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Objective: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines. Design: Focus group study. Setting: Four online sessions. Population: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49). Methods: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC. Main Outcome Measures: Professionals' opinions and clinical practices regarding isolated STIC management. Results: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations. Conclusions: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC.

BACKGROUND: Gestational trophoblastic disease (GTD) is an uncommon but highly treatable condition. There is limited local evidence to guide therapy. AIMS: To report the experience of a statewide registry in the treatment of low-risk gestational trophoblastic neoplasia (GTN) over a 20-year period. MATERIALS AND METHODS: A retrospective review of the prospectively maintained GTD registry database was conducted. There were 144 patients identified with low-risk GTN, of which 115 were analysed. Patient demographics, treatment details and outcomes, including development of resistance, toxicity or relapse were reviewed. RESULTS: The incidence of GTD was 2.6/1000 live births. There was 100% survival. The mean time from diagnosis to commencing treatment was 1.9 days (range 0-29 days). Seventy-seven percent of patients treated with methotrexate achieved complete response. Thirteen patients (11.3%) required multi-agent chemotherapy, for the treatment of resistant or relapsed disease. There was a higher rate of treatment resistance in those with World Health Organization (WHO) risk scores 5-6 (odds ratio (OR) 6.56, 95% CI 1.73-24.27, P = 0.005) and those with pre-treatment human chorionic gonadotropin >10 000 (OR 4.00 95% CI 1.73-24.27 P = 0.007). Four patients (3.5%) were diagnosed with choriocarcinoma after commencing treatment. Nine patients (7.8%) had successful surgical treatment for GTN, both alone and in combination with chemotherapy. The relapse rate was 4.3%; all were treated successfully with a combination of chemotherapy and surgery, and 93.9% of patients completed follow up through the registry. CONCLUSIONS: Methotrexate is a highly effective treatment for low-risk GTN, especially with WHO risk score ≤4. The optimal treatment for those with risk scores of 5-6 requires further investigation.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival.

Tumors of the breast and reproductive organs that occur in children, adolescents, and young adults (AYA) have different biological features and can present special challenges. Although prognosis for these tumors is generally favorable, the long-term effects of treatment can be debilitating. Treatments are often multimodal and may include surgery as well as chemotherapy and/or radiation, which can cause considerable distress and anxiety related to loss of femininity or masculinity, concern over future fertility, or sexual dysfunction. Thus, tumors of the reproductive organs in pediatric/AYA patients require special consideration of the treatment effects beyond the intended oncologic outcome. Multidisciplinary teams should be involved in their care and address issues of fertility, sexual dysfunction, and psychosexual concerns before treatment begins. This review addresses histology, risk factors, prognosis, staging and treatment of gynecologic, breast and testicular cancers in pediatric and AYA patients.

BACKGROUND: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. METHODS: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. RESULTS: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRK

OBJECTIVE: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. DESIGN: Prospective multicentre observational study. SETTING: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. SAMPLE: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late-stage ovarian cancer. MAIN OUTCOME MEASURES: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30). Secondary: EORTC ovarian cancer module (OV28), progression-free survival. RESULTS: Patients' preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre-surgical baseline in the EORTC QLQ-C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high-SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated-measures model, there were no clinically or statistically meaningful differences in EORTC QLQ-C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high-SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post-surgery, which resolved by 6-12 months. CONCLUSIONS: The global QoL of patients undergoing low-, intermediate- and high-SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery. TWEETABLE ABSTRACT: Compared with surgery of lower complexity, extensive surgery does not result in poore

PURPOSE: Endometrial cancer is associated with the highest comorbid disease burden of any cancer. The aim of this trial was to assess the feasibility and safety of an allied health intervention during adjuvant treatment. METHODS: A mixed-methods pilot randomized (2:1) controlled trial with concealed allocation and assessor-blinding. Eligibility criteria: adjuvant endometrial cancer treatment scheduled, disease stage I-IIIC1, ECOG 0-2 and able to perform unsupervised physical activity (PA). Participants received usual care and 8 sessions of weekly, individualized, lifestyle education (diet and PA) with behavior change and social support (intervention group), delivered predominantly by telehealth, or usual care alone. Feasibility outcomes: recruitment and consent rates, decline reasons, program acceptability, intervention adherence and retention. RESULTS: 22/44 eligible patients (50%, 95%CI: 36%, 64%) were recruited over 10 months (14 intervention, 8 usual care). The recruitment rate was 2.2 patients/month (95%CI: 1.4, 3.3). Patients who declined had too much going on (7/22, 32%) or were not interested (6/22, 27%). Mean (SD) age and BMI were 63.2 years (6.8) and 31.9 kg/m2 (6.7). A majority were FIGO stage I (15/22, 68%) and received vaginal brachytherapy (14/22, 64%). Adherence was high, 11/14 (79%, 95%CI: 52%, 92%) participants attended >70% of scheduled sessions. Retention was 100% (95%CI: 85%, 100%) at 9 weeks, however completion of objective measures was impacted by COVID-19 restrictions. Telehealth and online questionnaires enabled participation. No serious adverse events occurred. CONCLUSION: The intervention was acceptable to participants with high levels of adherence and retention. Trial findings will be used to design a future RCT. TRIAL REGISTRATION: The trial was registered on www.anzctr.org.au (ACTRN12619000631101) 29/04/2019.

UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indica

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.

Objectives Uterine carcinosarcoma (UCS) is a rare neoplasm with a poor prognosis and a paucity of evidence on treatment. The objective was to review the characteristics, treatment and outcomes of UCS cases across two gynaeoncology units and five private gynaeoncology practices in Melbourne. Methods UCS cases were identified from hysterectomy pathology records between 1994 and 2020 inclusive. Patient characteristics, histopathological stage, adjuvant therapy, recurrence and survival status were extracted from patient records. Results 208 cases of UCS were identified. The overall recurrence rate was 26.0% and the overall death rate was 60.1%. Increasing age at diagnosis was associated with an increased risk of death (adjusted OR 1.04, 95% CI 1.01-1.08, p=0.019). Risk of death was highest in Stage III disease (adjusted OR 4.37, 95% CI 1.67-11.40). Recurrence was a strong determinant of death, with an adjusted OR of 7.58 (p<0.001). Conclusions In this relatively large homogenous cohort of UCS cases, significant predictors for survival included age at diagnosis, stage of disease and recurrence.

Objectives Uterine carcinosarcoma (UCS) is a rare neoplasm with a poor prognosis and a paucity of evidence on treatment. The objective was to review the characteristics, treatment and outcomes of UCS cases across two gynaeoncology units and five private gynaeoncology practices in Melbourne. Methods UCS cases were identified from hysterectomy pathology records between 1994 and 2020 inclusive. Patient characteristics, histopathological stage, adjuvant therapy, recurrence and survival status were extracted from patient records. Results 208 cases of UCS were identified. The overall recurrence rate was 26.0% and the overall death rate was 60.1%. Increasing age at diagnosis was associated with an increased risk of death (adjusted OR 1.04, 95% CI 1.01-1.08, p=0.019). Risk of death was highest in Stage III disease (adjusted OR 4.37, 95% CI 1.67-11.40). Recurrence was a strong determinant of death, with an adjusted OR of 7.58 (p<0.001). Conclusions In this relatively large homogenous cohort of UCS cases, significant predictors for survival included age at diagnosis, stage of disease and recurrence.

BACKGROUND: Human epididymis protein 4 (HE4) has shown promising utility as a prognostic biomarker in endometrial cancer. Increased serum HE4 levels may be associated with deeper myometrial invasion, extrauterine disease and poorer prognosis. AIM: To evaluate the use of serum HE4 level, compared to and alongside other investigations, to accurately guide management in apparent early-stage endometrial cancer. MATERIALS AND METHODS: This is a single-site prospective study of 100 patients with histologically confirmed endometrial cancer. All patients underwent preoperative measurements of HE4 and CA125 levels and a preoperative magnetic resonance imaging (MRI) to assess the depth of invasion, nodal status and tumour size. Correlation was sought between serum HE4 level, CA125 level, MRI findings and intra-operative frozen section with tumour type, grade and stage. RESULTS: While both median HE4 and CA125 levels were higher with worsening clinicopathological features, serum HE4 level showed a more consistent association with high-risk features. Patients with a low-grade biopsy preoperatively and a low HE4 level (<70 pmol/L) demonstrated an 86.8% likelihood of having low-risk disease on final histopathology. In comparison, preoperative MRI or intraoperative frozen section alongside a low-grade biopsy demonstrated a similar likelihood of 86.2 and 87.7%, respectively. CONCLUSIONS: When used in conjunction with an initial low-grade endometrial biopsy, serum HE4 level demonstrated a similar likelihood to both preoperative MRI and intraoperative frozen section in identifying low-risk disease on final histopathology. As a triaging tool this may be significant given that a preoperative, serum-based assay would likely be the least invasive, least resource-intensive and most cost-effective approach.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

