What happens after menopause? (WHAM): A prospective controlled study of vasomotor symptoms and menopause-related quality of life 24 months after premenopausal risk-reducing salpingo-oophorectomy (RRSO).

OBJECTIVE: To measure vasomotor symptoms and menopause-related quality of life up to 24 months after RRSO, and the effects of Menopausal Hormone Therapy (MHT). METHODS: Prospective observational study of 104 premenopausal women at elevated risk of ovarian cancer planning RRSO and age-matched comparators (n = 102) who retained their ovaries. Vasomotor symptoms and quality of life were measured using the Menopause-specific QoL Intervention (MENQOL-I) scale. Changes in QoL were examined using a population-averaged linear regression model. The study was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12615000082505. RESULTS: At 24 months after RRSO the prevalence of vasomotor symptoms had increased from 6 % at baseline to 59 % and night sweats from 21 % to 39 %. There was a clinically and statistically significant difference of 1.14 points in MENQOL score (95 % CI 0.71, 1.57, p < 0.001) in the change from baseline to 24 months in vasomotor symptoms between the RRSO vs comparison group. Following RRSO, 61 % started MHT, most (79 %) within 3 months. At 24 months, 54 % of MHT users reported vasomotor symptoms of which around half (52 %) categorized these as "mild". Amongst non-MHT users, 88 % reported vasomotor symptoms at 24 months of which 72 % categorized these as "mild". Menopause-related QoL decreased after RRSO but was stable in comparators. Menopause related quality of life was higher in MHT users vs non-users. CONCLUSIONS: Vasomotor symptoms peak by 3 months after RRSO and are stable over 24 months. MHT mitigates but does not fully resolve vasomotor symptoms and improves menopause-related QoL.

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.

BACKGROUND: Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS: We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS: Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS: The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING: Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Clinical research in endometrial cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide.

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.

PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Bilateral salpingectomy as an option of permanent contraception at time of caesarean section: A survey of practice.

BACKGROUND: Opportunistic bilateral salpingectomy during benign gynaecologic surgery is advocated as a risk-reducing strategy due to the inverse association of epithelial ovarian cancers observed in epidemiological studies in a low-risk setting. Currently, no formal guidance exists for permanent surgical contraception at time of caesarean section in Australia. AIMS: Our aim was to survey Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) regarding bilateral salpingectomy compared to other procedures offered for permanent contraception at the time of caesarean section. MATERIALS AND METHODS: An online survey was utilised to collect clinician demographics, opinions, barriers, and justifications in regard to options of permanent surgical contraception at time of caesarean section. RESULTS: Bilateral salpingectomy was identified as the most effective method of permanent contraception at time of caesarean section. However, only 62% of respondents offer the procedure as a method of permanent contraception. The two most common reasons for clinicians to offer bilateral salpingectomy at time of caesarean section were evidence suggesting a link between the fallopian tube and gynaecological cancer (80%) and efficacy as a permanent form of contraception (16%). The primary barrier identified by 51% of respondents was perceived increased risk of surgical complications, followed by reasoning that it would not allow the possibility of future tubal reversal. CONCLUSION: This study identifies diverse opinions on surgical approach to permanent contraception at time of caesarean section and offered by clinicians of RANZCOG. Further research is required to establish safety profiles and short- and long-term risks of bilateral salpingectomy.

Direct oral anticoagulants (DOACs) use for prolonged venous thromboembolism prophylaxis following surgery for gynaecological malignancies in Australia and New Zealand - A clinician survey.

BACKGROUND: Current international guidelines recommend 28 days of enoxaparin as venous thromboembolism (VTE) prophylaxis after surgery for gynaecologic cancer. Direct oral anticoagulants (DOACs) have been investigated as an alternative to enoxaparin for post-operative VTE prophylaxis. High-quality evidence to demonstrate safety and efficacy is lacking. AIMS: We aim to investigate the current practice regarding VTE prophylaxis among gynaecological oncologists in Australia and New Zealand following laparotomy for gynaecological malignancy, in particular the use of DOACs for VTE prophylaxis. MATERIALS AND METHODS: Sixty-seven practising gynaecologic oncologists (GO) were identified through Royal Australia and New Zealand College of Obstetricians and Gynaecologists database and emailed online surveys that asked about VTE prophylaxis practice and views of DOACs in this setting. Data were then collected through Survey Monkey and evaluated. RESULTS: The majority (77.1%) routinely prescribed 28 days of enoxaparin following laparotomy for gynaecological malignancies. In clinical circumstance such as laparoscopy for gynaecological malignancies and surgery for vulva malignancies, there was variation in thromboprophylaxis practices. No GO reported routine use of DOACs in any clinical circumstance. There were 56% of GOs who used a DOAC in their practice at some point. Barriers to routine use of DOACs in current practice included insufficient evidence (68%), issue with cost (40.4%) and concerns about safety (29.7%). CONCLUSIONS: Enoxaparin prescribed for 28 days remains the current clinical practice in preventing VTE following laparotomy for gynaecological malignancy. The main barrier to routine DOAC use as post-operative thromboprophylaxis is a lack of evidence which reflects the need for a larger prospective study.

Follow-up assessment of sleep-related symptoms in patients after treatment for cancer: responses to continuous positive airway pressure treatment for co-morbid obstructive sleep apnoea.

PURPOSE: To assess changes in sleep-related symptoms in patients with breast cancer, endometrial cancer and melanoma previously examined for sleep-related symptoms and the presence of PSG (polysomnography)-determined OSA, ≥ 3 years post-treatment; and to evaluate how CPAP treatment affects sleep-related symptoms in patients previously diagnosed with OSA. METHODS: Patients initially recruited from breast cancer, endometrial cancer, and melanoma follow-up clinics at Westmead Hospital (Sydney, Australia) participated in this questionnaire-based study. Demographic and change in cancer status data were collected at follow-up. Patients completed the Pittsburgh Sleep Quality Index [poor sleep quality, PSQITOTAL ≥ 5au], Insomnia Severity Index, Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire; with ΔPSQITOTAL ≥ 3au indicating a clinically meaningful change in sleep quality over follow-up. PSG-determined OSA was confirmed using the apnoea-hypopnoea index. CPAP compliance was determined via self-report (CPAP compliant, CPAP; not compliant, non-CPAP). Logistic regression models determined if changes in cancer status, AHI, cancer subgroup or CPAP treatment was predictive of ΔPSQITOTAL ≥ 3 au and p < 0.05 indicated statistical significance. RESULTS: The 60 patients recruited had breast cancer (n = 22), endometrial cancer (n = 15), and melanoma (n = 23). Cancer subgroups were similarly aged, and all had median follow-up PSQITOTAL scores ≥ 5au; breast cancer patients scoring the highest (p < 0.05). The CPAP group had significantly reduced PSQITOTAL scores (p = 0.02) at follow-up, unlike the non-CPAP group. Cancer subgroups had similar median ISITOTAL, ESSTOTAL and FOSQ-10TOTAL scores at follow-up, regardless of CPAP treatment. There were no significant predictors of ΔPSQITOTAL ≥ 3 au at follow-up. CONCLUSION: Sleep-related symptoms persist in patients with cancer ≥ 3 years after treatment, although these symptoms improve with CPAP. Future studies should evaluate how CPAP affects survival outcomes in cancer patients with comorbid OSA.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The use of intraperitoneal chemotherapy for advanced ovarian cancer - The experience of a tertiary referral centre.

