low-Grade Serous Ovarian Cancer Steering Committee and chair of the ANZGOG Translational subcommittee. Michael Friedlander reports consulting fees from AstraZeneca, GSK, MSD, Eli Lilly and Company, Takeda and Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra-Zeneca, GSK and ACT Genomics; and support for attending meetings and/or travel from AstraZeneca. He sits on the Australasian Gastrointestinal Trial Group independent data monitoring committee and is a Steering Committee member for Abbvie’s VELIA trial. Catherine Kennedy is a member of the International Society for Biological and Environmental Repositories Science Policy Committee and of the Australasian Biospecimen Network (ABNA) Management Committee. She is past president and treasurer of ABNA. Liv Cecilie Vestrheim Thomsen reports grants from AstraZeneca, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer and AstraZeneca. She sits on an advisory board for Eisai Co. Ignace Vergote reports consulting fees from Deciphera Pharmaceuticals, Jazz Pharmaceuticals and Oncoinvent AS, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Agenus, AkseBio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai Co., F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Jazz Pharmaceuticals, Karyopharm Therapeutics, MSD, Novocure, Novartis, Oncoinvent AS, Seagen and Sotio Biotech. He sits on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai Co., F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, MSD, Novocure, Novartis, Seagen and Sotio Biotech. Penelope Webb reports a speaker’s honorarium from AstraZeneca. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Importance: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied., Objective: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer., Design, Setting, and Participants: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy., Exposures: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group)., Main Outcomes and Measures: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score., Results: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas., Conclusions and Relevance: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

Background: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC., Methods: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source., Results: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes., Conclusions: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To perform a cost-effectiveness analysis to examine the utility and effectiveness of OS performed at the time of elective cholecystectomy [laparoscopic cholecystectomy (LAP-CHOL)]., Summary Background Data: OS has been adopted as a strategy to reduce the risk of ovarian cancer in women undergoing hysterectomy and tubal sterilization, although the procedure is rarely performed as a risk reducing strategy during other abdominopelvic procedures., Methods: A decision model was created to examine women 40, 50, and 60 years of age undergoing LAP-CHOL with or without OS. The lifetime risk of ovarian cancer was assumed to be 1.17%, 1.09%, and 0.92% for women age 40, 50, and 60 years, respectively. OS was estimated to provide a 65% reduction in the risk of ovarian cancer and to require 30 additional minutes of operative time. We estimated the cost, quality-adjusted life-years, ovarian cancer cases and deaths prevented with OS., Results: The additional cost of OS at LAP-CHOL ranged from $1898 to 1978. In a cohort of 5000 women, OS reduced the number of ovarian cancer cases by 39, 36, and 30 cases and deaths by 12, 14, and 16 in the age 40-, 50-, and 60-year-old cohorts, respectively. OS during LAP-CHOL was cost-effective, with incremental cost-effectiveness ratio of $11,162 to 26,463 in the 3 age models. In a probabilistic sensitivity analysis, incremental cost-effectiveness ratio for OS were less than $100,000 per quality-adjusted life-years in 90.5% or more of 1000 simulations., Conclusions: OS at the time of LAP-CHOL may be a cost-effective strategy to prevent ovarian cancer among average risk women., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Sentinel lymph node (SLN) biopsy has been incorporated into surgical care for many malignancies; however, the utility has not been examined in ovarian cancer. This study examined population-level trends, characteristics, and outcomes related to SLN biopsy in early stage ovarian cancer., Methods: This is a retrospective cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 2003-2018. The study population consisted of 11,512 women with stage I ovarian cancer who had adnexectomy-based surgical staging including lymph node evaluation. Exposure allocation was based on SLN biopsy use. Main outcomes measured were (i) trends and characteristics associated with SLN biopsy use, assessed by multivariable logistic regression model, and (ii) overall survival assessed with inverse provability of treatment weighting propensity score., Results: SLN biopsy was performed in less than 1% of study population. In a multivariable analysis, recent surgery (2011-2018 versus 2003-2010, odds ratio [OR] 1.64, 95% confidence interval [CI] 1.03-2.59), smaller tumor size (< 10 versus ≥ 10 cm, OR 3.07, 95% CI 1.20-7.84), and East registry area (OR 2.74, 95% CI 1.73-4.36) remained independent characteristics for SLN biopsy use. In a propensity score weighted model, 5-year overall survival rate was 90.5% for the SLN biopsy-incorporated group and 88.6% for the lymphadenectomy group (hazard ratio 0.96, 95% CI 0.53-1.73)., Conclusion: SLN biopsy was rarely performed for early ovarian cancer surgery during the study period with insufficient evidence to interpret the survival effect. SLN biopsy in early ovarian cancer appears to be in early development phase, warranting further study and careful evaluation to assess feasibility and oncologic outcome., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To examine characteristics and survival of patients who developed secondary ovarian cancer after external beam radiotherapy (EBRT) for a prior nonovarian pelvic malignancy., Methods: This is a population-based retrospective cohort study, querying the Surveillance, Epidemiology, and End Result program from 1975 to 2016. 