INTRODUCTION: 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. OBJECTIVE: To compare clinical practice guidelines and patterns of care across seven high-income countries. METHODS: 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. RESULTS: 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 (rs=0.94, p=0.017). For systemic/radiation therapies, guideline differences were more pronounced, particularly for bevacizumab and PARP (poly (ADP-ribose) polymerase) inhibitors. Reported health system-related barriers also varied internationally and included a lack of adequate hospital staffing and treatment monitoring via local and national audits. DISCUSSION: Findings suggest international variations in ovarian cancer treatment. Characteristics relating to countries with high

STUDY QUESTION What is the evidence to guide the management of women who wish to conceive following abdominopelvic radiotherapy (AP RT) or total body irradiation (TBI)? SUMMARY ANSWER Pregnancy is possible, even following higher doses of post-pubertal uterine radiation exposure; however, it is associated with adverse reproductive sequelae and pregnancies must be managed in a high-risk obstetric unit. WHAT IS KNOWN ALREADY In addition to primary ovarian insufficiency, female survivors who are treated with AP RT and TBI are at risk of damage to the uterus. This may impact on its function and manifest as adverse reproductive sequelae. STUDY DESIGN, SIZE, DURATION A review of the literature was carried out and a multidisciplinary working group provided expert opinion regarding assessment of the uterus and obstetric management. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductive outcomes for postpubertal women with uterine radiation exposure in the form of AP RT or TBI were reviewed. This included Pubmed listed peer-reviewed publications from 1990 to 2019, and limited to English language.. MAIN RESULTS AND THE ROLE OF CHANCE The prepubertal uterus is much more vulnerable to the effects of radiation than after puberty. Almost all available information about the impact of radiation on the uterus comes from studies of radiation exposure during childhood or adolescence. An uncomplicated pregnancy is possible, even with doses as high as 54 Gy. Therefore, tumour treatment doses alone cannot at present be used to accurately predict uterine damage. LIMITATIONS, REASONS FOR CAUTION Much of the data cannot be readily extrapolated to adult women who have had uterine radiation and the publications concerning adult women treated with AP RT are largely limited to case reports. WIDER IMPLICATIONS OF THE FINDINGS This analysis offers clinical guidance and assists with patient counselling. It is important to include patients who have undergone AP RT or TBI in prospective studies to pro

High-grade mucinous ovarian cancer (HGMOC) is often a misnomer as the majority of cases are metastatic disease with a gastro-intestinal origin. The standard platinum-based ovarian cancer (OC) chemotherapy regimens are often ineffective, and there are insufficient data to support the use of colorectal cancer (CRC) chemotherapy regimens due to the rarity of HGMOC. We described a cohort of four consecutive suspected HGMOC cases treated at the Royal Women’s Hospital, Melbourne in 2012. Two cases were treated as primary MOC, whereas the other two were considered to be metastatic CRC based on histopathological and clinical evidence. From the RNAseq analysis, we identified two cases of HGMOC whose gene expression profiles were consistent with mucinous epithelial OC, one case that was treated as metastatic CRC with gene expression profile correlated with CRC and one case with neuroendocrine (NET) gene expression features. Interestingly, glucagon was over-expressed in this tumor that was subsequently confirmed by immunohistochemistry. These findings suggest a rare glucagonoma-like NET appendiceal tumor that had metastasized to the surface of ovary and were unresponsive to CRC chemotherapy regimens. In summary, a carefully curated panel of expression markers and selected functional genomics could provide diagnosis and treatment guidance for patients with possible HGMOC.

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.Copyright © 2018, The Author(s).

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Introduction: Residual disease following debulking surgery for advanced epithelial ovarian cancer (EOC) is an important prognostic factor. We aimed to audit the surgical outcomes following standard and extended surgical debulking procedures carried out for management of ovarian cancer. Our secondary aim was to assess the feasibility of introducing extended procedures in a single Australian gynaecological oncology centre. Method(s): A prospective audit of outcomes for patients undergoing surgical debulking for epithelial ovarian cancer was carried out over a 24-month period at The Royal Women's Hospital, Melbourne. The outcome data for standard and extended surgical procedures was analysed for women diagnosed with stage II through to stage IV ovarian cancer. Result(s): Ovarian cancer was diagnosed at stages II-IV in 54 women. 28 (51.9%) of these patients underwent standard surgery and 26 (48.1%) had extended surgery. More patients had complete/optimal debulking in the extended surgery group (84.6%) compared to the standard surgery group (71.4%) for advanced disease (p = 0.495). Grade 3/4 adverse events were recorded in one case in the standard surgery group and eight cases in the extended surgery group. There was no difference in median interval between surgery and commencement of chemotherapy between the two groups (p = 0.79). There were no cases of post-operative mortality. Discussion(s): Implementation of extended surgical procedures for advanced EOC at a tertiary referral centre is feasible with a high rate of complete and optimal debulking and an acceptable level of morbidity.