BACKGROUND: Platinum-based chemotherapy is the backbone of the medical management of ovarian cancer. The dose, route and timing of treatment are ongoing areas of debate. Intraperitoneal (IP) chemotherapy is an alternative delivery method treatment to the conventional intravenous (IV) route for patients with epithelial ovarian cancer, with efficacy supported by Level 1 evidence. AIMS: To compare the outcomes and feasibility of IP to IV delivery of platinum-based chemotherapy in patients with advanced epithelial ovarian cancer. MATERIALS AND METHODS: In a single institution, patients receiving adjuvant chemotherapy (IP and IV) for Stages III and IV epithelial ovarian cancer over the period January 2006-December 2018 were identified through a prospectively maintained database. All patients with an IP port inserted were included. A control group of patients treated with IV chemotherapy was created using criteria identified during the study and in the randomised trials that tested IP chemotherapy. Assessments were made for relapse-free survival (RFS) and overall survival (OS) for each cohort. RESULTS: A total of 639 patients received adjuvant chemotherapy (73 IP and 566 IV) during the study period. Both the IP group and matched IV control group (65 patients) had a median RFS of 26 months. The median OS in the IP group was 63.9 months, and in the IV group was 57.2 months. At ten years, a significantly higher proportion of patients were alive in the IP group cohort (16% vs 3%, relative risk 5.5, 95% CI 1.29-24, P = 0.012). IP chemotherapy was well tolerated by our cohort. In the IP group, 73% had four or more IP cycles and 99% received six or more cycles of chemotherapy. CONCLUSIONS: Our cohort had a high rate of completion of IP chemotherapy with excellent rates of completion of six cycles of any treatment. The RFS and OS in the IP chemotherapy group were comparable to each other and reflected those in the published literature. A significantly higher proportion of patients in the IP cohort were alive at ten years than in the IV cohort.

Exercise during CHemotherapy for Ovarian cancer (ECHO) trial: design and implementation of a randomised controlled trial.

INTRODUCTION: Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The Exercise during CHemotherapy for Ovarian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer. METHODS AND ANALYSIS: Participants (target sample size: n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage. ETHICS AND DISSEMINATION: Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ANZCTRN12614001311640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367123&isReview=true).

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Offshore decommissioning horizon scan: Research priorities to support decision-making activities for oil and gas infrastructure.

Thousands of oil and gas structures have been installed in the world's oceans over the past 70 years to meet the population's reliance on hydrocarbons. Over the last decade, there has been increased concern over how to handle decommissioning of this infrastructure when it reaches the end of its operational life. Complete or partial removal may or may not present the best option when considering potential impacts on the environment, society, technical feasibility, economy, and future asset liability. Re-purposing of offshore structures may also be a valid legal option under international maritime law where robust evidence exists to support this option. Given the complex nature of decommissioning offshore infrastructure, a global horizon scan was undertaken, eliciting input from an interdisciplinary cohort of 35 global experts to develop the top ten priority research needs to further inform decommissioning decisions and advance our understanding of their potential impacts. The highest research priorities included: (1) an assessment of impacts of contaminants and their acceptable environmental limits to reduce potential for ecological harm; (2) defining risk and acceptability thresholds in policy/governance; (3) characterising liability issues of ongoing costs and responsibility; and (4) quantification of impacts to ecosystem services. The remaining top ten priorities included: (5) quantifying ecological connectivity; (6) assessing marine life productivity; (7) determining feasibility of infrastructure re-use; (8) identification of stakeholder views and values; (9) quantification of greenhouse gas emissions; and (10) developing a transdisciplinary decommissioning decision-making process. Addressing these priorities will help inform policy development and governance frameworks to provide industry and stakeholders with a clearer path forward for offshore decommissioning. The principles and framework developed in this paper are equally applicable for informing responsible decommissioning of offshore renewable energy infrastructure, in particular wind turbines, a field that is accelerating rapidly.

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma.

BACKGROUND: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. METHODS: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. RESULTS: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). CONCLUSIONS: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.

Mainstream genetic testing for high-grade ovarian, tubal and peritoneal cancers: A tertiary referral centre experience.

