112MO - Triple-negative breast cancer evolution and therapy response: Breast TRACERx

Background

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. Hence, there is a clear unmet clinical need to improve our understanding of breast cancer evolution, and the drivers of genomic instability in primary breast cancers.

Methods

To this end, we have analysed multi-region sequencing data from 280 treatment-naïve primary breast cancer tumour 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, clonal whole-genome doubling (WGD) occurs in ∼77% of TNBC tumours, suggesting that whole-genome duplication is primarily an early event in TNBC evolution. Furthermore, in 27% of tumours we observe subclonal WGD, 8% of these cases harboured a clonal WGD event that occurred prior. We observe that defects in homologous recombination repair (HRD) occur early in TNBC evolution, which may be driven by the truncal selection of BRCA1 mutations. Furthermore, HRD were significantly higher in BRCA mutated TNBC tumours, here 17% of TNBC tumours demonstrated either germline or tumour driver mutations in BRCA in addition to an LOH event in the wild-type allele. BRCA deficient tumours were significantly enriched for clonal WGD events, here suggesting increased chromosomal instability early in tumour evolution for BRCA mutated tumours. However, BRCA wild-type tumours, demonstrated a significant enrichment for subclonal WGD events, which may be driving branched evolution in this subset of tumours. Parallel evolutionary events occur in 20% of TNBC tumours, demonstrating loss of genes such as FAT1 and B2M recurring in separate subclones of the same tumour on two or more occasions.

Conclusions

These data demonstrate the evolutionary landscape of primary TNBC tumours and highlight the magnitude of events driving chromosomal instability in TNBC.

Editorial acknowledgement

Clinical trial identification

Breast TRACERx: NCT03077776; SCANDARE: NCT03017573.

Legal entity responsible for the study

The authors.

Funding

BCRF, CRUK, Unicancer, National Cancer Institute.

Disclosure

S. Michiels: Financial Interests, Personal, Other, DSMB member: Servier, Biophytis, Yuhan, Iqvia, Kedrion; Financial Interests, Personal, Advisory Board, Study Scientific Committee member: Roche. T. De La Motte Rouge: Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, GSK, Clovis Oncology, Roche, MSD, Mylan, Tesaro, Gilead, Sanofi, Seagen; Financial Interests, Personal, Invited Speaker: Novartis, MSD; Financial Interests, Institutional, Research Grant: Novartis, Pfizer, MSD, Seagen; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, GSK, MSD, Pfizer, Netris Pharma; Non-Financial Interests, Personal, Advisory Role: French National Cancer Institute, Unicancer; Non-Financial Interests, Personal, Principal Investigator: Arcagy, Unicancer; Non-Financial Interests, Personal, Other, Co-Principal Investigator: Unicancer; Non-Financial Interests, Personal, Other, Partnership Using a Natera Solution for a Clinical Trial Funded by Academic Grant: Natera. A. Gonçalves: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, MSD, Innate Pharma, Parexel, Gilead; Financial Interests, Institutional, Invited Speaker: Novartis, Roche, MSD, AstraZeneca, Daiichi Sankyo; Other, Personal, Other, Travel Accommodation Meeting Registration: Mylan; Other, Personal, Other, Travel Accommodation Meeting Registration: Novartis; Other, Personal, Other, Travel, Accommodation, Meeting Registration: Roche, Menarini. M. Arnedos: Financial Interests, Institutional, Research Grant: Merrimack; Non-Financial Interests, Personal, Advisory Board: Merrimack. C. Le Tourneau: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck Serono, Nanobiotix, Roche, Rakuten, Seattle Genetics, GSK, Celgene, ALX Oncology, Exscientia. F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi Sankyo, Guardant Health, Owkin. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Cancer cachexia research advisory board: Pfizer; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. N. Kanu: Financial Interests, Institutional, Research Grant: AstraZeneca, The Rosetrees Trust, CRUK. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, Ad Board - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Advisory Board, Scientific Advisory Board and Stock options from September 2023: Relay Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: SAGA Diagnostics; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock options: Relay Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.