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Introduction: Residual disease following debulking surgery for advanced epithelial ovarian cancer (EOC) is an important prognostic factor. We aimed to audit the surgical outcomes following standard and extended surgical debulking procedures carried out for management of ovarian cancer. Our secondary aim was to assess the feasibility of introducing extended procedures in a single Australian gynaecological oncology centre. Method(s): A prospective audit of outcomes for patients undergoing surgical debulking for epithelial ovarian cancer was carried out over a 24-month period at The Royal Women's Hospital, Melbourne. The outcome data for standard and extended surgical procedures was analysed for women diagnosed with stage II through to stage IV ovarian cancer. Result(s): Ovarian cancer was diagnosed at stages II-IV in 54 women. 28 (51.9%) of these patients underwent standard surgery and 26 (48.1%) had extended surgery. More patients had complete/optimal debulking in the extended surgery group (84.6%) compared to the standard surgery group (71.4%) for advanced disease (p = 0.495). Grade 3/4 adverse events were recorded in one case in the standard surgery group and eight cases in the extended surgery group. There was no difference in median interval between surgery and commencement of chemotherapy between the two groups (p = 0.79). There were no cases of post-operative mortality. Discussion(s): Implementation of extended surgical procedures for advanced EOC at a tertiary referral centre is feasible with a high rate of complete and optimal debulking and an acceptable level of morbidity.

BACKGROUND: Endometrial cancer is the most common invasive gynaecological cancer in Australia. Despite the fact that review after treatment of early endometrial cancer has not been shown to detect recurrent disease, practice at several hospitals brings women back for specialist hospital review for 5 years after definitive cancer surgery. AIM: Implement an improved model of follow-up care following hospital treatment for early endometrial cancer. EVALUATION METHODS: Quantitative and qualitative. RESULTS: Seventy-three of the eligible 81 women undertook the model of care. All general practitioners (GPs) agreed to follow-up care. Thirty-one women (42%) and 37 GPs (51%) returned surveys. All women found the nurse consultation very useful or useful with 77% reporting making lifestyle changes and 87% found the GP consultation very useful or useful with 72% reporting making lifestyle changes. Eighty-nine percent of GPs found the care plan useful, 94% set up patient recall systems, 79% used the care plan to develop their own care plan, 100% felt confident in providing follow-up care with 91% reporting the care plan and hospital processes improved their confidence. Comparison with the pre-cohort women showed: higher rates of communication at various care points to GPs (from P < 0.001); more referrals (P < 0.001); and a projected decrease of nine hospital doctor appointments per patient. DISCUSSION: With an increasing number of people surviving cancer, in order to address holistic health needs and maintain tertiary service capacity, general practice will be required to provide more follow-up care. Our model demonstrates an acceptable and quality mechanism for this to occur.

INTRODUCTION: Adenocarcinoma in situ (AIS) of the uterine cervix is the precursor to invasive endocervical adenocarcinoma. An excisional biopsy such as a cold knife cone biopsy (CKC) should be performed to exclude invasive adenocarcinoma. Loop electrosurgical excision procedure (LEEP) is an alternative modality to CKC but is controversial in AIS. There is a perception that there is a greater likelihood of incomplete excision of AIS with LEEP because the depth of excised tissue tends to be smaller and the tissue margins may show thermal artefact which can interfere with pathology assessment. In the USA, guidelines recommend that any treatment modality can be used to excise AIS, provided that the specimen remains intact with interpretable margins. However, there are no high-quality studies comparing LEEP with CKC and well-designed prospective studies are needed. If such a study were to show that LEEP was non-inferior to CKC for the outcomes of post-treatment persistence, recurrence and adenocarcinoma, LEEP could be recommended as an appropriate treatment option for AIS in selected patients. This would benefit women because, unlike CKC, LEEP does not require general anaesthesia and may be associated with reduced morbidity. METHODS AND ANALYSIS: The proposed exploratory study is a parallel group trial with an allocation ratio of 2:1 in favour of the intervention (LEEP: CKC). Participants are women aged ≥18 to ≤45 years diagnosed with AIS on cervical screening and/or colposcopically directed biopsy in Australia and New Zealand, who are to receive excisional treatment in a tertiary level centre. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the St John of God Healthcare Human Research Ethics Committee (reference number #1137). Results from the study will be presented at conferences and published in a peer-reviewed scientific journal. REGISTRATION: ANZCTR registration number ACTRN12617000132347 https://www.anzctr.org.au/Trial/Registration/Tri

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4 weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the

High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.