167,269 women who received EBRT for 7 malignancies (anus, rectum, bladder, cervix, uterus, vulva, or vagina) were examined to identify subsequent secondary ovarian cancer diagnosis after EBRT. Then, within the ovarian cancer cohort (n = 147,618), characteristics and survival of patients with secondary ovarian cancer after EBRT were compared to those with ovarian cancer who did not receive prior EBRT., Results: Following EBRT for a pelvic malignancy, 215 (1.3 per 1000) patients developed secondary ovarian cancer. Among those, the most frequent prior malignancy was cervical cancer (45.6%), followed by rectal cancer (20.9%). The median time from prior EBRT to secondary ovarian cancer was 8.8 years (interquartile range, 2.8-14.5). In multivariable analysis, patients with secondary ovarian cancer after EBRT were more likely to be older, and have a recent year of diagnosis, but less likely to have early-disease compared to ovarian cancer patients without prior EBRT (all, P < 0.05). In weighted model, patients with secondary ovarian cancer after EBRT had decreased overall survival compared to those with ovarian cancer without prior EBRT (5-year rates, 19.6% versus 39.9%, hazard ratio 1.62, 95% confidence interval 1.43-1.85). Similar association was observed in ages <70, ≥70, White, non-White, early-disease, and advanced-disease in sensitivity analyses., Conclusion: Radiotherapy-related secondary ovarian cancer may be associated with decreased overall survival., Competing Interests: Declaration of competing interest Consultant, Quantgene (L.D.R.)., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery., Methods: This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS., Results: Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53)., Conclusions: The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR., Methods: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS)., Results: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029)., Conclusions: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively., Competing Interests: Declaration of Competing Interest During the conduct of the study, BF reports grants from NIH; KFH reports grants from CPRIT; AKS reports grants from NIH; and SNW reports grants from NIH and GOG Foundation. Outside the submitted work, RLC reports grants and personal fees from AstraZeneca, grants from Merck, personal fees from GSK, grants and personal fees from Clovis, grants and personal fees from Genmab, grants and personal fees from Roche/Genentech, grants and personal fees from Janssen, personal fees from Agenus, personal fees from Regeneron, and personal fees from OncoQuest; NDF reports personal fees from Tesaro, personal fees from BMS/Pfizer, and personal fees from GSK; KH reports grants and personal fees from MSD, grants from Daiichi-Sankyo, personal fees from Chugai, grants and personal fees from Takeda, personal fees from Mochida, personal fees from Eisai, grants from Abbott, and grants from Ono; CJL reports personal fees from Agenus; KMatsuo reports other from Chugai; KMoore reports personal fees and other from Astra Zeneca, grants, personal fees and other from Genentech/Roche, grants, personal fees and other from Immunogen, grants, personal fees and other from Clovis, grants, personal fees and other from GSK/Tesaro, other from Pfizer, personal fees from Aravive, personal fees from VBL Therapeutics, personal fees from Onco Med, grants and other from Lilly, personal fees from Eisai, personal fees from Vavotar, personal fees from Abbvie, personal fees from Tarveda, personal fees from Myriad, personal fees from Rubius, personal fees from Elevar, personal fees from Merck, personal fees from Mersana, personal fees from Sorrento, and personal fees from OncXerna; AKS reports grants from M-Trap, other from Biopath, personal fees from Merck, personal fees from Kiyatec, and personal fees from Astra Zeneca; SNW reports grants and personal fees from AstraZeneca, grants and personal fees from Clovis Oncology, grants and personal fees from GSK/Tesaro, grants and personal fees from Roche/Genentech, grants and personal fees from Novartis, personal fees from Merck, personal fees from Pfizer, personal fees from Eisai, grants from Cotinga Pharmaceuticals, grants from Bayer, grants from ArQule, personal fees from CIrculogene, personal fees from Agenus, grants from Mereo, and grants from Bio-Path. The remaining authors report no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects., Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data., Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54)., Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival., Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer., (©2021 American Association for Cancer Research.)

Background: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear., Materials and Methods: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status., Results: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways., Conclusions: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation., Competing Interests: Declaration of Competing Interest Following was outside the submitted work: Honorarium, Chugai, textbook editorial expense, Springer, and investigator attendance expense, VBL Therapeutics (K.M.); others reported no potential conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Opportunistic salpingectomy is now recommended at the time of routine gynecologic surgery to reduce the risk of future ovarian cancer, and performance of opportunistic salpingectomy has increased markedly at the time of benign hysterectomy. Salpingectomy has also been suggested to be feasible at the time of cesarean delivery in women desiring sterilization; however, uptake has not been previously studied on a national level., Objective: This study aimed to examine recent population trends in the utilization and characteristics of salpingectomy at the time of cesarean delivery in the United States., Study Design: This is a population-based retrospective observational study querying the National Inpatient Sample between October 2015 and December 2018. The primary outcome measure was the temporal trend of bilateral salpingectomy at cesarean delivery, assessed with linear segmented regression with log transformation utilizing 3-month time increments. The secondary outcome measures included patient characteristics associated with bilateral salpingectomy, assessed with a multinomial regression model, and surgical outcome (hemorrhage, blood transfusion, hysterectomy, and oophorectomy) at the time of bilateral salpingectomy vs bilateral tubal ligation, assessed with generalized estimating equation in a propensity score-matched model., Results: There were 3,813,823 women at the age of 15 to 49 years who had cesarean deliveries included, of whom 397,260 (10.4%) had bilateral salpingectomy and 203,400 (5.3%) had bilateral tubal ligation overall. During the time period studied, performance of bilateral salpingectomy among women undergoing cesarean delivery significantly increased from 4.6% to 13.2% (odds ratio for the fourth quarter of 2018 vs the fourth quarter of 2015, 2.69; 95% confidence interval, 2.63-2.75; Figure panel). In contrast, performance of bilateral tubal ligation among women undergoing cesarean delivery significantly decreased from 11.3% to 2.4% (odds ratio, 0.20; 95% confidence interval, 0.19-0.21). By the third quarter of 2016, the number of women who had bilateral salpingectomy exceeded those who had bilateral tubal ligation at cesarean delivery (8.6% vs 7.3%). Increasing the utilization of bilateral salpingectomy