ORCID Profile
0000-0002-2122-2003
Current Organisations
Maastricht University
,
Brigham and Women's Hospital
,
Dana Farber Cancer Institute
,
Harvard Medical School
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Publisher: Springer Science and Business Media LLC
Date: 12-04-2023
DOI: 10.1038/S41586-023-05729-X
Abstract: Metastatic disease is responsible for the majority of cancer-related deaths 1 . We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases erged early, before the last clonal sweep in the primary tumour, and early ergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic ergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour s ling resulted in 83% of late ergence cases being misclassified as early, highlighting the importance of extensive primary tumour s ling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early erging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.
Publisher: Springer Science and Business Media LLC
Date: 04-2023
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.RADONC.2018.10.027
Abstract: Refinement of radiomic results and methodologies is required to ensure progression of the field. In this work, we establish a set of safeguards designed to improve and support current radiomic methodologies through detailed analysis of a radiomic signature. A radiomic model (MW2018) was fitted and externally validated using features extracted from previously reported lung and head and neck (H&N) cancer datasets using gross-tumour-volume contours, as well as from images with randomly permuted voxel index values i.e. images without meaningful texture. To determine MW2018's added benefit, the prognostic accuracy of tumour volume alone was calculated as a baseline. MW2018 had an external validation concordance index (c-index) of 0.64. However, a similar performance was achieved using features extracted from images with randomized signal intensities (c-index = 0.64 and 0.60 for H&N and lung, respectively). Tumour volume had a c-index = 0.64 and correlated strongly with three of the four model features. It was determined that the signature was a surrogate for tumour volume and that intensity and texture values were not pertinent for prognostication. Our experiments reveal vulnerabilities in radiomic signature development processes and suggest safeguards that can be used to refine methodologies, and ensure productive radiomic development using objective and independent features.
Publisher: Springer Science and Business Media LLC
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 05-04-2023
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2022
DOI: 10.1200/JCO.2022.40.6_SUPPL.159
Abstract: 159 Background: Androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer, but treatment tolerance is variable. Prior work has demonstrated the correlation between body composition (BC) and clinical outcomes in prostate cancer. Specifically, high visceral fat density has been associated with fat depletion phenomenon and poor prognosis in prostate cancer. However, the interaction of long-term ADT tolerance and body fat composition is less studied. We investigated if BC could predict for outcomes and treatment tolerance in patients with high-risk prostate cancer with planned ADT. Methods: An IRB-approved retrospective review was conducted at a tertiary care center of patients with high-risk (T3a or prostate-specific antigen [PSA] 20 ng/mL or Gleason score 8-10 or N/M+) prostate cancer who received definitive external beam radiation therapy (RT) from 2006 to 2013. A previously validated, fully automated deep learning BC analysis pipeline was performed on RT simulation scans to compute BC at the top of L3 slice, including total skeletal muscle (SM), subcutaneous fat (SF), and visceral fat (VF) surface area (cm 2 ) and average CT density (Hounsfield Units (HU)) results were manually validated by experts. BC was stratified by median value. Adult Comorbidity Evaluation-27 (ACE) was used to measure co-morbidity. Long-term ADT was defined as 2 years, tolerance was defined as unplanned discontinuation 3-month difference in intended/actual duration of ADT. The association between BC markers, oncologic outcomes, and treatment tolerance was analyzed using univariable Cox regression and chi-square test. Results: A total of 207 men were analyzed with a median follow up time of 10.8 years (range 0.7-17.3y). Median age was 65 (range 42-83), with 61 (29.4%) patients classified as high-risk, 134 (64.7%) very-high-risk, and 12 (5.8%) N+/M+ at diagnosis. High VF density was associated with worse overall survival (OS) (HR 1.71, 95%CI 1.09-2.68, p = 0.0204) but not cancer-specific survival (CSS) (p = 0.08) or biochemical-relapse free survival (bRFS) (p = 0.97). SM and SF density, as well as area of SM, VF, SF, and total fat were not associated with outcomes. N/M stage was associated with bRFS (p = 0.0139), and N/M stage (p = 0.0101) and higher ACE score (p = 0.0218) were associated with OS. Among 88 (42.5%) patients planned for long-term ADT use, 24 (27%) patients discontinued ADT prior to duration, of which 15 (17%) patients discontinued due to toxicity. BC markers did not correlate with tolerance to long-term ADT (p = 0.17). Tolerance to long-term ADT was not associated with bRFS or OS. Conclusions: High VF density is associated with worse OS but not bRFS or CSS in high-risk prostate cancer patients, and not associated with adipose area or ADT tolerance. VF density may be a biomarker of underlying metabolic health in prostate cancer patients independent of disease, and a potential area of intervention.
Publisher: Informa UK Limited
Date: 12-08-2015
Publisher: MDPI AG
Date: 14-05-2021
Abstract: Locally advanced non-small cell lung cancer patients represent around one third of newly diagnosed lung cancer patients. There remains a large unmet need to find treatment strategies that can improve the survival of these patients while minimizing therapeutical side effects. Increasing the availability of patients’ data (imaging, electronic health records, patients’ reported outcomes, and genomics) will enable the application of AI algorithms to improve therapy selections. In this review, we discuss how artificial intelligence (AI) can be integral to improving clinical decision support systems. To realize this, a roadmap for AI must be defined. We define six milestones involving a broad spectrum of stakeholders, from physicians to patients, that we feel are necessary for an optimal transition of AI into the clinic.
Publisher: Springer Science and Business Media LLC
Date: 04-2023
Publisher: Springer Science and Business Media LLC
Date: 13-04-2023
Publisher: Springer Science and Business Media LLC
Date: 12-04-2023
DOI: 10.1038/S41586-023-05771-9
Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS) 1,2 . Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive 1,2 . Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma 3 . We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are lified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Publisher: Radiological Society of North America (RSNA)
Date: 05-2022
DOI: 10.1148/RYAI.210285
Publisher: Springer Science and Business Media LLC
Date: 22-05-2020
DOI: 10.1038/S43018-020-0066-Y
Abstract: Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2023
DOI: 10.1038/S41586-023-05783-5
Abstract: Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions s led at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS . We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET , ROS1 , ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Springer Science and Business Media LLC
Date: 27-05-2020
No related grants have been discovered for Hugo Aerts.