Paul A. Cohen

Routine Tumor Testing for Homologous Recombination Deficiency in Patients With High Grade Epithelial Ovarian Cancer at a Statewide Gynecological Cancer Service in Western Australia: An Observational Study

ABSTRACTBackgroundPoly‐ADP ribose polymerase inhibitors have been shown to improve progression‐free survival in patients with advanced high‐grade epithelial non‐mucinous ovarian cancers characterized by a deficiency in homologous recombination (HRD). Guidelines recommend all patients with advanced high‐grade epithelial ovarian cancer undergo genomic tumor testing for HRD. Our aim was to evaluate the first year of HRD testing at the statewide Western Australia Gynecologic Cancer Service to assess factors associated with obtaining a diagnostic HRD testing result.MethodsRetrospective chart review.ResultsHRD testing was indicated in 84 patients, and ordered in 79, of which three had non‐diagnostic/inconclusive results, all due to insufficient tumor quantity. One patient had the sample collected using a 20‐gauge core biopsy needle under image guidance, one patient following interval debulking surgery, and one following primary debulking surgery. Of 76 patients with an HRD result, HRD was positive in 29 (38.2%). A somatic BRCA mutation was detected in six of these 29 patients (20.6%) and HRD positive, BRCAwt was detected in 23 of 29 patients (79.4%). All core biopsies with 16‐ and 18‐gauge needles had a diagnostic HRD result. Ten of 11 patients who were treated by neoadjuvant chemotherapy and whose biopsies were obtained at interval cytoreductive surgery had sufficient tumor tissue for testing and had a diagnostic HRD result. All ascitic/pleural fluid samples sent for HRD testing yielded diagnostic results.ConclusionsCompliance with HRD testing was high, and only three of 79 (3.8%) patients had non‐diagnostic results.

A Single Arm Pilot Observational Study to Evaluate the Safety and Feasibility of a Pre‐Operative Very Low Calorie Diet in Severely Obese Patients With Endometrial Cancer

ABSTRACTBackgroundPre‐operative very low calorie diets (VLCDs) can achieve rapid and safe weight loss, yet no studies have evaluated VLCDs in the severely obese endometrial cancer population prior to surgery. Our aim was to evaluate the safety and feasibility of a 4–6 week pre‐operative nutritional intervention with the Optifast VLCD prior to surgery in patients with clinical stage 1, Grade 1 endometrioid endometrial adenocarcinoma and a body mass index ≥ 35 kg/m2.MethodsThis was an investigator‐initiated single‐arm prospective observational study. Co‐primary endpoints were safety and feasibility. Secondary endpoints were changes in anthropometric measures, blood pressure, biochemistry, perioperative complications, length of stay and final tumour stage. Tolerability and compliance of the VLCD were assessed by fortnightly questionnaires and urinary ketones.ResultsTwenty‐eight patients were enrolled, of which 25 underwent the intervention. 22/25 patients (88%) completed at least 4 weeks of Optifast. Mean (SD) age was 56.4 (6.3) years, and mean body mass index (BMI) was 45.2 (7.1) kg/m2. Significant decreases in weight (mean 8.2 kg [3.6]), BMI (mean 3.1 kg/m2 [1.3]), waist and hip circumference (mean 5.7 [6.5] and 4.5 cm [4.1], respectively), and diastolic blood pressure (10 mmHg [14.1]) were observed (p < 0.001 for all). One patient had a flare of gout. All patients had laparoscopic surgery without adverse events. Optifast was considered acceptable, and compliance was 40% to 61.9%. Eighty‐eight percent (22/25) of patients had FIGO 2009 Stage 1A Grade 1 endometrioid endometrial adenocarcinoma on final staging.ConclusionsA 4–6 week pre‐operative VLCD in severely obese clinically low‐risk endometrial cancer patients appears safe, feasible and well tolerated.