did not vary across age groups; the salpingectomy rate increased from 7.5% to 21.1% among women at the age of ≥35 years and from 3.8% to 10.7% among women at the age of <35 years (both, P<.001). In a propensity score matched model, women in the bilateral salpingectomy group were more likely to have hemorrhage (3.8% vs 3.1%; odds ratio, 1.24; 95% confidence interval, 1.15-1.33), blood product transfusion (2.1% vs 1.8%; odds ratio, 1.16; 95% confidence interval, 1.04-1.30), hysterectomy (0.8% vs 0.4%; odds ratio, 2.28; 95% confidence interval, 1.84-2.82), and oophorectomy (0.3% vs 0.2%; odds ratio, 2.02; 95% confidence interval, 1.47-2.79) than those in the bilateral tubal ligation group. When restricted to the nonhysterectomy cases, the bilateral salpingectomy group had a higher rate of hemorrhage (3.4% vs 3.0%; odds ratio, 1.16; 95% confidence interval, 1.06-1.26) and oophorectomy (0.3% vs 0.1%; odds ratio, 1.75; 95% confidence interval, 1.22-2.50) than the bilateral tubal ligation group., Conclusion: In the United States, the utilization of bilateral salpingectomy at the time of cesarean delivery increased rapidly between 2015 and 2018, replacing tubal ligation as the most common type of sterilization performed with cesarean delivery. The higher surgical morbidity in the bilateral salpingectomy group than the bilateral tubal ligation group observed in this study warrants further investigation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study aimed to investigate the cytotoxicity of a cluster of differentiation 70 antibody-drug conjugate (CD70-ADC) against ovarian cancer in in vitro and in vivo xenograft models. CD70 expression was assessed in clinical samples by immunohistochemical analysis. Western blotting and fluorescence-activated cell sorting analyses were used to determine CD70 expression in the ovarian cancer cell lines A2780 and SKOV3, and in the cisplatin-resistant ovarian cancer cell lines A2780cisR and SKOV3cisR. CD70 expression after cisplatin exposure was determined in A2780 cells transfected with mock- or nuclear factor (NF)-κB-p65-small interfering RNA. We developed an ADC with an anti-CD70 monoclonal antibody linked to monomethyl auristatin F and investigated its cytotoxic effect. We examined 63 ovarian cancer clinical samples; 43 (68.3%) of them expressed CD70. Among patients with advanced stage disease (n = 50), those who received neoadjuvant chemotherapy were more likely to exhibit high CD70 expression compared to those who did not (55.6% [15/27] vs 17.4% [4/23], P < .01). CD70 expression was confirmed in A2780cisR, SKOV3, and SKOV3cisR cells. Notably, CD70 expression was induced after cisplatin treatment in A2780 mock cells but not in A2780-NF-κB-p65-silenced cells. CD70-ADC was cytotoxic to A2780cisR, SKOV3, and SKOV3cisR cells, with IC 50 values ranging from 0.104 to 0.341 nmol/L. In A2780cisR and SKOV3cisR xenograft models, tumor growth in CD70-ADC treated mice was significantly inhibited compared to that in the control-ADC treated mice (A2780cisR: 32.0 vs 1639.0 mm 3 , P < .01; SKOV3cisR: 232.2 vs 584.9 mm 3 , P < .01). Platinum treatment induced CD70 expression in ovarian cancer cells. CD70-ADC may have potential therapeutic implications in the treatment of CD70 expressing ovarian cancer., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: To examine the effects of intraoperative ovarian capsule rupture on progression-free survival and overall survival in women who are undergoing surgery for early-stage ovarian cancer., Data Sources: MEDLINE using PubMed, EMBASE (Elsevier), ClinicalTrials.gov, and Scopus (Elsevier) were searched from inception until August 11, 2020., Methods of Study Selection: High-quality studies reporting survival outcomes comparing ovarian capsule rupture to no capsule rupture among patients with early-stage epithelial ovarian cancer who underwent surgical management were abstracted. Study quality was assessed with the Newcastle-Ottawa Scale, and studies with scores of at least 7 points were included., Tabulation, Integration, and Results: The data were extracted independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between ovarian capsule rupture and oncologic outcomes. Seventeen studies met all the criteria for inclusion in the meta-analysis. Twelve thousand seven hundred fifty-six (62.6%) patients did not have capsule rupture and had disease confined to the ovary on final pathology; 5,532 (33.7%) patients had intraoperative capsule rupture of an otherwise early-stage ovarian cancer. Patients with intraoperative capsule rupture had worse progression-free survival (hazard ratio [HR] 1.92, 95% CI 1.34-2.76, P<.001), with moderate heterogeneity (I2=41%, P=.07) when compared with those without capsule rupture. Pooled results from these studies showed a worse overall survival (HR 1.48, 95% CI 1.15-1.91, P=.003), with moderate heterogeneity (I2=53%, P=.02) when compared with patients without intraoperative capsule rupture. This remained significant in a series of sensitivity analyses., Conclusion: This systematic review and meta-analysis of high-quality observational studies shows that intraoperative ovarian capsule rupture results in decreased progression-free survival and overall survival in women with early-stage ovarian cancer who are undergoing initial surgical management., Systematic Review Registration: PROSPERO, CRD42021216561., Competing Interests: Financial Disclosure Dr. Hou has served as a consultant for Foundation Medicine. Dr. Tergas reports money was paid to her from Auro Vaccines. Dr. Matsuo received an honorarium from Chugai and investigator meeting attendance expense from VBL Therapeutics outside this study. Dr. Wright has served as a consultant for Clovis Oncology, received royalties from UpToDate, and received research support from Merck. The other authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC., (© 2020 Union for International Cancer Control.)

