Kelechi Njoku

Quantitative SWATH-based proteomic profiling of urine for the identification of endometrial cancer biomarkers in symptomatic women

Abstract Background A non-invasive endometrial cancer detection tool that can accurately triage symptomatic women for definitive testing would improve patient care. Urine is an attractive biofluid for cancer detection due to its simplicity and ease of collection. The aim of this study was to identify urine-based proteomic signatures that can discriminate endometrial cancer patients from symptomatic controls. Methods This was a prospective case–control study of symptomatic post-menopausal women (50 cancers, 54 controls). Voided self-collected urine samples were processed for mass spectrometry and run using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning techniques were used to identify important discriminatory proteins, which were subsequently combined in multi-marker panels using logistic regression. Results The top discriminatory proteins individually showed moderate accuracy (AUC > 0.70) for endometrial cancer detection. However, algorithms combining the most discriminatory proteins performed well with AUCs > 0.90. The best performing diagnostic model was a 10-marker panel combining SPRR1B, CRNN, CALML3, TXN, FABP5, C1RL, MMP9, ECM1, S100A7 and CFI and predicted endometrial cancer with an AUC of 0.92 (0.96–0.97). Urine-based protein signatures showed good accuracy for the detection of early-stage cancers (AUC 0.92 (0.86–0.9)). Conclusion A patient-friendly, urine-based test could offer a non-invasive endometrial cancer detection tool in symptomatic women. Validation in a larger independent cohort is warranted.

Impact of socio‐economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis

ObjectiveTo assess the impact of socio‐economic deprivation on endometrial cancer survival.DesignSingle‐centre prospective database study.SettingNorth West England.PopulationWomen with endometrial cancer treated between 2010 and 2015.MethodsAreal‐level socio‐economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan–Meier estimation and multivariable Cox regression.Main outcome measuresOverall survival, cancer‐specific survival and patterns and rates of recurrence.ResultsA total of 539 women, with a median age of 66 years (interquartile range, IQR 56–73 years) and a body mass index (BMI) of 32 kg/m2 (IQR 26–39 kg/m2), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55–72 years) and more obese (median 34 kg/m2, IQR 28–42 kg/m2) than women in the least deprived group (median age 68 years, IQR 60–74 years; BMI 29 kg/m2, IQR 25–36 kg/m2; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two‐fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07–3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77–3.04, P = 0.221) increase in cancer‐specific mortality compared with women in the least deprived group. There were no differences in overall survival.ConclusionsWe found that socio‐economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors.Tweetable abstractSocio‐economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England.

Impact of pre-treatment prognostic nutritional index and the haemoglobin, albumin, lymphocyte and platelet (HALP) score on endometrial cancer survival: A prospective database analysis

Purpose The Onodera’s prognostic nutritional index (PNI) and the haemoglobin, albumin, lymphocyte and platelet (HALP) score are immune-nutritional indices that correlate with survival outcomes in several adult solid malignancies. The aim of this study was to investigate whether PNI and HALP are associated with survival outcomes in endometrial cancer. Patients and methods Women undergoing management for endometrial cancer were recruited to a single centre prospective cohort study. Pre-treatment PNI and HALP scores were computed for study participants and analysed as continuous variables and by selecting cut-off values based on previous publications. Both parameters were analysed in relation to overall, endometrial cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox proportional regression. Results A total of 439 women, with a median age of 67 years (interquartile range (IQR), 58, 74) and BMI of 31kg/m2 (IQR 26, 37) were included in the analysis. Most had low-grade (63.3%), early-stage (84.4% stage I/II) endometrial cancer of endometrioid histological subtype (72.7%). Primary treatment was surgery in 98.2% of cases. Adjusted overall mortality hazard ratios for PNI and HALP as continuous variables were 0.97(95%CI 0.94–1.00, p = 0.136) and 0.99(95%CI 0.98–1.01, p = 0.368), respectively. Women with pre-treatment PNI ≥45 had a 45% decrease in both overall (adjusted HR = 0.55, 95% CI 0.33–0.92, p = 0.022) and cancer-specific mortality risk (adjusted HR = 0.55, 95%CI 0.30–0.99, p = 0.048) compared to those with PNI <45. There was no evidence for an effect of PNI on recurrence free survival. HALP scores were associated with adverse clinico-pathologic factors, but not overall, cancer-specific or recurrence-free survival in the multivariable analysis. Conclusion PNI is an independent prognostic factor in endometrial cancer and has the potential to refine pre-operative risk assessment.

Detection of endometrial cancer in cervico-vaginal fluid and blood plasma: leveraging proteomics and machine learning for biomarker discovery

The anatomical continuity between the uterine cavity and the lower genital tract allows for the exploitation of uterine-derived biomaterial in cervico-vaginal fluid for endometrial cancer detection based on non-invasive sampling methodologies. Plasma is an attractive biofluid for cancer detection due to its simplicity and ease of collection. In this biomarker discovery study, we aimed to identify proteomic signatures that accurately discriminate endometrial cancer from controls in cervico-vaginal fluid and blood plasma. Blood plasma and Delphi Screener-collected cervico-vaginal fluid samples were acquired from symptomatic post-menopausal women with (n = 53) and without (n = 65) endometrial cancer. Digitised proteomic maps were derived for each sample using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning was employed to identify the most discriminatory proteins. The best diagnostic model was determined based on accuracy and model parsimony. A protein signature derived from cervico-vaginal fluid more accurately discriminated cancer from control samples than one derived from plasma. A 5-biomarker panel of cervico-vaginal fluid derived proteins (HPT, LG3BP, FGA, LY6D and IGHM) predicted endometrial cancer with an AUC of 0.95 (0.91-0.98), sensitivity of 91% (83%-98%), and specificity of 86% (78%-95%). By contrast, a 3-marker panel of plasma proteins (APOD, PSMA7 and HPT) predicted endometrial cancer with an AUC of 0.87 (0.81-0.93), sensitivity of 75% (64%-86%), and specificity of 84% (75%-93%). The parsimonious model AUC values for detection of stage I endometrial cancer in cervico-vaginal fluid and blood plasma were 0.92 (0.87-0.97) and 0.88 (0.82-0.95) respectively. Here, we leveraged the natural shed of endometrial tumours to potentially develop an innovative approach to endometrial cancer detection. We show proof of principle that endometrial cancers secrete unique protein signatures that can enable cancer detection via cervico-vaginal fluid assays. Confirmation in a larger independent cohort is warranted. Cancer Research UK, Blood Cancer UK, National Institute for Health Research.