Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial

Mattia Rediti, David Venet, Andrea Joaquin Garcia, Marion Maetens, Delphine Vincent, Samira Majjaj, Sarra El-Abed, Serena Di Cosimo, Takayuki Ueno, Miguel Izquierdo, Martine Piccart, Lajos Pusztai, Sherene Loi, Roberto Salgado, Giuseppe Viale, Françoise Rothé and Christos Sotiriou ()
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Mattia Rediti: Université Libre de Bruxelles (ULB)
David Venet: Université Libre de Bruxelles (ULB)
Andrea Joaquin Garcia: Université Libre de Bruxelles (ULB)
Marion Maetens: KU Leuven
Delphine Vincent: Université Libre de Bruxelles (ULB)
Samira Majjaj: Université Libre de Bruxelles (ULB)
Sarra El-Abed: Breast International Group
Serena Di Cosimo: Fondazione IRCCS Istituto Nazionale dei Tumori
Takayuki Ueno: Japanese Foundation for Cancer Research
Miguel Izquierdo: Novartis Pharma AG
Martine Piccart: Université Libre de Bruxelles (ULB)
Lajos Pusztai: Yale Cancer Center
Sherene Loi: Peter MacCallum Cancer Centre
Roberto Salgado: Peter MacCallum Cancer Centre
Giuseppe Viale: European Institute of Oncology IRCCS
Françoise Rothé: Université Libre de Bruxelles (ULB)
Christos Sotiriou: Université Libre de Bruxelles (ULB)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54621-3

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