Objective: To examine trends and outcomes related to neoadjuvant chemotherapy (NACT) use for advanced ovarian cancer based on patient and tumor factors., Methods: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program to examine women with stage III-IV high-grade serous ovarian carcinoma from 2010 to 2016. Propensity score inverse probability of treatment weighting was used to assess the age-, cancer stage-, and tumor extent-specific survival estimates related to NACT use., Results: Utilization of NACT has significantly increased in older women (≥65 years; 48.4% relative increase), followed by stage IV disease (35.2% relative increase), and stage III disease (25.0% relative increase) (all, P-trend < 0.05). Women who received NACT had overall survival (OS) similar to those who had primary cytoreductive surgery (PCS) in older women (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.95-1.20, P = 0.284), stage IV disease (HR 0.96, 95%CI 0.84-1.10, P = 0.564), and more disease extent cases (T3/N1/M1, HR 1.06, 95%CI 0.84-1.32, P = 0.640). Moreover, NACT use was associated with decreased other cause mortality risk compared to PCS in the older women (sub-distribution HR 0.61, 95%CI 0.40-0.94, P = 0.025) and stage IV disease (sub-distribution HR 0.49, 95%CI 0.27-0.90, P = 0.021). In contrast, women who received NACT had decreased OS compared to those who had PCS in the younger group (HR 1.22, 95%CI 1.07-1.38, P = 0.004), stage III disease (HR 1.26, 95%CI 1.13-1.41, P < 0.001), and lesser disease extent cases (T3/N0/M0, HR 1.38, 95%CI 1.20-1.58, P < 0.001)., Conclusion: Our study suggests that survival effect of NACT for advanced ovarian cancer may differ based on patient and tumor factors. In older women, stage IV disease, and greater disease extent, NACT was associated with similar OS compared to PCS., Competing Interests: Declaration of Competing Interest Consultant, Quantgene (L.D.R.); honorarium, Chugai, textbook editorial expense, Springer, and investigator meeting attendance expense, VBL therapeutics (K.M.); advisory board, Tesaro, GSK (M.K.); research funding, MSD (S.M.); Scientific advisory board, Kiyatec, shareholder, Biopath, research funding, M-Trap and Merck (A.K.S.)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity., Methods: We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices., Results: BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality., Conclusions: BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background., Competing Interests: Declaration of Competing Interest Stephen Gruber is co-founder of Brogent International LLC and reports research funding from Myriad Genetics and consulting from Fulgent Genetics and 23&Me. Lynda Roman is a consultant for Quantgene. Koji Matsuo received honorarium from Chugai., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Mounting evidence for the role of distal fallopian tubes in the pathogenesis of epithelial ovarian cancer has led to opportunistic salpingectomy being increasingly performed at the time of benign gynecologic surgery. Opportunistic salpingectomy has now been recommended as best practice in the United States to reduce future risk of ovarian cancer even in low-risk women. Preliminary analyses have suggested that performance of opportunistic salpingectomy is increasing., Objective: To examine trends in opportunistic salpingectomy in women undergoing benign hysterectomy and to determine how the publication of the tubal hypothesis in 2010 may have contributed to these trends., Study Design: This is a population-based, retrospective, observational study examining the National Inpatient Sample between January 2001 and September 2015. Women younger than 50 years who underwent inpatient hysterectomy for benign gynecologic disease were grouped as hysterectomy alone vs hysterectomy with opportunistic salpingectomy. All women had ovarian conservation, and those with adnexal pathology were excluded. Linear segmented regression with log transformation was used to assess temporal trends. An interrupted time-series analysis was then used to assess the impact of the 2010 publication of the tubal hypothesis on opportunistic salpingectomy trends. A regression-tree model was constructed to examine patterns in the use of opportunistic salpingectomy. A binary logistic regression model was then fitted to identify independent characteristics associated with opportunistic salpingectomy. Sensitivity analysis was performed in women aged 50-65 years to further assess surgical trends in a wider age group., Results: There were 98,061 (9.0%) women who underwent hysterectomy with opportunistic salpingectomy and 997,237 (91.0%) women who underwent hysterectomy alone without opportunistic salpingectomy. The rate at which opportunistic salpingectomy was being performed gradually increased from 2.4% to 5.7% between 2001 and 2010 (2.4-fold increase; P<.001), predicting a 7.0% rate of opportunistic salpingectomy in 2015. However, in 2010, the rate of opportunistic salpingectomy began to increase substantially and reached 58.4% by 2015 (10.2-fold increase; P<.001). In multivariable analysis, the largest change in the performance of opportunistic salpingectomy occurred after 2010 (adjusted odds ratio, 5.42; 95% confidence interval, 5.34-5.51; P<.001). In a regression-tree model, women who had a hysterectomy at urban teaching hospitals in the Midwest after 2013 had the highest chance of undergoing opportunistic salpingectomy during benign hysterectomy (76.4%). In the sensitivity analysis of women aged 50-65 years, a similar exponential increase in opportunistic salpingectomy was observed from 5.8% in 2010 to 55.8% in 2015 (9.8-fold increase; P<.001)., Conclusion: Our study suggests that clinicians in the United States rapidly adopted opportunistic salpingectomy at the time of benign hysterectomy following the publication of data implicating the distal fallopian tubes in ovarian cancer pathogenesis in 2010. By 2015, nearly 60% of women had undergone opportunistic salpingectomy at benign hysterectomy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Epithelial ovarian cancer (EOC) can be a devastating diagnosis in women of reproductive age who desire future fertility. However, in early-stage disease, fertility-sparing surgery (FSS) can be considered in appropriately selected patients., Methods: This is a narrative descriptive review of the recent literature on FSS for EOC from oncologic, reproductive and endocrinologic perspectives., Results: The recurrence rate following FSS performed for stage I EOC in published retrospective studies collectively is 13% but ranges from 5 to 29%, while mortality ranges from 0 to 18%. Five-year disease-free survival following FSS is over 90% but decreases with higher stage and grade. Recurrences following FSS are more likely to be localized with a more favorable prognosis compared to recurrences following radical surgery. Adjuvant chemotherapy is recommended in women with high-risk disease, and strategies to minimize gonadotoxicity during chemotherapy such as gonadotropin-releasing hormone (GnRH) agonists may be considered. Oocyte, embryo and/or ovarian cryopreservation can also be offered to patients desiring future biologic children. Reproductive outcomes following FSS, including pregnancy and miscarriage rates, resemble those of the general population, with a chance of successful pregnancy of nearly 80%., Conclusion: In retrospective data, FSS appears to be oncologically safe in stage IA and IC grade 1-2 non-clear cell EOC. In patients with grade 3 tumors or clear cell histology, treatment can be individualized, weighing a slightly higher risk of recurrence with fertility goals. A multidisciplinary approach with oncology and reproductive endocrinology may be of utility to help these patients achieve their fertility goals., (© 2020 Japan Society of Obstetrics and Gynecology.)

Objective: To examine trends and associated characteristics and outcomes of minimally invasive surgery (MIS) for women with early-stage ovarian cancer., Methods: The National Inpatient Sample was queried to examine early-stage ovarian cancer treated with MIS from 2001 to 2011. Annualized hospital surgical volume was defined in the unweighted model as the average number of procedures performed per year in which at least one case was performed. Trends, characteristics, and outcomes related to MIS use were assessed in the weighted model., Results: Among 73,707 oophorectomy cases, there were 4822 (6.5%) MIS cases. Utilization of MIS increased from 3.9% to 13.5% from 2001 to 2011 (3.5-fold increase, P < 0.001), and the number of MIS-offering centers also increased from 10.6% to 36.2% (3.4-fold increase, P < 0.001). MIS was associated with a decreased complication rate (20.3% versus 35.4%) and shorter hospital stay (median, 2 versus 4 days) compared to laparotomy (both, P < 0.001). Of the 472 hospitals at which MIS was performed, the majority were minimum-volume with one MIS oophorectomy per year (340 [72.0%], n = 1929 [40.0%]), followed by mid-volume (85 [18.0%], n = 1272 [26.4%]) and topdecile-volume (47 [10.0%] hospitals, n = 1621 [33.6%]). The topdecile-volume group had the highest rate of lymphadenectomy compared to other groups (62.2% versus 39.2-55.1%, P < 0.05). On multivariable analysis, a one increment increase in annualized hospital surgical volume was associated with an 11% decrease in multiple complications (adjusted-odds ratio 0.89, 95% confidence interval 0.82-0.97, P = 0.006)., Conclusion: Utilization of MIS for early-stage ovarian cancer has significantly increased in the United States in 2000s. In 2011, one in eight surgeries performed for early ovarian cancer were performed via MIS. MIS procedures performed at hospitals with a higher surgical volume may be associated with improved short-term perioperative outcomes., Competing Interests: Declaration of competing interest Consultant, Clovis Oncology, Tesaro, research funding, Merck (J.D.W.); consultant, Quantgene (L.D.R.); advisory board, Tesaro, GSK (M.K.); research funding, MSD (S.M.); honorarium, Chugai, textbook editorial expense, Springer, and investigator meeting attendance expense, VBL therapeutics (K.M.); scientific consulting, Kiyatec, Merck, shareholder, Biopath, research funding, M-Trap (A.K.S.); none for others., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers., Methods: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1973 to 2013. Among ovarian cancer (n = 133,149) and breast cancer (n = 1,143,219) cohorts, women with both diagnoses were identified and temporal trends, tumor characteristics and survival were examined., Results: There were 6446 women with both malignancies, representing 4.8% of the ovarian cancer cohort and 0.6% of the breast cancer cohort. Women with ovarian cancer who had secondary breast cancer were younger than those without secondary breast cancer early in the study period (52.3 versus 59.2 in 1973) but older in more recent years (68.5 versus 62.1 in 2013, P < 0.001). The number of breast cancer survivors who developed postcedent ovarian cancer decreased from 1.5 to 0.2% from 1979 to 2008 (relative risk reduction 90.0%, P < 0.05). Similarly, the number of ovarian cancer survivors who developed postcedent breast cancer decreased from 7.2 to 2.0% from 1973 to 2008 (relative risk reduction 72.4%, P < 0.05). Tumor characteristics were more likely to be favorable in women with ovarian cancer who developed postcedent breast cancer but unfavorable in those who had antecedent breast cancer (all, P < 0.05). Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer regardless of breast cancer timing (P < 0.05)., Conclusion: Our study demonstrated that the demographics of women who develop breast cancer and ovarian cancer have changed over time and diagnosis of secondary breast cancer after ovarian cancer has decreased.

Purpose: To assess the qualitative and quantitative measures of the effect of pelvic lymph node involvement on survival of women with borderline ovarian tumors (BOTs)., Methods: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program between 1988 and 2003. Women with stage T1-3 BOTs who had results of pelvic lymph node status at surgery were included. The effect of lymph node involvement on cause-specific survival (CSS) was evaluated using multivariable analysis with the following approaches: (1) any involvement, (2) involvement of multiple nodes (≥ 2 nodes), and (3) lymph node ratio (LNR), defined as the ratio of the number of tumor-containing lymph nodes to the total number of harvested lymph nodes., Results: A total of 1524 women were examined for analysis. Median count of sampled nodes was 8 (interquartile range 3-15), and there were 81 (5.3%, 95% confidence interval [CI] 4.2-6.4) women who had lymph node involvement. Median follow-up was 15.8 (interquartile range 13.8-18.9) years, and 83 (5.4%) women died of BOTs. After controlling for age, histology, stage, and tumor size, only LNR remained an independent prognostic factor for decreased CSS (adjusted hazard ratio [HR] per percentage unit 1.015, 95% CI 1.003-1.026, P = 0.014), whereas any involvement (adjusted HR 1.700, 95% CI 0.843-3.430, P = 0.138) and involvement of multiple nodes (adjusted HR 1.644, 95% CI 0.707-3.823, P = 0.249) did not. On cutoff analysis, LNR ≥ 13% had the largest magnitude of significance on multivariable analysis of CSS (adjusted HR 2.399, 95% CI 1.163-4.947, P = 0.018)., Conclusion: Our study suggests that high pelvic LNR may be a prognostic factor associated with decreased CSS in women with BOTs.

Objective: To compare the effectiveness and safety of neoadjuvant chemotherapy with carboplatin/paclitaxel followed by interval debulking surgery (NACT-IDS) to primary debulking surgery plus postoperative chemotherapy (PDS) for advanced ovarian cancer., Methods: A comprehensive systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Multiple public search engines including PubMed/MEDLINE and the Cochrane Database, were searched in March 2019 using the entry keywords "ovarian cancer [all fields]" AND "interval debulking surgery [all fields]", AND "neoadjuvant chemotherapy [all fields]". Key inclusion criteria were prospective clinical trials examining platinum-based NACT for stage II-IV epithelial ovarian cancer. The primary outcome of interest was survival, and the secondary outcome was adverse events with each intervention., Results: After screening 333 studies, four phase III randomized clinical trials were identified that met the inclusion criteria. These trials included 1692 women (847 receiving NACT-IDS and 845 receiving PDS). It was found that NACT-IDS and PDS had similar overall survival (hazard ratio [HR]: 0.97, 95% confidence interval [CI]: 0.87-1.07, P = 0.53) and progression-free survival (HR: 0.98, 95%CI: 0.90-1.08, P = 0.74). In contrast, NACT-IDS was associated with significantly lower rates of perioperative complications (odds ratio [OR] 0.27, 95%CI: 0.20-0.36, P < 0.001) and perioperative mortality (OR: 0.17, 95%CI: 0.06-0.50, P < 0.001) compared to PDS., Conclusion: This systematic review and meta-analysis suggests that NACT-IDS with carboplatin and paclitaxel does not negatively impact the survival of women with advanced ovarian cancer compared to PDS, while perioperative complications and mortality are significantly reduced by 70-80%., Competing