Sena Teixeira Mendes, Larissa; (2024) Proliferation, inflammation and morphological features of hormone sensitive clinically advanced prostate cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Most newly diagnosed prostate cancers are indolent neoplasms that can be managed conservatively but a subset of patients will present with locally advanced or metastatic disease at diagnosis that is often lethal. However, among these latter patients, there is marked heterogeneity of outcome. Current tools for risk stratification (prostate specific antigen, Gleason score, tumour, nodal and metastatic stage) do not grant the granularity needed to tackle this long-term variability in outcome prediction. New biomarkers to better predict relapse and death are essential to distinguish patients who can avoid overtreatment from those more likely to benefit from treatment intensification. This PhD was embedded in the STRATOSPHERE consortium, designed to evaluate biomarkers on tumour tissue collected from a large cohort of patients recruited to the STAMPEDE trial. Clinical samples consisted of diagnostic formalin-fixed paraffin-embedded needle core biopsies or trans-urethral resections of the prostate. This thesis focuses fundamental aspects involved in carcinogenesis: morphological features, proliferation and inflammation. These features were characterised and then tested for associations with prospectively-collected clinical outcomes data recorded in the STAMPEDE trial, using multi-variable models adjusted for clinical variables (PSA levels, Gleason score, T-stage and metastatic status). Firstly, I evaluated the impact of cribriform architecture in clinically-advanced prostate cancer (N=481). Cribriform architecture associated with earlier biochemical failure (adjusted hazard ration [aHR]: 1.10, 95%CI: 1.02-1.18; p=0.011) and disease progression (aHR: 1.09, 95%CI: 1.00-1.18; p=0.055) but I found no evidence of an association with survival (p:0.307). Then I assessed a proliferation marker (Ki-67) as a prognostic and predictive biomarker in high-risk, non-metastatic patients randomised between standard-of-care and abiraterone ± enzalutamide (N=1145). Patients with highly-proliferative tumours were more likely to be node-positive and die from prostate cancer (aHR: 1.20, 95%CI: 1.05-1.38; p=0.012). Finally, I investigated the association between tumour inflammation and outcomes. Prominent tumour-associated inflammation (>15%) was more commonly seen in patients with high-grade morphology (p=7.263e 13) and presence of metastasis at diagnosis (p=7.334e 08). In non-metastatic patients (N=1370) high TILs was associated with a worse failure-free survival only (aHR: 1.09 [95%CI: 1.02-1.17]; p=0.010) but I did not find evidence of an association with worse survival. In metastatic patients (N=886) high TILs associated negatively with all outcomes tested (overall survival: aHR: 1.11 [95%CI: 1.04-1.19]; p=0.001). Further evaluation using transcriptome-wide analysis identified a sub group of non-metastatic patients with high interferon signalling who had worse outcomes in non metastatic disease. In conclusion, this thesis evaluated the impact of morphological, proliferative and inflammation features on the outcomes of clinically-advanced prostate cancer patients. It identifies hypothesis-generating biological inferences and proposes clinically-implementable biomarkers that could be integrated into clinical management.

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