BACKGROUND: Fifteen percent of ovarian, tubal, and peritoneal (OTP) invasive epithelial cancers are linked to an underlying heritable pathogenic variant (PV) in the BRCA1/2 cancer susceptibility genes. Identifying a PV has management implications for an affected individual and relatives. Cancer team-facilitated genetic testing (mainstreaming) aims to provide equitable systematic access to genetic testing for appropriate patients. AIM: To evaluate a multi-disciplinary team (MDT)-led mainstream germline genetic testing program for OTP cancer at a tertiary referral centre. MATERIALS AND METHODS: We conducted a retrospective review of our MDT-led mainstream genetic testing program initiated in June 2017. We included all patients diagnosed with OTP cancer registered with the hospital gynaecological oncology MDT from program initiation to December 2020. Patients were considered eligible for testing if they were diagnosed with a high-grade epithelial OTP AND ≤70 years, OR if >70 with a first/second degree relative with breast and/or ovarian cancer OR Jewish ancestry. RESULTS: Of 205 women diagnosed with high-grade epithelial OTP cancer, 140 were eligible for mainstreaming. Eight-five percent were mainstreamed, with the gynae-oncologists facilitating 64.5% of tests. The overall PV detection rate in BRCA1/2 was 10.1% (BRCA1 n = 9, BRCA2 n = 3). The median turnaround time (TAT) was 44.5 days (range 16-118). All women with PV were referred to the Familial Cancer Service for further assessment and five (of six eligible; 83%) were subsequently treated with polyadenosine diphosphate ribose polymerase inhibitors. Cascade testing was undertaken in 75% of families with a mean of three relatives tested per proband. CONCLUSION: Mainstreamed genetic testing is feasible, with an acceptable TAT, ensuring adequate opportunity to inform treatment decisions. Tumour testing and inclusion of moderate-risk cancer predisposition genes in mainstreaming represent potential pathways that will require further exploration.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Screening for obstructive sleep apnoea in post-treatment cancer patients.

BACKGROUND AND AIMS: For cancer patients, comorbid obstructive sleep apnea (OSA) poses additional risk to their surgical/anaesthetic outcomes, quality of life, and survival. However, OSA screening is not well-established in oncology settings. We tested two screening tools (STOP-Bang questionnaire [SBQ] and the at-home monitoring device, ApneaLink™Air), for predicting polysomnography (PSG) confirmed OSA in post-treatment cancer patients. METHODS: Breast (n = 56), endometrial (n = 37) and melanoma patients (n = 50) were recruited from follow-up clinics at Westmead Hospital (Sydney, Australia). All underwent overnight PSG, 137 completed SBQ, and 99 completed ApneaLink™Air. Positive (PPV) and negative (NPV) predictive values for PSG-determined moderate-to-severe OSA and severe OSA, were calculated using an SBQ threshold ≥3 au and ApneaLink™Air apnoea-hypopnea index thresholds of ≥10, ≥15 and ≥30 events/h. RESULTS: Both SBQ and ApneaLink™Air had high NPVs (92.7% and 85.2%-95.6% respectively) for severe OSA, but NPVs were lower for moderate-to-severe OSA (69.1% and 59.1%-75.5%, respectively). PPV for both tools were relatively low (all <73%). Combining both tools did not improve screening performance. CONCLUSIONS: These screening tools may help identify cancer patients without severe OSA, but both are limited in identifying those with moderate-to-severe or severe OSA. PSG remains optimal for adequately identifying and managing comorbid OSA in cancer patients.

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Pathways to diagnosis of endometrial and ovarian cancer in the 45 and Up Study cohort.

PURPOSE: To determine pathways to endometrial or ovarian cancer diagnosis by comparing health service utilization between cancer cases and matched cancer-free controls, using linked health records. METHODS: From cancer registry records, we identified 238 incident endometrial and 167 ovarian cancer cases diagnosed during 2006-2013 in the Australian 45 and Up Study cohort (142,973 female participants). Each case was matched to four cancer-free controls on birthdate, sex, place of residence, smoking status, and body mass index. The use of relevant health services during the 13-18-, 7-12-, 0-6-, and 0-1-months pre-diagnosis for cases and the corresponding dates for their matched controls was determined through linkage with subsidized medical services and hospital records. RESULTS: Healthcare utilization diverged between women with cancer and controls in the 0-6-months, particularly 0-1 months, pre-diagnosis. In the 0-1 months, 74.8% of endometrial and 50.3% of ovarian cases visited a gynecologist/gynecological oncologist, 11.3% and 59.3% had a CA125 test, 5.5% and 48.5% an abdominal pelvic CT scan, and 34.5% and 30.5% a transvaginal pelvic ultrasound, respectively (versus ≤ 1% of matched controls). Moreover, 25.1% of ovarian cancer cases visited an emergency department in the 0-1-months pre-diagnosis (versus 1.3% of matched controls), and GP visits were significantly more common for cases than controls in this period. CONCLUSION: Most women with endometrial or ovarian cancer accessed recommended specialists and tests in the 0-1-months pre-diagnosis, but a high proportion of women with ovarian cancer visited an emergency department. This reinforces the importance of timely specialist referral.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.