A three protein signature fails to externally validate as a biomarker to predict surgical outcome in high-grade epithelial ovarian cancer.

INTRODUCTION: For patients with advanced epithelial ovarian cancer, complete surgical cytoreduction remains the strongest predictor of outcome. However, identifying patients who are likely to benefit from such surgery remains elusive and to date few surgical outcome prediction tools have been validated. Here we attempted to externally validate a promising three protein signature, which had previously shown strong association with suboptimal surgical debulking (AUC 0.89, accuracy 92.8%), (Riester, M., et al., (2014)). METHODS: 238 high-grade epithelial ovarian cancer samples were collected from patients who participated in a large multicentre trial (ICON5). Samples were collected at the time of initial surgery and before randomisation. Surgical outcome data were collated from prospectively collected study records. Immunohistochemical scores were generated by two independent observers for the three proteins in the original signature (POSTN, CXCL14 and pSmad2/3). Predictive values were generated for individual and combination protein signatures. RESULTS: When assessed individually, none of the proteins showed any evidence of predictive affinity for suboptimal surgical outcome in our cohort (AUC POSTN 0.55, pSmad 2/3 0.53, CXCL 14 0.62). The combined signature again showed poor predictive ability with an AUC 0.58. CONCLUSIONS: Despite showing original promise, when this protein signature is applied to a large external cohort, it is unable to accurately predict surgical outcomes. This could be attributed to overfitting of the original model, or differences in surgical practice between cohorts.

The DNA damage response in advanced ovarian cancer: functional analysis combined with machine learning identifies signatures that correlate with chemotherapy sensitivity and patient outcome.

BACKGROUND: Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants. METHODS: We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods. RESULTS: DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS. CONCLUSIONS: Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

Factors determining ultra-short-term survival and the commencement of active treatment in high-grade serous ovarian cancer: a case comparison study.

BACKGROUND: Despite improvements in median survival some patients with advanced ovarian cancer die within 100 days of diagnosis; the reasons for which remain poorly understood. Here we investigate if ultra short-term survival can be explained by patient characteristics or treatment pathways. METHODS: A nested case comparison study was used to examine differences between patients with high grade serous ovarian/fallopian tube cancer who died within 100 days (n = 28) compared to a comparison group of patients matched for histology and including any survival greater than 100 days (n = 134). RESULTS: Cases and comparison patients had similar ages, BMI, ACE-27, deprivation indices, and distribution of disease on CT. There were no significant delays in time to diagnosis or treatment (p = 0.68) between the groups. However, cases had lower serum albumin, haemoglobin and higher platelet counts than matched comparison patients (p < 0.0001) and a worse performance score (P = 0.006). CONCLUSION: Patients who die rapidly after a diagnosis of ovarian cancer are only slightly older and have similar pre treatment frailty compared to patients whose survival approaches the median. However they do appear to undergo greater physiological compromise as a result of their disease.

Decision-Making in Gynaecological Oncology Multidisciplinary Team Meetings: A Cross-Sectional, Observational Study of Ovarian Cancer Cases.

INTRODUCTION: Multidisciplinary team (MDT) meetings are widely used across the UK to provide expert decisions and improve cancer outcomes. However, little is known about the underlying mechanisms of MDT decision-making. We investigated how decisions are made regarding the management of advanced ovarian cancer in gynaecological oncology MDT meetings. METHODS: A cross-sectional observational study was performed, focussing on 41/ 223 MDT case discussions across six hospitals. The validated MDT-MODe tool was adapted to increase relevance to gynaecological oncology. Case information and contributions from seven disciplines were rated on a five-point Likert scale. Spearman's correlation investigated relationships between factors and an exploratory factor analysis examined the underlying structure of MDT discussion. RESULTS: Forty-one MDT decisions were made for patients with FIGO Stage III/IV ovarian cancer. MDT case discussions were structured by four factors: "Clinical Presentation," "Patient Factors," "Chair's Direction" and "Input from Other Specialties." Nurses were often quiet but facilitated discussion of patient factors. Junior doctors were not involved in MDT decision-making. CONCLUSIONS: The decision-making process in MDT meetings is driven by four underlying factors, the most significant of which represents patient history, tumour markers, images and radiologist input. Patient factors were underrepresented, and nurses should be empowered to overcome this.