Tracking tumour evolution through adjuvant therapy in Triple Negative Breast Cancer
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Date
2024-05-20ICR Author
Author
Turner N
Coakley, M
Turner, N
Type
Thesis or Dissertation
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Abstract
Relapsed Triple Negative Breast Cancer (TNBC) carries a poor prognosis. Improved understanding of the molecular features of early disease, and the evolution of TNBC from early to relapsed disease, is likely to be key to developing therapies to overcome treatment resistance.
c-TRAK TN recruited 161 patients with early-stage moderate-high risk TNBC into prospective ctDNA surveillance for Molecular Residual Disease (MRD) with digital PCR (dPCR) assays after completion of curative treatment. A subset of patients who relapsed provided a relapse biopsy. Tissue samples were whole exome sequenced (WES) and relapse plasma DNA was subject to error-corrected WES. Digitalised pathology and multiplexed immunofluorescence characterised the immune microenvironment of early tumour tissue samples. Clonal evolution analysis was performed in patients with a minimum of two samples which completed WES, where MRD was detected, or with paired samples before and after neoadjuvant chemotherapy. Individual clones were tracked through plasma samples taken every three months from trial entry until relapse using ctDNA personalised sequencing assays.
The rate of germline pathogenic variants of BRCA1/BRCA2 in this cohort was lower than other published cohorts of TNBC. Neoadjuvant chemotherapy was associated with a loss of heterogeneity of the HLA alleles and a reduction in CD20+ cells. MRD was first detected by personalised sequencing assays in 47.9% of patients, 0% first detected by dPCR assays, and 52.1% with both assays simultaneously. Clonal structures were constructed for 56 patients. Subclones from the primary cancer frequently metastasised. Neoadjuvant chemotherapy provided a substantial evolutionary bottle neck, with subclones detected post neoadjuvant chemotherapy most likely to persist into the MRD and contribute to relapsed disease.
This is the largest and most detailed study of clonal evolution in triple negative breast cancer, and the first to investigate clonal evolution through MRD. Sub-clonal persistence poses a key therapeutic challenge in overcoming treatment resistance.
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Research team
Molecular Oncology
Language
eng
License start date
2024-05-20
Citation
2024
Publisher
Institute of Cancer Research (University Of London)