Interests: Declaration of competing interest Honorarium, Chugai, textbook editorial, Springer, and investigator meeting attendance expense, VBL therapeutics (K.M.); none for others., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: To describe how population-based statistics for rare epithelial ovarian cancers are evolving., Methods: This is a retrospective observational study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2016. Overall survival (OS) of clear cell (OCCC), mucinous (MOC), and low-grade serous (LGSOC) ovarian cancers were compared to high-grade serous ovarian cancer (HGSOC) by fitting a propensity score matching., Results: Among 113,365 ovarian malignancies, 5780 OCCCs (5.1%), 7561 MOCs (6.7%), and 2021 LGSOCs (1.8%) were compared to 38,199 HGSOCs. OCCCs and MOCs were more likely to be diagnosed with stage I disease compared to HGSOC (57.0-59.5% versus 8.6%, P<0.001). For early-stage disease, OCCC (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.82-1.01) and MOC (HR 0.94, 95%CI 0.85-1.04) had similar OS to HGSOC whereas LGSOC had superior OS (HR 0.93, 95%CI 0.89-0.97) versus HGSOC. Conversely, for advanced-stage disease, OCCC (HR 1.42, 95%CI 1.32-1.53) and MOC (HR 1.11, 95%CI 1.09-1.13) had poorer OS whereas LGSOC (HR 0.86, 95%CI 0.84-0.89) had superior OS compared to HGSOC. OCCC (HR range, 1.92-2.45) and MOC (HR range, 1.73-2.22) had particularly poorer OS in the first three years following diagnosis compared to HGSOC. Population-level statistics for advanced-stage disease showed that 5-year OS rates have increased in HGSOC (16.9% to 36.8%, P<0.001) and LGSOC (50.8% to 66.4%, P=0.010); but remain unchanged for OCCC (21.0% to 28.2%, P=0.174) and MOC (21.4% to 16.5%, P=0.102)., Conclusion: OCCC, MOC, and LGSOC comprise 2-7% of ovarian malignancies, have distinct characteristics and survival compared to HGSOC. While these rare tumors have a favorable to comparable prognosis in early-stage disease, disproportionally poor survival in advanced-stage OCCC and MOC highlights the need for further research into novel treatment strategies., Competing Interests: Declaration of competing interest Consultant, Clovis Oncology, Tesaro, research funding, Merck (J.D.W.); scientific consulting, Kiyatec, Merck, shareholder, Biopath, research funding, M-Trap (A.K.S.); Stock and other ownership interests, Celgene, Johnson & Johnson, Biogin, consulting or advisory role, Clovis Oncology, research funding, Novartis, royalties from Elsevier as book editor, royalties from UpToDate for authorship (D.M.G.); honorarium, Chugai, textbook editorial expense, Springer, investigator meeting attendance expense, VBL therapeutics (K.M.); consultant, Quantgene (L.D.R); research funding, MSD (none for others)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To determine changes in the characteristics of low-grade serous ovarian cancer (LGSOC) and serous borderline ovarian tumor (serous-BOT) in a time-specific manner., Methods: We conducted a population-based retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2000. Trends, demographics, and outcomes of 775 women with well-differentiated serous ovarian cancer, used as a surrogate for LGSOC, were compared to 3937 women with serous-BOT., Results: In the multivariable analysis, women with LGSOC were more likely to be older, have stage II-IV disease, and have undergone hysterectomy at surgery, but less likely to be a Western U.S. resident compared to those with serous-BOT (all, adjusted-P < 0.05). During the study period, the number of LGSOCs decreased by 25.9%, particularly stage I disease (37.6% relative decrease) compared to stage II-IV disease (21.1% relative decrease) (all, P < 0.05). With a median follow-up of 16.9 years, there was a decreasing trend in the 15-year overall survival rates among LGSOC (28.7% relative decrease, P = 0.056) but not in serous-BOT (2.5% relative increase, P = 0.416) as a whole cohort. The magnitude of hazard risk from all-cause death for women with LGSOC compared to those with serous-BOT increased by 68.9% from 1988 to 2000 (P < 0.001). LGSOC remained an independent prognostic factor for decreased overall survival compared to serous-BOT (adjusted-P < 0.05)., Conclusion: Our study suggests that the decreasing number and survival of LGSOC over time may be due to a diagnosis-shift from LGSOC to serous-BOT. Given the distinct characteristics and outcomes of LGSOC compared to serous-BOT, our study endorses the importance of making the correct diagnosis upfront. Whether this diagnostic-shift supports a hypothesis that serous-BOT is a precursor lesion of LGSOC merits further investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Ovarian steroid cell tumor (SCT) is a rare tumor with steroid-producing ability. We report a 22-year-old woman with secondary amenorrhea and hirsutism caused by an ovarian SCT-not otherwise specified (NOS), who underwent successfully laparoscopic resection of the tumor., Case Report: A 22-year-old null gravida woman presented to a hospital, having amenorrhea for 18 months and increasing facial hair. Physical examination revealed obesity (body mass index, 37.3 kg/m 2 ) with evident facial and trunk hair. Total and free serum testosterone, and dehydroepiandrosterone sulfate levels were found to be elevated. Levels of serum adrenocorticotropic hormone, gonadotropins, cortisol, aldosterone, and ovarian steroids were observed to be within reference intervals. Although polycystic ovaries were not found, a hyperechogenic solid tumor (3 cm) was detected on transvaginal ultrasonography. Laparoscopic resection of the tumor was performed. One month post-surgery, total and free testosterone levels were observed to have decreased, and menstruation resumed two months thereafter. The patient was histologically diagnosed with ovarian SCT-NOS. Expression of ovarian steroidogenic enzymes, which are related to hyperandrogenism, was observed. No disease recurrence has been reported for more than 5 years post-surgery.

Introduction : Ovarian cancer is the leading cause of gynecologic cancer death, owing to high rates of incurable, recurrent disease after initial treatment. Serine threonine kinases (STKs) have been proposed as potential therapeutic targets in ovarian cancer because of their role in the initiation and progression of cancers. Experience in non-ovarian cancers suggests that STK inhibitors are active against tumors with specific molecular alterations. Areas covered : This review discusses STK inhibitors in active development in phase II/III clinical trials for ovarian cancer. PubMed and ClinicalTrials.gov were systematically searched to identify STK inhibitor trials for ovarian cancer; active development was confirmed via Pharmaprojects. Available data regarding the efficacy and safety of these compounds are explored. Expert opinion : STK inhibitors currently in development have modest activity as single agents and are unlikely to achieve approval as monotherapy for unselected ovarian cancer patients. Combination trials of STK inhibitors with chemotherapy and/or targeted therapies have suggested an acceptable efficacy/toxicity ratio for certain combinations but confirmatory studies are needed. Carefully designed trials, especially those including somatic molecular analysis, may help identify the subsets of patients most likely to benefit from these therapeutic strategies and determine the role of STK inhibitors in the evolving landscape of precision oncology.

