Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications

Pascal Jézéquel (1, 2, 3) , Olivier Kerdraon (4) , Hubert Hondermarck (5) , Catherine Guérin-Charbonnel (2, 3, 6) , Hamza Lasla (3) , Wilfried Gouraud (2, 3, 6) , Jean-Luc Canon (7) , Andrea Gombos (8) , Florence Dalenc (9) , Suzette Delaloge (10) , Jérôme Lemonnier (11) , Delphine Loussouarn (12) , Veronique Verriele (4) , Mario Campone (1, 13)

1 CRCINA-ÉQUIPE 8 - Stress Adaptation and Tumor Escape in Breast Cancer
2 Site René Gauducheau - Unité Mixte de Génomique du Cancer [ICO, Saint Herblain]
3 Unité de bioinfomique [ICO, Saint Herblain]
4 Laboratoire d’Anatomie et Cytologie Pathologiques [ICO, Saint Herblain]
5 School of Biomedical Sciences and Pharmacy [Callaghan, Australia]
6 CRCINA-ÉQUIPE 11 - Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression
7 Département Oncologie-Hématologie [Charleroi, Belgium]
8 Département Oncologie Médicale [Bruxelles, Belgium]
9 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
10 Département de médecine oncologique [Gustave Roussy]
11 R&D UNICANCER - French Breast Cancer Intergroup - UCBG [Paris]
12 Laboratoire d'anatomie et cytologie pathologiques [CHU Nantes]
13 Centre René Gauducheau - ICO - Département d'oncologie médicale [Saint Herblain]

BACKGROUND: Heterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC), and therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study was to define robust TNBC subtypes with clinical relevance. METHODS: Gene expression profiling by means of DNA chips was conducted in an internal TNBC cohort composed of 238 patients. In addition, external data (n = 257), obtained by using the same DNA chip, were used for validation. Fuzzy clustering was followed by functional annotation of the clusters. Immunohistochemistry was used to confirm transcriptomics results: CD138 and CD20 were used to test for plasma cell and B lymphocyte infiltrations, respectively; MECA79 and CD31 for tertiary lymphoid structures; and UCHL1/PGP9.5 and S100 for neurogenesis. RESULTS: We identified three molecular clusters within TNBC: one molecular apocrine (C1) and two basal-like-enriched (C2 and C3). C2 presented pro-tumorigenic immune response (immune suppressive), high neurogenesis (nerve infiltration), and high biological aggressiveness. In contrast, C3 exhibited adaptive immune response associated with complete B cell differentiation that occurs in tertiary lymphoid structures, and immune checkpoint upregulation. External cohort subtyping by means of the same approach proved the robustness of these results. Furthermore, plasma cell and B lymphocyte infiltrates, tertiary lymphoid structures, and neurogenesis were validated at the protein levels by means of histological evaluation and immunohistochemistry. CONCLUSION: Our work showed that TNBC can be subcategorized in three different subtypes characterized by marked biological features, some of which could be targeted by specific therapies.

Mots clés: Breast cancer; Immunome; Molecular subtypes; Neurogenesis; Tertiary lymphoid structures; Transcriptomics; Triple-negative

Domaines: Cancer

Pascal Jézéquel, Olivier Kerdraon, Hubert Hondermarck, Catherine Guérin-Charbonnel, Hamza Lasla, et al.. Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications. Breast Cancer Research, 2019, 21 (1), pp.65. ⟨10.1186/s13058-019-1148-6⟩. ⟨inserm-02140196⟩