Abstract 6613: Triple-negative breast cancer evolution and therapy response: Breast TRACERx
Authors: Ieva Usaite, Thomas B. Watkins, Olivia Lucas, Carlos Marínez-Ruiz, Francois Legrand, Constance Lamy, Marta Jimenez, Nusaïbah Ibrahimi, Stephan Michiels, Simone Zaccaria, Thibault de la Motte Rouge, Anthony Gonçalves, Jean-Yves Pierga, Monica Arnedos, Christophe Le Tourneau, Fabrice André, Mariam Jamal-Hanjani, Nnennaya Kanu, Charles Swanton
Journal: Cancer Research (2025)

Abstract Introduction: Breast cancer is the most commonly diagnosed cancer and the main cause of cancer-related mortality in women worldwide. Despite advances in our knowledge of the underlying genetic alterations and improvements in treatment, 25-30% of patients with early breast cancers still relapse with distant metastatic disease. Presenting a clear unmet clinical need to improve our understanding of breast cancer evolution, and the drivers of genomic instability in primary breast cancers. Methodology: We have analyzed multi-region sequencing data from 280 treatment-naïve primary breast cancer tumor regions sampled from 139 patients with triple-negative breast cancer (TNBC) prospectively enrolled into the Breast TRACERx and SCANDARE studies. Here we aim to decipher breast cancer evolution and address the primary study endpoints: determining the relationship between intratumor heterogeneity and clinical outcomes. Results: In TNBC, 74% of tumors demonstrated a whole-genome doubling event (WGD), whereby 77% of these events were clonal, suggesting that whole-genome duplication is primarily an early event in TNBC evolution. Additionally, 27% of these events where subclonal, and 8% of cases harboured a clonal followed by a second subclonal WGD event. Defects in homologous recombination repair (HRD) occur early in TNBC evolution, which may be driven by the truncal selection of BRCA1 mutations. Furthermore, HRD levels are significantly higher in BRCA-deficient TNBC tumours, here 17% of TNBC tumours demonstrated either a germline or tumour driver mutation in BRCA in addition to an LOH event in the wild-type allele. BRCA-wild-type tumours were significantly enriched for clonal WGD events, here suggesting increased chromosomal instability early in evolution within these tumours. BRCA-wild-type tumours demonstrated selection for mutation in tumour suppressor genes such as RB1, which were not selected for in BRCA-deficient tumours, suggest alternative routes to generating chromosomal instability (CIN) compared to HRD in BRCA-deficient tumours. Amplification of CCND1 were observed across both BRCA -wild-type and -deficient tumors, however the timing of these events suggests additional CIN in BRCA-deficient tumors later during tumor evolution, with amplifications occurring subclonally, and clonal amplifications in BRCA-wild-type tumors. Parallel evolutionary events occur in 22% of TNBC tumors, demonstrating loss of genes such as B2M and LILR receptor family genes, which have been implicated in cancer immune evasion. TNBC tumors further demonstrated additional patterns of immune evasion through parallel gains of genes such as CD274 and PDCD1LG2, suggesting selection for an immuno-suppressed phenotype. Conclusions: These data demonstrate the evolutionary landscape of primary TNBC tumors and highlight the magnitude of events driving chromosomal instability in TNBC. Citation Format: Ieva Usaite, Thomas B. Watkins, Olivia Lucas, Carlos Marínez-Ruiz, Francois Legrand, Constance Lamy, Marta Jimenez, Nusaïbah Ibrahimi, Stephan Michiels, Simone Zaccaria, Thibault de la Motte Rouge, Anthony Gonçalves, Jean-Yves Pierga, Monica Arnedos, Christophe Le Tourneau, Fabrice André, Mariam Jamal-Hanjani, Nnennaya Kanu, Charles Swanton. Triple-negative breast cancer evolution and therapy response: Breast TRACERx [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6613.