Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial
In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent. Additionally, we validate the biological profiles of the subtypes and explore their prognostic/predictive value in external cohorts, namely the NeoALTTO trial (NCT00553358), SCAN-B (NCT02306096), I-SPY2 (NCT01042379), METABRIC and TCGA. Immune-enriched tumors present better survival outcomes, in contrast to mesenchymal/stroma-enriched and proliferative/metabolic-enriched tumors, while luminal and ERBB2-dependent tumors are characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.
Authors
- Serena Di Cosimo (ORCID: https://orcid.org/0000-0002-4666-8052)
- Sarra El-Abed (ORCID: https://orcid.org/0000-0002-8783-9671)
- Sherene Loi (ORCID: https://orcid.org/0000-0001-6137-9171)
- Marion Maetens (ORCID: https://orcid.org/0000-0002-0505-2622)
- Roberto Salgado (ORCID: https://orcid.org/0000-0002-1110-3801)
- Andrea Joaquin Garcia (ORCID: https://orcid.org/0000-0002-5847-1310)
- Lajos Pusztai (ORCID: https://orcid.org/0000-0001-9632-6686)
- Delphine Vincent (ORCID: https://orcid.org/0000-0002-9083-015X)
- Françoise Rothé (ORCID: https://orcid.org/0009-0003-2625-5642)
- David Venet (ORCID: https://orcid.org/0000-0001-9038-5271)
- Samira Majjaj (ORCID: https://orcid.org/0009-0000-7047-0663)
- Christos Sotiriou (ORCID: https://orcid.org/0000-0002-5745-9977)
- Takayuki Ueno (ORCID: https://orcid.org/0000-0002-9080-9377)
- Mattia Rediti (ORCID: https://orcid.org/0000-0002-6713-2599)
- Miguel Izquierdo (ORCID: https://orcid.org/0000-0002-3596-928X)
- Martine Piccart (ORCID: https://orcid.org/0000-0001-9068-8504)
- G. Viale
Institutions
- Novartis (Switzerland) (CH)
- Université Libre de Bruxelles (BE)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Institut Jules Bordet (BE)
- Yale Cancer Center (US)
- Breast International Group (BE)
- IFOM (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Japanese Foundation For Cancer Research (JP)
- European Institute of Oncology (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1038/s41467-024-54621-3
- Citations
- 13
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 3.67
Funders
- Breast Cancer Research Foundation
- GlaxoSmithKline
- Fonds De La Recherche Scientifique - FNRS
- National Cancer Institute