Objective: To examine the incidence and prognostic effects of intraoperative capsule rupture and to assess the effectiveness of postoperative chemotherapy for intraoperative tumor rupture in apparent stage I epithelial ovarian cancer., Methods: This is a society-based retrospective observational study in Japan that examined 15,163 women with stage IA-IC1 epithelial ovarian cancer who underwent primary surgical treatment between 2002 and 2015. Associations between intraoperative capsule rupture and cause-specific survival, and between postoperative chemotherapy and cause-specific survival among intraoperatively ruptured cases were examined by histology type (clear cell n=6,107, endometrioid n=3,910, mucinous n=3,382, and serous n=1,764)., Results: Clear cell histology had the highest risk of intraoperative capsule rupture (57.3%), followed by endometrioid (48.8%), serous (41.8%), and mucinous (32.0%) histologies (P<.001). On multivariable analysis, clear cell type exhibited the largest effect of intraoperative capsule rupture on cause-specific survival (adjusted hazard ratio [HR] 1.99, 95% CI 1.45-2.75), followed by serous (adjusted HR, 1.61, 95% CI 0.84-3.11), mucinous (adjusted HR 1.28, 95% CI 0.79-2.09), and endometrioid (adjusted HR, 1.14, 95% CI 0.64-2.01) tumors. Postoperative chemotherapy for intraoperatively ruptured cases did not improve cause-specific survival in any histologic types in multivariable analysis: clear cell, adjusted HR 0.86, 95% CI 0.56-1.31; serous, adjusted HR 1.08, 95% CI 0.42-2.74; mucinous, adjusted HR 1.11, 95% CI 0.55-2.27; and endometrioid, adjusted HR 2.81, 95% CI 0.85-9.30 (all, P>.05). In the cohort-level analysis of ruptured cases (n=7,227), postoperative chemotherapy use has significantly decreased in mucinous (16.3% relative decrease), endometrioid (13.1% relative decrease), and clear cell (9.3% relative decrease) (all, P<.05); but, the cohort-level 5-year cause-specific survival rate did not change over time (all, P>.05)., Conclusion: Among apparent stage I epithelial ovarian cancer, the clear cell type possesses a disproportionally high risk of capsule rupture during adnexectomy and is associated with the most adverse effect on survival. A decrease in the use of postoperative chemotherapy for intraoperatively ruptured cases in Japan is likely the result of increasing awareness of the absence of survival benefits.

Objective: To examine the association between postoperative chemotherapy and survival of women with stage IC mucinous ovarian cancer (MOC)., Methods: Comprehensive nationwide tumor registry data from the Commission on Cancer-accredited facilities in the United States from 2004 to 2014 were retrospectively examined. Women with stage IC MOC who underwent primary surgery followed by postoperative chemotherapy were compared to those who did not receive. Clinico-pathological factors associated with chemotherapy use, and overall survival associated with chemotherapy use were examined with multivariable models and propensity score inverse probability of treatment weighting (IPTW). External validation was performed by examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2014., Results: There were 532 (58.5%) women who received postoperative chemotherapy and 377 (41.5%) women who did not. On multivariable analysis, those with moderately-/poorly-differentiated tumors, large tumor size, and who underwent lymphadenectomy were more likely to receive postoperative chemotherapy whereas young women and those with capsule rupture alone were less likely to receive postoperative chemotherapy (all, P < 0.05). After IPTW, there was no difference in overall survival among women who received postoperative chemotherapy versus those who did not on multivariable analysis (adjusted 4-year rates: 85.8% versus 86.3%, adjusted-hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.60-1.31). Similarly, there was no benefit with chemotherapy regardless of patient age, tumor differentiation, performance of nodal dissection, and substage groups. Among 912 cases in the validation cohort (postoperative chemotherapy use, n = 520 [57.0%]), postoperative chemotherapy use was not associated with cause-specific survival (adjusted-HR 1.296, 95% CI 0.846-1.984, P = 0.233) or overall survival (adjusted-HR 1.131, 95% CI 0.849-1.508, P = 0.400)., Conclusion: Postoperative chemotherapy was received by fewer than 60% of women with stage IC MOC, and postoperative chemotherapy was not associated with improved survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To examine the trends of epithelial ovarian cancer histologic subtypes in Japan., Methods: A nationwide retrospective registry study was performed between 2002 and 2015 (Japan cohort, n = 48,640). Trends were also examined in The Surveillance, Epidemiology, and End Results Program (US cohort, n = 49,936). Time-specific proportional changes of four major histological subtypes (serous, clear cell, endometrioid, and mucinous) were examined., Results: The Japan cohort had more stage I disease (44.1% versus 24.9%) and less stage IV disease (10.0% versus 23.1%) than the US cohort (P < 0.001). The Japan cohort had more non-serous histology, particularly clear cell carcinoma (26.9% versus 8.4%), than the US cohort (P < 0.001). In the Japan cohort, proportion of clear cell carcinoma increased significantly from 23.4% to 29.1% between 2002 and 2010 (P < 0.001). Among stage I disease, clear cell carcinoma increased significantly in the Japan cohort from 32.9% to 40.3% between 2002 and 2015 (P < 0.001), whereas mucinous carcinoma increased significantly in the US cohort from 15.0% to 24.8% (P = 0.01). In 2015, clear cell carcinoma was most common among women aged <50 years from the Japan cohort (30.2%) versus serous carcinoma in the US cohort (50.8%). In the Japan cohort, the peak age was 75 years for serous, 57 for clear cell, and 45 for endometrioid carcinoma (P < 0.001). Mucinous carcinoma decreased until 43 years and increased again after age 73 years (P < 0.001)., Conclusion: Characteristics of epithelial ovarian cancer in Japan are largely different compared to the US. In Japan, clear cell carcinoma has increased significantly in recent years to account for nearly 30% of epithelial ovarian cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To examine survival of women who had uterine and ovarian preservation during surgical treatment for early-stage borderline ovarian tumors (BOTs)., Methods: The Surveillance, Epidemiology, and End Results Program was used to identify women aged < 50 years with stage I BOTs who underwent ovarian conservation at surgical treatment between 1988 and 2003. Survival outcomes were examined based on the use of concurrent hysterectomy at surgery., Results: Among 6379 cases of BOT, there were 1065 women who had utero-ovarian preservation at surgery, and there were 52 women who had hysterectomy with ovarian preservation alone. Women who had uterine preservation were more likely to be single and diagnosed in recent years (both, P < 0.05). On univariable analysis, women who had utero-ovarian preservation had cause-specific survival similar to those who had ovarian preservation alone without uterine preservation (10-year rates: 99.2% versus 98.1%, P = 0.42); however, overall survival was higher in the utero-ovarian preservation group compared to the hysterectomy group (95.8% versus 87.6%, P < 0.001). On multivariable analysis, utero-ovarian preservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.35, 95% confidence interval 0.15-0.79, P = 0.012). Cardiovascular disease mortality was lower in the utero-ovarian preservation group compared to the hysterectomy group, but it did not reach statistical significance (20-year cumulative rate, 0.8% versus 3.0%, P = 0.29)., Conclusion: Our study suggests that utero-ovarian preservation for young women with early-stage BOTs may be associated with improved overall survival compared to ovarian preservation alone without affecting BOT-related survival outcome.