Patterns of care and development of quality indicators in patients with non-epithelial and rare ovarian tumors in Australia: insights from the National Gynae-Oncology Registry

The Rare Ovarian Tumor Module forms part of the National Gynae-Oncology Registry (NGOR) which measures compliance with the optimal care pathways for gynecologic cancer in Australia. Our objectives were to evaluate patterns of care in patients with non-epithelial ovarian tumors and to develop appropriate clinical quality indicators. A multidisciplinary reference group developed a module dataset in the NGOR REDCap database to collect clinical data using an opt-out recruitment model across participating Australian hospitals. Clinical quality indicators were developed and refined using consensus methods, with annual reports provided to participating sites to benchmark performance and drive improvement in patient care. As of November 2023, 232 patients from 18 Australian hospitals were enrolled. All cases had histologic confirmation with the majority being adult granulosa cell tumors (47.8%). Almost all patients (97.8%) were presented at a multidisciplinary team meeting. Most had early-stage disease (stage, I 70.3%; II 9.9%; III 9.1%; IV 3.4%; not documented 7.3%) and had surgery alone (72.4%). Thirty-four patients underwent multiple surgeries as primary treatment (14.7%), with a median time to a second surgical procedure of 47 days (interquartile range 36-71). Two-thirds of patients (65.4%) had their first surgery performed by a gynecologic oncologist. Rates of intra-operative and 30-day post-operative adverse events (Clavien-Dindo ≥ grade III) were low, 4.3% and 1.9% respectively. Of 52 patients with stage II disease and higher, 37 (71.2%) received systemic therapy. A high rate of adherence to the 4 clinical quality indicators as measures of best practice care was observed. The NGOR Rare Ovarian Tumor Module has successfully collated relevant data to study patterns of care to inform the development of clinical quality indicators and enable research for these rare tumors. This national collaboration has the potential for benchmarking outcomes in Australia with international experience.

Response to: Correspondence on ‘Medicolegal, infrastructural,and financial aspects in gynecologic cancer surgery and their implications in decision making processes: Quo Vadis?’ by Nevin and Bolton

Predictors of endometrial carcinoma in patients with atypical endometrial hyperplasia at a tertiary gynaecological cancer centre in Western Australia

AbstractAimOur objective was to assess clinical and pathological factors associated with a final diagnosis of endometrial carcinoma in patients with atypical endometrial hyperplasia with a particular emphasis on the grading of atypia.Materials and methodsA retrospective review over five years on patients (N = 97) who underwent hysterectomy for a diagnosis of atypical endometrial hyperplasia at a statewide public tertiary gynaecologic oncology centre. Clinical and pathological characteristics were obtained.ResultsThe rate of concurrent endometrial carcinoma was 34% (n = 33) with most being stage 1A endometrioid. A significant group difference was reported for age at diagnosis (t = −2.20 P = 0.031 d = 0.43) with carcinoma patients on average older (Mage = 60.2 (8.9) years) than patients without carcinoma (Mage = 55.5 (12.3) years). No significant group differences were found for body mass index, endometrial thickness or time between diagnosis and treatment. Significantly higher rates of carcinoma were reported in patients with moderate atypical hyperplasia (27.6%) and severe atypical hyperplasia (66.7%), compared to mild atypical hyperplasia (7.1%). Only severe atypical hyperplasia (odds ratio (OR) = 21.5, 95% CI 2.8–163.1, P = 0.003) and postmenopausal status (OR = 13.2, 95% CI 1.3–139.0, P = 0.032) significantly increased the risk of carcinoma in a multivariate model.ConclusionSevere atypical hyperplasia and postmenopausal status were significant predictors of concurrent endometrial carcinoma in patients with atypical endometrial hyperplasia. The grading of atypical hyperplasia may be utilised by gynaecologic oncologists in the triage and referral process of managing these patients; however, the grading system requires external validation in larger prospective studies.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry

In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Incidence of germline BRCA1/2 mutations in women with tubo-ovarian high-grade serous carcinomas with and without serous tubal intra-epithelial carcinomas

