The Christie School of Oncology: Christie Research Publications Repository
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The germline and somatic origins of prostate cancer heterogeneity
No full textThis study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations
Microbiome analysis of 940 lung cancers in never-smokers reveals lack of clinically relevant associations
No full textIn spite of the growing interest in the microbiome in human cancer, there are currently only small-scale lung cancer microbiome studies conducted directly on tissue. As part of the Sherlock-Lung study, we studied the microbiomes of 940 lung cancers (4090 samples) in never smokers (LCINS) directly from lung tissue using three data types: 16S rRNA gene sequencing (16S), whole-genome sequencing (WGS) with paired blood, and RNA-seq. We observe very low biomass and few microbiome associations in LCINS using 16S and WGS tissue. Using RNA-seq, we observe more total microbial reads, and decreased relative abundance of several commensal bacteria at the genus and species levels in tumors relative to paired normal lung tissue. Among all datasets, we see no consistent associations between the lung tissue microbiome, or circulating bacterial DNA, and any available demographic and clinical features, including age, sex, genetic ancestry, second-hand tobacco smoking exposure, LCINS histology, stage, and overall survival. We also observe no microbiome associations with any human genomic alterations within the same samples. Every null result should be interpreted with caution given the possibility of future methodological breakthroughs. However, all together, using multiple data types in nearly 1000 patients, we find no substantive role for the lung cancer microbiome in treatment-na & iuml;ve LCINS
Evaluation of the impact of breast radiation therapy on quality of life requires appropriate instruments at relevant timepoints
No full textAutomated contouring and radiotherapy treatment planning of spine metastases using atlas-based auto-segmentation and knowledge-based planning approaches
No full textOBJECTIVES: Spine metastases are routinely treated with conventional external beam radiotherapy (cEBRT) where there is no delineation of target volumes (TV) or organs at risk (OAR), or attempt to optimize dose distribution. Automated contouring and treatment planning could facilitate conformal planning of spine metastases in the clinical environment. METHODS: Atlas-based auto-segmentation (ABAS) using SmartSegmentation was developed for delineation of thoracic and lumbar vertebrae, and OAR; knowledge-based planning (KBP) using RapidPlan was developed for conformal volumetric-modulated arc therapy treatment planning. Plans produced using this automated approach were compared to the equivalent cEBRT plans. RESULTS: TV coverage for automated ABAS/KBP conformal treatment plans were superior to cEBRT. The planning target volume (PTV) Dmean = 7.86 ± 0.16 Gy, Dmin = 3.46 ± 1.79 Gy, Dmax = 8.56 ± 0.05 Gy compared to PTV Dmean = 7.78 ± 0.24 Gy, Dmin = 1.83 ± 1.08 Gy, Dmax = 10.46 ± 0.41 Gy, with homogeneity index and conformity index 0.236 ± 0.215 and 1.201 ± 0.121, respectively, for ABAS/KBP compared to 0.508 ± 0.137 and 1.789 ± 0.437 for cEBRT. Dose to dose-limiting spinal cord and cauda equina was reduced in ABAS/KBP plans, with Dmax of 7.91 ± 0.16 Gy and 7.94 ± 0.13 Gy, respectively, compared to 8.67 ± 0.13 Gy and 8.90 ± 0.16 Gy for cEBRT. CONCLUSIONS: Automated conformal treatment planning was achievable, with improved sparing of dose-limiting OAR and superior plan quality compared to cEBRT. Automation of the planning process makes this feasible for implementation in the clinical environment. ADVANCES IN KNOWLEDGE: Automated contouring and treatment planning are feasible in the clinical environment using this approach. We describe the first use of ABAS and KBP for radiotherapy treatment of spine metastases that would allow patients to receive conformal as opposed to the widely used approach of cEBRT
Rare pathogenic structural variants show potential to enhance prostate cancer germline testing for African men
No full textProstate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for Africans. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising clinico-methodologically matched deep-sequenced whole-genome data for 113 African versus 57 European PCa patients, we interrogate 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identify 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair MLH1 and BARD1 and tumour suppressors FOXP1, WASF1 and RB1. Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African-associated disparity
