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.

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

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.

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.

Policies are Needed to Increase the Reach and Impact of Evidence-Based Parenting Supports: A Call for a Population-Based Approach to Supporting Parents, Children, and Families.

Parents can be essential change-agents in their children's lives. To support parents in their parenting role, a range of programs have been developed and evaluated. In this paper, we provide an overview of the evidence for the effectiveness of parenting interventions for parents and children across a range of outcomes, including child and adolescent mental and physical health, child and adolescent competencies and academic outcomes, parental skills and competencies, parental wellbeing and mental health, and prevention of child maltreatment and family violence. Although there is extensive research showing the effectiveness of evidence-based parenting programs, these are not yet widely available at a population level and many parents are unable to access support. We outline how to achieve increased reach of evidence-based parenting supports, highlighting the policy imperative to adequately support the use of these supports as a way to address high priority mental health, physical health, and social problems.

Feasibility of Microlearning for Improving the Self-Efficacy of Cancer Patients Managing Side Effects of Chemotherapy.

Lung cancer patients have a high symptom burden that negatively affects their quality of life. Increasing patient self-efficacy to deal with treatment side effects can ameliorate their symptom burden. Education programs can help enhance patient self-efficacy by giving patients more control over their condition through increased disease literacy. This study aimed to evaluate the feasibility of microlearning for delivering lung cancer patients' information on side effects of chemotherapy. Secondary objectives of the program are to understand the acceptability of microlearning for delivery this type of education to lung cancer patients and the potential impact of microlearning on patient self-efficacy, knowledge and confidence managing side effects of chemotherapy. A mixed-methods prepost test (or quasi-experimental) study design was used to better enable patients to identify and manage the side effects of their condition and chemotherapy. Participants were patients diagnosed with stage II to stage IV lung cancer, who had a life expectancy of greater than 3 months and were aged 18 years or older. Multiple validated scales were used to assess patient self-efficacy pre- and post-intervention. The online program was evaluated using quantitative data of completion rates extracted from the online platform. Semi-structured interviews were used to explore the impact of the online program on perceived self-efficacy and quality of life. Twenty-three participants agreed to participate in the study and five agreed to complete a semi-structured interview. Participants found the content comprehensive, relevant and engaging. The program improved perceived disease literacy and helped participants develop coping strategies to manage side effects. Participants also found the platform easy to use and navigate. Additional courses and features were requested. Patients with a diagnosis of cancer receive a large amount of information about the side effects of chemotherapy and how to manage them. This information is often provided soon after diagnosis or upon commencement of therapy, which can be overwhelming for some patients. Microlearning, a method of online learning that spaces distributing of content over several weeks, may be a useful tool for supporting delivering of health information to this group of patients.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Improving Cancer MDT performance in Western Sydney - three years' experience.

BACKGROUND: While multidisciplinary teams (MDTs) are now considered an essential part of cancer care decision-making, how they perform varies widely. The authors hypothesised that a comprehensive, multipronged improvement program, and associated annual member survey, could strengthen MDT performance across a whole cancer service. METHODS: The study comprised the introduction of a structured program, the Tumour Program Strengthening Initiative (TPSI) linked with an annual survey of member's perceptions of their performance. Three iterations of the survey have been completed (2017, 2018 and 2019). Generalised estimating equations (GEEs) were used to test for a difference in the proportion of positive survey responses between 2017 and 2019 adjusted for team clustering. RESULTS: Twelve teams participated in TPSI. One hundred twenty-nine, 118 and 146 members completed the survey in 2017, 2018 and 2019, respectively. Of the 17 questions that were asked in all three years, nine showed significant improvement and, of these, five were highly significant. Documenting consensus, developing Terms of Reference (TORs), establishing referral criteria and referring to clinical practice guidelines showed most improvement. Questions related to patient considerations, professional development and quality improvement (QI) activities showed no significant change. CONCLUSIONS: TPSI resulted in sustained and significant improvement. The MDT survey not only allowed MDT members to identify their strengths and weaknesses but also provided insights for management to flag priority areas for further support. Overall program improvement reflected the strengthening of the weakest teams as well as further improvement in highly performing MDTs. Importantly, the initiative has the potential to achieve behaviour change amongst clinicians.

Developing an Intranet-Based Lymphedema Dashboard for Breast Cancer Multidisciplinary Teams: Design Research Study.

BACKGROUND: A large quantity of data is collected during the delivery of cancer care. However, once collected, these data are difficult for health professionals to access to support clinical decision making and performance review. There is a need for innovative tools that make clinical data more accessible to support health professionals in these activities. One approach for providing health professionals with access to clinical data is to create the infrastructure and interface for a clinical dashboard to make data accessible in a timely and relevant manner. OBJECTIVE: This study aimed to develop and evaluate 2 prototype dashboards for displaying data on the identification and management of lymphedema. METHODS: The study used a co-design framework to develop 2 prototype dashboards for use by health professionals delivering breast cancer care. The key feature of these dashboards was an approach for visualizing lymphedema patient cohort and individual patient data. This project began with 2 focus group sessions conducted with members of a breast cancer multidisciplinary team (n=33) and a breast cancer consumer (n=1) to establish clinically relevant and appropriate data for presentation and the visualization requirements for a dashboard. A series of fortnightly meetings over 6 months with an Advisory Committee (n=10) occurred to inform and refine the development of a static mock-up dashboard. This mock-up was then presented to representatives of the multidisciplinary team (n=3) to get preliminary feedback about the design and use of such dashboards. Feedback from these presentations was reviewed and used to inform the development of the interactive prototypes. A structured evaluation was conducted on the prototypes, using Think Aloud Protocol and semistructured interviews with representatives of the multidisciplinary team (n=5). RESULTS: Lymphedema was selected as a clinically relevant area for the prototype dashboards. A qualitative evaluation is reported for 5 health professionals. These participants were selected from 3 specialties: surgery (n=1), radiation oncology (n=2), and occupational therapy (n=2). Participants were able to complete the majority of tasks on the dashboard. Semistructured interview themes were categorized into engagement or enthusiasm for the dashboard, user experience, and data quality and completeness. CONCLUSIONS: Findings from this study constitute the first report of a co-design process for creating a lymphedema dashboard for breast cancer health professionals. Health professionals are interested in the use of data visualization tools to make routinely collected clinical data more accessible. To be used effectively, dashboards need to be reliable and sourced from accurate and comprehensive data sets. While the co-design process used to develop the visualization tool proved effective for designing an individual patient dashboard, the complexity and accessibility of the data required for a cohort dashboard remained a challenge.