To compare the germline A retrospective study was performed of patients in Western Australia diagnosed with high-grade serous tubo-ovarian and primary peritoneal carcinoma and referred for genetic counseling and A total of 269 women with high-grade serous tubo-ovarian and primary peritoneal carcinoma were referred for genetic counseling and testing. 114 patients were excluded because the serous tubal intra-epithelial carcinoma status was not assessable or because patients did not attend for genetic assessment. 155 patients (55 serous tubal intra-epithelial carcinoma-positive and 100 serous tubal intra-epithelial carcinoma-negative) underwent genetic testing. The

Skeletal muscle morphology in patients receiving primary versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer

Our primary aim was to compare muscle morphology (skeletal muscle mass and density) between patients who underwent primary cytoreductive surgery versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer. Secondarily, we explored the associations of muscle morphology with survival outcomes. We retrospectively analysed computed tomography (CT) images for 88 ovarian cancer patients (aged 38-89 years) to calculate skeletal muscle index (cm At baseline, 44.3% of patients had low skeletal muscle index and 50.6% had low skeletal muscle density, with interval surgery patients having significantly lower mean skeletal muscle density than primary surgery patients (32.2±8.9 vs 37.3±8.6 HU, p=0.014). Although both groups had similar reductions in skeletal muscle index following treatment (p=0.49), primary surgery patients had a greater reduction in skeletal muscle density compared with interval surgery patients (-2.4 HU, 95% CI -4.3 to -0.5, p=0.016). Patients who experienced skeletal muscle density loss >2% during treatment (HR 5.16, 95% CI 1.33 to 20.02) and had low skeletal muscle density post-treatment (HR 58.87, 95% CI 3.70 to 935.68) had significantly worse overall survival. Low skeletal muscle index and skeletal muscle density were prevalent at ovarian cancer diagnosis. While both groups experienced muscle mass loss, greater reductions in skeletal muscle density occurred in patients undergoing primary surgery. In addition, skeletal muscle density loss during treatment and low skeletal muscle density post-treatment were associated with poorer overall survival. Supportive care involving resistance exercise targeting muscle hypertrophic drive, and nutrition counseling during and after ovarian cancer treatment may help preserve/enhance muscle mass and density.

Exploring international differences in ovarian cancer treatment: a comparison of clinical practice guidelines and patterns of care

The International Cancer Benchmarking Partnership demonstrated international differences in ovarian cancer survival, particularly for women aged 65-74 with advanced disease. These findings suggest differences in treatment could be contributing to survival disparities. To compare clinical practice guidelines and patterns of care across seven high-income countries. A comparison of guidelines was performed and validated by a clinical working group. To explore clinical practice, a patterns of care survey was developed. A questionnaire regarding management and potential health system-related barriers to providing treatment was emailed to gynecological specialists. Guideline and survey results were crudely compared with 3-year survival by 'distant' stage using Spearman's rho. Twenty-seven guidelines were compared, and 119 clinicians completed the survey. Guideline-related measures varied between countries but did not correlate with survival internationally. Guidelines were consistent for surgical recommendations of either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery with the aim of complete cytoreduction. Reported patterns of surgical care varied internationally, including for rates of primary versus interval debulking, extensive/'ultra-radical' surgery, and perceived barriers to optimal cytoreduction. Comparison showed that willingness to undertake extensive surgery correlated with survival across countries (r Findings suggest international variations in ovarian cancer treatment. Characteristics relating to countries with higher stage-specific survival included higher reported rates of primary surgery; willingness to undertake extensive/ultra-radical procedures; greater access to high-cost drugs; and auditing.

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a

Getting the MOST out of follow-up: a randomized controlled trial comparing 3 monthly nurse led follow-up via telehealth, including monitoring CA125 and patient reported outcomes using the MOST (Measure of Ovarian Symptoms and Treatment concerns) with routine clinic based or telehealth follow-up, after completion of first line chemotherapy in patients with epithelial ovarian cancer

Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective. Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy. Emotional wellbeing at 12 months. 150 patients. July 2023. Results expected in 2025, 24 months after the last participant is enrolled. ACTRN12620000332921.

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones

Abstract High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.