An international and multidisciplinary EORTC survey on resectability of stage III non-small cell lung cancer
No full textINTRODUCTION: The EORTC-Lung Cancer Group initiated a Delphi consensus process to establish a consensual definition of resectable stage III non-small cell lung cancer (NSCLC) for the use in clinical trials, including a systematic review, survey, and review of clinical cases. Here, the survey results are presented, aimed to identify areas of controversy. METHODS: A survey was distributed among the members of six international organizations related to lung cancer. Respondents were interrogated on the resectability (not limited to the technical resectability) of all stage III NSCLC TNM-subsets (8th edition). Additionally, four N2-subdivisions were used. The threshold for agreement was 75%. Answers with 'yes' were considered upfront resectable. 'Yes' and 'maybe' were grouped together and considered potentially resectable. Answers with 'no' were considered unresectable. RESULTS: 558 responses were collected from thoracic surgeons (38%), radiation oncologists (27%), medical oncologists (17%), pulmonologists (14%), and others (4%). Most worked in a specialized center (80%), had >5 years of experience (80%), were European (76%), male (73%), and treated >20 patients with stage III NSCLC annually (77%). Agreement was found in 26 (70%) out of 37 TNM-subsets: 9 (24%) were considered (potentially) resectable, and 17 (46%) unresectable. There was no agreement for 11 (30%) TNM-subsets: smaller tumors with N2-multistation, larger tumors with N2-single station, and invasive T4-tumors with maximum N2-single station involvement. CONCLUSIONS: This international and multidisciplinary survey showed agreement on the resectability for the majority of stage III NSCLC TNM-subsets, but also identified several TNM-subsets for which no agreement was found
Development and implementation of a patient advisory group for novel research aiming to minimise facial asymmetry in children after radiotherapy
No full textDosimetric evaluation of two cardiac substructure segmentation approaches: walls versus chambers
No full textCombination Therapies in Locally Advanced and Metastatic Hormone-sensitive Prostate Cancer
No full textBACKGROUND AND OBJECTIVE: The treatment landscape for advanced prostate cancer has evolved significantly over the past decade. The introduction of docetaxel, androgen receptor pathway inhibitors (ARPIs), poly(ADP-ribose) polymerase inhibitors, and targeted radionuclides has redefined the treatment paradigm, with a focus now on early treatment intensification through combination therapies. This narrative collaborative review summarises the current evidence of combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC). METHODS: We conducted a literature search up to November 2024. Search terms included 'metastatic hormone-sensitive prostate cancer', 'metastatic castration-sensitive prostate cancer', 'locally advanced prostate cancer', 'combination', 'intensification', and 'de-escalation'. Articles were selected by the authors based on their scientific merit, clinical impact, and relevance to provide a summary of the evidence surrounding combination therapy in locally advanced prostate cancer and mHSPC. KEY FINDINGS AND LIMITATIONS: A doublet approach with an androgen deprivation therapy (ADT) backbone and an ARPI is now considered the standard treatment for mHSPC, with a triplet regimen incorporating docetaxel considered in select subgroups. Similar efforts to improve survival in the high-risk localised and locally advanced disease setting have led to several trials evaluating the benefit of combination therapy in addition to standard-of-care surgery or radiotherapy with ADT. Continued improvements in survival have turned the focus to optimising patient selection for treatment intensification and, in some cases, de-escalation, with the goal of reducing unnecessary overtreatment and minimising harm from long-term treatment toxicity. This is particularly important with the integration of prostate-specific membrane antigen positron emission tomography, which has led to the earlier detection of metastatic disease. CONCLUSIONS AND CLINICAL IMPLICATIONS: In select subgroups, early treatment intensification with combination therapy leads to improved survival, though it can be associated with long-term toxicity