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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. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

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.

Supplementary Methods

Supplementary Figures S1-S13

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.

Supplementary Tables S1-S11

Background Approximately 20% of women with gynecologic cancers are under age 40 and with delayed childbearing, women may be diagnosed before their first pregnancy. Although fertility preservation is a priority for many women, attitudes to conception have not previously been investigated in these patients or their partners. We explored attitudes to conception in partners and young women, following fertility preserving treatment for gynecologic cancers. Methods A total of 16 telephone interviews were conducted with a purposive sample of patients who had had an early stage gynecologic cancer or borderline ovarian tumor treated by fertility sparing surgery in Western Australia between January 1st, 2005 to December 31st, 2016. The interviews were audio recorded, transcribed and thematic analysis was conducted. Results Four main themes were identified: (i) Emotions at diagnosis and perception of information given; (ii) Discussions of fertility and factors affecting childbearing; (iii) Role of partners in decision making and relationship pressures; (iv) Decision for treatment and postoperative regrets. Conclusions Regret and relationship breakdown were commonly reported. Women need appropriate support including inviting their partners to attend clinic appointments and may need several appointments before treatment. Regret was commonly reported by women who opted for completion surgery. .

Objective Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. We aimed to compare margins status, specimen size and fragmentation after loop electrosurgical excision procedure (LEEP) and ‘cold knife cone biopsy’ (CKC). Methods The EXCISE Trial was an investigator-initiated, multicenter, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. Results Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p = 1·00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p = ·00). There were no differences in grade three complications (p = ·65). Conclusions LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardized protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted.

Background: Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. Two common procedures are loop electrosurgical excision procedure (LEEP) and ‘cold knife cone biopsy’ (CKC), yet no randomised trials have compared these modalities. We aimed to compare margins status, specimen size and fragmentation after LEEP and CKC. Methods: The EXCISE Trial was an investigator-initiated, multicentre, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC by computer generated random numbers. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. Findings: Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. All patients were included in the analysis. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p=1.00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p=.00). There were no differences in grade three complications (p=.65). Interpretation: LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardised protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted. Trial Registration: The study is registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR registration number ACTRN12617000132347). Funding Statement: Australia New Zealand Gynaecological Oncology Group [#FNR2016/03]. Declaration of Interests: PAC and CDHW have received honoraria from Seqirus unrelated to this work. All other authors declare no competing interests. Ethics Approval Statement: Ethical approval for the study was granted by the St John of God Healthcare Human Research Ethics Committee (Reference number #1137) and approvals were obtained at all participating sites.

93 Background: Efforts to increase physical activity in cancer survivors have typically been facility-based, and results have generally not been durable. Home-based interventions provide a more feasible option, and are likely to produce longer-lasting benefits. Wearable trackers present a novel opportunity for monitoring physical activity in a practical way. The Health Action Process Approach model suggests that strategies such as action-planning and overcoming barriers may be effective for transitioning individuals from intention to behavioural change. This trial aims to increase physical activity in cancer survivors at cardiovascular risk, by implementing a 24-week self-monitoring and action-planning intervention using Fitbits. Methods: Sixty-eight cancer survivors were recruited to participate in the trial. Eligibility criteria included: insufficiently physically active, presence of cardiovascular risk factors, and completion of active cancer treatment in the five years prior to recruitment. Trial assessments are performed at baseline, 12-weeks, and 24-weeks, and measure physical activity (using 7-day accelerometer data), BMI, blood pressure, physical activity attitudes, barriers and perceived outcomes. Participants were randomly allocated to treatment and control groups, following the baseline assessment. Each participant in the treatment group was given a Fitbit Alta to monitor activity for the 24-week trial, attended two 2-hour group sessions involving goal-setting and action-planning activities, and a follow-up phone call to ensure program adherence. Results: Data collection is currently underway. Data analysis will use the Group x Time interaction from a General Linear Mixed Model analysis. Conclusions: As the population of cancer survivors is largely inactive and at cardiovascular risk, interventions are warranted. Specifically, physical activity interventions that are feasible, have robust theoretical underpinnings, and suit the preferences of cancer survivors post-treatment, show promise as a long-term solution. Clinical trial information: 2617000131358.

A sizeable proportion of patients with seemingly early-stage ovarian cancer confined to the ovary will have their disease upstaged by lymphadenectomy, and this has obvious prognostic importance. Tumor grade and histology are important when considering this pattern of spread, but the evidence for a survival benefit for lymphadenectomy is scarce, there has been no uniform agreement on the extent of lymphadenectomy, and long-term follow-up of patients who have undergone systematic lymphadenectomy in this context is lacking including quality of life studies.