Objective: Mucinous borderline ovarian tumor (mucinous-BOT) and invasive well-differentiated mucinous ovarian cancer (mucinous-OC) are often histopathologically misclassified. The objective of this study was to examine differences in clinico-pathological characteristics and outcomes of these two entities., Methods: This is a retrospective population-based study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2000. Stage I mucinous-BOTs and stage I well-differentiated mucinous-OC were compared for patient demographics, tumor characteristics, and outcomes. Propensity score matching and multivariable analysis were used to assess cause-specific survival (CSS)., Results: A total of 2130 mucinous-BOT and 581 mucinous-OC cases were examined for analysis. On multivariable analysis, women with mucinous-OC were more likely to be older, Eastern U.S. residents, and have undergone hysterectomy or lymphadenectomy compared to those with mucinous-BOT, and the number of women diagnosed with mucinous-OC decreased over time (all, P < 0.05). Mucinous-OCs were more likely to be stage T1c and have a smaller tumor size as compared to mucinous-BOT (both, adjusted-P < 0.05). After propensity score matching, women with mucinous-OC had significantly poorer CSS compared to those with mucinous-BOT on multivariable analysis (10-year rates: 92.7% versus 97.5%, adjusted-hazard ratio [HR] 2.03, P = 0.007). Similar results were observed among subgroups for reproductive age, stage T1a disease, large tumor, and unstaged cases (all, P < 0.05)., Conclusion: Stage I mucinous-BOT and stage I invasive well-differentiated mucinous-OC have distinct differences in clinical characteristics and patient survival. The inability to conduct centralized pathology review in our study limits our conclusions given the recognized issue of misclassification of mucinous-BOT and mucinous-OC, but further highlights the importance of making the proper histopathological diagnosis for invasive cancer when the ovarian tumor is of mucinous histology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated., Methods: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors., Results: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS., Conclusions: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study ( N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10 -7 . Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 , and SKAP1 . We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression., (©2018 American Association for Cancer Research.)

For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA /PACT in oxaliplatin resistance was interrogated. We focused on PRKRA , a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA /PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin., (©2018 American Association for Cancer Research.)

Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To examine the trends and survival for women with early-stage epithelial ovarian cancer who underwent adequate lymphadenectomy during surgical treatment., Methods: This is a retrospective observational study examining the Surveillance, Epidemiology, End Results program between 1988 and 2013. We evaluated 21,537 cases of stage I-II epithelial ovarian cancer including serous (n=7,466), clear cell (n=6,903), mucinous (n=4,066), and endometrioid (n=3,102) histology. A time-trend analysis of the proportion of patients who underwent adequate pelvic lymphadenectomy (≥8 per Gynecologic Oncology Group [GOG] criteria, ≥12 per Collaborative Group Report [CGR] criteria for bladder cancer, and >22 per Mayo criteria for endometrial cancer) and a survival analysis associated with adequate pelvic lymphadenectomy were performed., Results: There were significant increases in the proportion of women who underwent adequate lymphadenectomy: GOG criteria 3.6% to 28.6% (1988-2010); CGR criteria 2.4% to 22.4% (1988-2013); and Mayo criteria 0.7% to 9.5% (1988-2013) (all, p<0.05). On multivariable analysis, adequate lymphadenectomy was independently associated with improved cause-specific survival compared to inadequate lymphadenectomy: GOG criteria, adjusted-hazard ratio (HR)=0.75, CGR criteria, adjusted-HR=0.77, and Mayo criteria, adjusted-HR=0.85 (all, p<0.05). Compared to inadequate lymphadenectomy, adequate lymphadenectomy was significantly associated with improved cause-specific survival for serous (HR range=0.67-0.73), endometrioid (HR range=0.59-0.61), and clear cell types (HR range=0.66-0.73) (all, p<0.05) but not in mucinous type (HR range=0.80-0.91; p>0.05)., Conclusion: Quality of lymphadenectomy during the surgical treatment for early-stage epithelial ovarian cancer has significantly improved. Adequate lymphadenectomy is associated with a 15%-25% reduction in ovarian cancer mortality compared to inadequate lymphadenectomy., Competing Interests: Dr. Wright has served as a consultant for Clovis Oncology and Tesaro. The other authors have nothing to disclose., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: To examine survival of teenage women with pregnancies complicated by primary ovarian cancer., Methods: This is a secondary analysis of a previously organized systematic literature review of primary ovarian cancer diagnosed during pregnancy. Cases eligible for analysis were patients whose age at cancer diagnosis and survival outcome were known (n=201). Pregnancy and oncologic outcome were then examined based on patient age., Results: These were comprised of 95 (47.3%) epithelial ovarian cancers (EOCs), 82 (40.8%) malignant germ cell tumors (MGCTs), and 24 (11.9%) sex-cord stromal tumors (SCSTs). Teenage pregnancy was seen in 21 (10%) cases, and was highest among the SCST group compared to the other cancer types (EOC, 1.1%; MGCT, 14.6%; and SCST, 29.2%, p<0.001). Live birth rates, neonatal weight, full term delivery rates, and Cesarean section rates were similar between the teenage group and the non-teenage group (all, p>0.05); however, teenage pregnancy was significantly associated with an increased risk of serious maternal/neonatal adverse events (50% vs. 22.7%, p=0.013). On univariable analysis, teenage pregnancy was significantly associated with decreased ovarian cancer-specific survival (5-year rate: age ≥30, 79.6%; age 20-29, 87.2%; and age <20, 41.6%; p<0.001). On multivariable analysis controlling for calendar year, cancer type, cancer stage, and gestational age at ovarian cancer diagnosis, teenage pregnancy remained an independent prognostic factor for decreased ovarian cancer-specific survival compared to women aged ≥30 (adjusted-hazard ratio=4.71; 95% confidence interval=1.17-18.9; p=0.029)., Conclusion: Teenage women with pregnancies complicated by primary ovarian cancer may be at increased risk of poor survival from ovarian cancer., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)