Presentation
Organizer: IRB BioMed Seminars
Date: Friday, 14 July 2023 at 12 PM
Place: Auditorium, PCB
Speaker: Dr. Mariam Jamal-Hanjani, PhD. Group Leader - Cancer Metastasis Laboratory - CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute | London, United Kingdom
Title: "Insights into lung cancer evolution and metastases in TRACERx and PEACE "
Host: Dr. Salvador Aznar Benitah - Group Leader - Stem Cells and Cancer - Aging and Metabolism Programme Coordinator - IRB Barcelona
Abstract:
TRACERx is a prospective longitudinal cancer evolution programme which investigates the relationship between intratumour heterogeneity and clinical outcomes in non-small cell lung cancer (NSCLC). Early findings from the study demonstrated the prognostic relevance of increased chromosomal, as opposed to mutational, heterogeneity, as well as the clinical utility of circulating tumour DNA (ctDNA) in tracking cancer evolution. Heterogeneity in gene expression was found to identify a cohort of patients with early stage I NSCLC with high risk disease, suggesting a role for adjuvant therapy in patients who would otherwise not receive it. Tumour immune evasion was prevalent and prognostically relevant in treatment-naïve NSCLCs, and neoantigen heterogeneity and clonality were adopted to establish early phase studies in adoptive T cell therapies.
In the current cohort of 421 patients with extended follow up, matched primary and metastatic analysis has led to further findings in relation to impact of cancer evolution on clinical practice and patient outcomes. Large dominant subclones in primary tumours were associated with positive subclonal selection, and mutations in specific genes were found to be under significant subclonal, and not clonal, selection. Subclonal genome doubling was identified in 20% of tumours and multiple genome doubling events were identified in 10% of tumours. Patients with tumours containing large recent subclonal expansions had significantly shorter disease-free survival (DFS), and as previously demonstrated, chromosomal instability was associated with poor outcomes, particularly, extrathoracic disease relapse.
Metastatic relapse was found to occur late in tumour evolution (late divergence; after the last clonal sweep in the primary tumour) in 75% of tumours, and early divergence (25% of tumours) was found to occur at predicted tumour volumes below the threshold for further investigation using radiological imaging, suggesting potential implications for clinical intervention. Metastasis-seeding subclones in primary tumours were subject to subclonal expansion, likely reflective of the acquisition of subclonal driver mutations and somatic copy number alterations. ctDNA analyses in this larger cohort demonstrated the value of ctDNA to predict the likelihood of future relapse, but also its use in tracking tumour growth dynamics and emergence of relapse. By integrating histological growth patterns with tumour genomics in lung adenocarcinoma, predominantly high-grade patterns were associated with increased chromosomal complexity, subclonal somatic copy number alterations and loss of heterozygosity. Specific copy number alterations were found to be associated with high- and low-grade patterns, suggesting distinct evolutionary trajectories according to growth patterns. The presence of specific growth patterns combined with other histological features and ctDNA identified patients with an increased risk of extrathoracic recurrence, suggesting a potential role for both morphological and genomic subtyping to aid risk stratification
IRB BioMed Seminar
IMPORTANT: For attendees outside the PCB community you must register at least 24h before the seminar.
In collaboration with:
