123P - Copy number from ulcWGS to predict TNBC molecular subtypes in the IBCSG 22-00 trial

Background

Triple-negative breast cancer (TNBC) is highly heterogeneous and traditionally classified into distinct molecular subtypes using RNA-seq data. This study proposes a novel approach to classifying TNBC molecular subtypes using copy number (CN) data derived from ultra-low-coverage whole-genome sequencing (ulcWGS), highlighting specific CN events.

Methods

We analyzed a cohort of 347 TNBC baseline FFPE samples using both RNA-seq and ulcWGS (<0.3× coverage) from the phase III IBCSG 22-00 trial. TNBC molecular subtypes were computed using RNA-seq data according to Bareche et al. CN were determined using ichorCNA. CN features were preselected using Wilcoxon tests (1 vs. the rest) for each subtype with an FDR < 0.05. For each molecular subtype, the preselected features served as inputs for an Elastic Net regression model with a nested cross-validation approach (outer loop k=5, inner loop k=5). The final model was validated on an external TNBC dataset (n=293) from the METABRIC study.

Results

For the basal-like subtype, the model achieved an AUC of 0.74 for testing and 0.82 for external validation. Predictive genes for this subtype included HMGB4 and CCN4, involved in migration and proliferation. For the luminal androgen receptor subtype, the testing AUC was 0.95 and the validation AUC was 0.89, with predictive genes, including ERBB2, at 17q12. Mesenchymal subtype had a testing AUC of 0.74 and a validation AUC of 0.71. Predictive genes for this subtype included SOX9, associated with epithelial mesenchymal transition. Mesenchymal stem-like subtype showed a testing AUC of 0.75, and a validation AUC of 0.75, predictive genes included NBL1 and PTEN. Immunomodulatory subtype achieved a testing AUC of 0.76 and a validation AUC of 0.58. Predictive genes for this subtype included ISG15 and OX40, involved in T-cell activation.

Conclusions

Our results suggest that the CN-based classification we have developed is a promising tool for predicting TNBC molecular subtypes. As ulcWGS is being studied in the context of liquid biopsy, this approach could potentially enable TNBC subtype prediction from circulating tumor DNA samples, thereby facilitating precision oncology with subtype-specific treatment strategies. These results warrant further evaluation in such setting.

Editorial acknowledgement

Clinical trial identification

NCT00022516.

Legal entity responsible for the study

International Breast Cancer Study Group.

Funding

FNRS (Televie).

Disclosure

R. Kammler: Non-Financial Interests, Personal, Leadership Role: European, Middle Eastern & African Society for Biopreservation and Biobanking (ESBB). M. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Personal, Leadership Role, Co-Chair Scientific Committee: International Breast Cancer Study Group. S. Loi: Financial Interests, Institutional, Advisory Board, Consultant: AstraZeneca, Novartis, Roche Genentech; Financial Interests, Institutional, Expert Testimony, Consultant: BMS; Financial Interests, Institutional, Expert Testimony, consultant: Daiichi Sankyo, Eli Lilly, Gilead Sciences, Merck; Financial Interests, Personal, Expert Testimony: Novartis, AstraZeneca, BMS, Domain Therapeutics; Financial Interests, Personal, Advisory Board: Amaroq Therapeutics, Mersana Therapeutics; Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, PUMA Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Seattle Genetics, Roche - Genentech; Non-Financial Interests, Personal, Advisory Role, Consultant (Non remunerated): Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Roche Genentech; Non-Financial Interests, Personal, Advisory Role, consultant (not compensated): Eli Lilly, Gilead Therapeutics. G. Viale: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, MSD Oncology, Pfizer; Financial Interests, Personal, Other, Consulting fees: Agilent; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Other, Educational webinar: Medscape; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting: Tolmar Pharmaceuticals; Financial Interests, Personal, Advisory Board: AstraZeneca, Tersera Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Financial Interests, Institutional, Funding, IBCSG translational research collaboration: Biotheranostics; Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb. E. Munzone: Financial Interests, Personal, Advisory Board: Eisai, Exact Science, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen. B. Thürlimann: Financial Interests, Personal, Expert Testimony: Gilead; Financial Interests, Personal, Advisory Board: Page Therapeutics; Financial Interests, Personal, Other, Expert Consultant Oncology: Innomedica; Financial Interests, Personal, Other, Expert Consultant: Enzym Management; Financial Interests, Personal, Invited Speaker, Med. education activities St. Gallen Breast Cancer Conference & Consensus: Medplus Honkong; Financial Interests, Personal, Member of Board of Directors: KFS, RTFCCR; Financial Interests, Personal, Other, Member QA Committee: Donna-sg; Financial Interests, Personal, Other, Speaker in med. education activities St. Gallen Breast Cancer Conference & Consensus: Medplus Honkong; Financial Interests, Personal, Other, Co-Chair: SG Oncology Conferences; Financial Interests, Personal, Stocks/Shares: Novartis, Roche, Merck, Alcon, Sandoz, Innomedica, Organon; Non-Financial Interests, Personal, Member of Board of Directors: Hospiz St. Gallen. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime Oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Personal, Advisory Board, Stock options: Signatur Biosciences. All other authors have declared no conflicts of interest.