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Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Objective Estrogen is a well‐established risk factor for various cancers. It causes endometrial proliferation, which is assessed routinely as endometrial thickness (ET) using transvaginal ultrasound (TVS). Only one previous study, restricted to endometrial and breast cancer, has considered ET and the risk of non‐endometrial cancer. The aim of this study was to explore the association between baseline and serial ET measurements and nine non‐endometrial hormone‐sensitive cancers, in postmenopausal women, using contemporary statistical methodology that attempts to minimize the biases typical of endogenous serial data. Methods This was a cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). In the ultrasound arm of UKCTOCS, 50639 postmenopausal women, aged 50–74, underwent annual TVS examination, of whom 38 105 had a valid ET measurement, no prior hysterectomy and complete covariate data, and were included in this study. All women were followed up through linkage to national cancer registries. The effect of ET on the risk of six estrogen‐dependent cancers (breast, ovarian, colorectal, bladder, lung and pancreatic) was assessed using joint models for longitudinal biomarker and time‐to‐event data, and Cox models were used to assess the association between baseline ET measurement and these six cancers in addition to liver cancer, gastric cancer and non‐Hodgkin's lymphoma (NHL). All models were adjusted for current hormone‐replacement therapy (HRT) use, body mass index, age at last menstrual period, parity and oral contraceptive pill use. Results The 38 105 included women had a combined total of 267 567 (median, 8; interquartile range, 5–9) valid ET measurements. During a combined total of 407 838 (median, 10.9) years of follow‐up, 1398 breast, 351 endometrial, 381 lung, 495 colorectal, 222 ovarian, 94 pancreatic, 79 bladder, 62 gastric, 38 liver cancers and 52 NHLs were registered. Using joint models, a doubling of ET increased significantly the risk of breast (hazard ratio (HR), 1.21; 95% CI, 1.09–1.36; P = 0.001), ovarian (HR, 1.39; 95% CI, 1.06–1.82; P = 0.018) and lung (HR, 1.25; 95% CI, 1.02–1.54; P = 0.036) cancers. There were no statistically significant associations between ET and the remaining six cancers. Conclusion Postmenopausal women with high/increasing ET on TVS are at increased risk of breast, ovarian and lung cancer. It is important that clinicians are aware of these risks, as TVS is a common investigation. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Ovarian cancer is most commonly diagnosed at an advanced stage (3 or 4) and remains the deadliest gynecologic malignancy. When diagnosed at stage 1, a survival rate of greater than 90% has been demonstrated, compared with a 5-year survival rate of 27% and 13% for stage 3 and stage 4 disease, respectively. Despite international efforts to identify robust screening methods and increase early-stage detection, to date no evidence that screening saves lives has been presented. The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomized controlled trial that demonstrated no evidence associated with screening for ovarian cancer and reduction in ovarian cancer-related deaths at primary analysis but requires further follow-up. This secondary analysis of the UKCTOCS randomized controlled trial aimed to provide a follow-up and report on the long-term mortality effects of ovarian cancer screening. The UKCTOCS is a multicenter randomized trial of 202,638 women aged 50 to 74 years assigned to 2 annual screening groups (multimodal screening [MMS] vs ultrasound screening [USS]). Women in the United Kingdom were recruited from 13 National Health Service (NHS) centers and randomized to MMS, USS, or no screening in a 1:1:2 ratio. Annual screening in the MMS group involved serum CA125 measurements used in conjunction with the risk of ovarian cancer (ROCA) calculation to guide follow-up involving either no additional screening, repeat CA125 ROCA in 3 months, or transvaginal USS as a second test. Annual screening in the USS group involved transvaginal ultrasound with follow-up involving either continuation of annual screening, repeat in 3 months, or requiring a scan with a senior ultrasonographer within 6 weeks. The primary study outcome was death due to ovarian cancer or tubal cancer. A total of 202,638 women were randomized between April 2001 and September 2005, with screening concluding in December 2011 and follow-up continuing until June 2020. The final analysis cohort consisted of 202,562 women, 50,625 in the MMS group, 50,623 in the USS group, and 101,314 in the no screening group. Compliance with screening was 81% in the MMS group versus 78% in the USS group, with a median of 8 annual screens per participant. The median follow-up was 16.3 years (interquartile range, 15.1–17.3). A total of 2055 participants were diagnosed with ovarian or tubal cancer. At 9.5 years after screening, there was a 47.2% (95% confidence interval, 19.7–81.1) greater incidence of stage 1 disease and a 24.5% (-41.8 to -2.0) lower incidence of stage IV disease in the MMS group compared with the no screening group. Overall, a 39.2% (95% confidence interval, 16.1–66.9) greater incidence of stage I or II disease and a 10.2% (-21.3 to 2.4) lower incidence of stage III or IV disease was observed in the MMS group compared with the no screening group. At follow-up conclusion, 1206 women had died of ovarian cancer (296/50,625 [0.6%] in the MMS group, 291/50,623 [0.6%] in the USS group, 619/101,314 [0.6%] in the no screening group) with no significant difference between the MMS (P = 0.58) and USS (P = 0.36) groups compared with the no screening group. The results of this large-scale ovarian cancer screening trial demonstrate that, on long-term follow-up, while the screening strategies defined here resulted in a greater likelihood of diagnosing early stage disease, neither MMS nor USS resulted in a significant reduction in deaths from ovarian or tubal cancer.

Objective There are widespread efforts to increase symptom awareness of ‘pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency’ in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the ‘no screen’ (control) UKCTOCS arm. Methods Of 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Results Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p, Highlights • This study explored the association of symptoms of ovarian cancer, interval and route to diagnosis with survival. • Focus on ‘high alert’ symptoms: pelvic/abdominal pain, increase abdominal size/bloating and difficulty eating/feeling full • The ovarian cancer ‘high alert’ symptom complexes identify postmenopausal women with a significantly poorer prognosis. • The study could not however exclude the possibility of better outcomes in those who are aware and acted on these symptoms.

OBJECTIVE To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. DESIGN Prospective cohort study. SETTING Thirteen NHS Trusts in England, Wales and Northern Ireland. POPULATION A total of 202 506 postmenopausal women recruited between 2001 and 2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. METHODS Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. MAIN OUTCOME MEASURES Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. RESULTS Hysterectomy with conservation of one or both adnexa was reported in 41 912 (20.7%; 41 912/202 506) women. Median follow up was 11.1 years (interquartile range 9.96-12.04), totalling >2.17 million woman-years. Among women who had undergone hysterectomy, 0.55% (231/41 912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160 594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (hazard ratio 0.98, 95% CI 0.85-1.13, P = 0.765). CONCLUSIONS This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. These data are important both for clinical counselling and for refining risk prediction models. TWEETABLE ABSTRACT Hysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer.

Background During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. Methods We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001–2020) using the Cox model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Results Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. Conclusions The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. Trial registration ISRCTN22488978. Registered on 6 April 2000.

Background There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Methods Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard). Results Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7–86.2%) and 94.0% (1679/1786; 95% CI 93.2–94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4–91.2%) and 96.7% (1482/1533, 95% CI 95.8–97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4–92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9–95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered. Conclusion Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses. Trial registration ISRCTN: ISRCTN22488978. Registered on 6 April 2000

BACKGROUND: While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. METHODS: We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6,872 EOC patients and 9,101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. RESULTS: In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR=1.45; 95%CI=1.01–2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR=1.71 vs 0.99; P-interaction=0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR=1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR=0.49, 95%CI=0.28–0.83) but with higher risk among women without any of those conditions (OR=1.64 95%CI=1.14–2.34; P-interaction=0.003). CONCLUSION: Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk

Background PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

There has been much progress in ovarian cancer screening and prevention in recent years. Improved tools that combine genetic and epidemiologic factors to predict an individual's ovarian cancer risk are set to become available for tailoring preventive and screening approaches. The increasing evidence on tubal origins of a proportion of ovarian cancer has paved the way to use of opportunistic bilateral salpingectomy at tubal ligation and hysterectomy in the general population. Clinical trials are in progress to estimate the long-term effects on endocrine function. In women at high risk, risk reducing salpingo-oophorectomy remains the standard of care with the current focus on management of resulting noncancer outcomes, especially sexual dysfunction in younger women. This has led to evaluation of early bilateral salpingectomy and delayed oophorectomy in this population. Meanwhile, modeling suggests that BRCA mutation carriers should consider using the oral contraceptive pill for chemoprevention. In the general population, the largest ovarian cancer screening trial to date, the UK Collaborative Trial of Ovarian Cancer Screening reported a stage shift with annual multimodal screening using the longitudinal CA 125 Risk of Ovarian Cancer Algorithm but not with annual transvaginal ultrasound screening. There was no definitive mortality reduction with either screening strategy compared with no screening. Further follow-up until December 2018 in now underway. Stage shift and higher rates of optimal cytoreduction were also reported during 3- to 4-monthly multimodal screening in the United Kingdom and U.S. high-risk screening trials. Although all agree that there is not yet evidence to support general population screening, recommendations for high-risk screening vary between countries. A key finding from the screening trials has been the better performance of longitudinal algorithms compared with a single cutoff for CA 125. A major focus of ovarian cancer biomarker discovery work has been tumor DNA markers in both plasma and novel specimens such as cervical cytology samples.

Background: Tubo-ovarian cancer (OC) continues to be the most lethal of all gynaecological cancers. Over half of women are diagnosed with late stage (III/IV) disease, which has a five-year survival rate of 11%. Socioeconomic status (SES) has been shown to have an impact on outcomes of several cancer types, including OC. This study aims to investigate any potential association between SES and stage at diagnosis of OC. Methods: Women from the non-screening arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) with a confirmed diagnosis of OC prior to 01 January 2015 and an English index of multiple deprivation (IMD) score were eligible for the study. The association between IMD and OC stage (FIGO) was analysed using an ordinal logistic regression model adjusted for age at diagnosis and BMI. Results: Four-hundred and fifty seven women were eligible for inclusion in the primary analysis. The odds of being diagnosed with the higher dichotomization of stage (I vs. II/III/IV, I/II vs. III/IV, I/II/III vs. IV) was 1.29 (p = 0.017, 95% CI: 1.048&ndash, 1.592) per unit SD (standard deviation) increase in IMD. This translates to a 29% increase in odds of being diagnosed at the higher stage per each unit SD increase in IMD. Conclusion: Increased deprivation is consistently associated with a higher probability of being diagnosed with later stage OC.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

Importance Cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+TILs, respectively (Pvalue for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8+TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Background Transvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4. Objective The objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses. Study Design This was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared. Results Of 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers. Conclusion Our population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

Given that the Women's Health Initiative reported in 2002 increased risks of breast cancer and cardiovascular events with hormone therapy (HT) use and many women discontinued use, we assessed the use and perceived efficacy of complementary and alternative medicines (CAMs) for menopausal symptom relief after discontinuation of HT.Postmenopausal women aged 50 to 65 years within the United Kingdom Collaborative Trial of Ovarian Cancer Screening who were willing to take part in a secondary study were mailed a survey to evaluate menopausal symptom management. Use and perceived efficacy of CAMs for relief of vasomotor symptoms (VMS) upon discontinuation of HT were examined.The survey was sent to 15,000 women between July 2 and July 9, 2008. Seventy-one percent (10,662 of 15,000) responded, and 10,607 women with complete data were included. Ever use of HT was reported by 60.2% (6,383 of 10,607). At survey completion, 79.3% (5,060 of 6,383) had discontinued HT, with 89.7% (4,540 of 5,060) of the latter reporting using one or more CAMs for VMS relief. About 70.4% (3,561 of 5,060) used herbal remedies, with evening primrose oil (48.6%; 2,205 of 4,540) and black cohosh (30.3%;1,377 of 4,540) being most commonly used. Exercise was used by 68.2% (3,098 of 4,540), whereas other behavioral/lifestyle approaches were less frequently reported (13.9%; 629 of 4,540). Contrarily, more women (57%-72%) rated behavioral/lifestyle approaches as effective compared with herbal remedies (28%-46%; rating ≥4 on a "helpfulness" scale from 1-10). Among medical treatments, selective serotonin reuptake inhibitors were used by 10% and rated effective by 72.1%.Although more women use over-the-counter medicines, behavioral/lifestyle approaches seem to provide better relief of VMS. There is a pressing need for better evidence-based lay information to support decision-making on CAM use for relief of VMS.

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is similar to 4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.