Abstract P6-07-07: Triple negative breast cancer classification according to cancer stem cell hypothesis

Background: Triple negative breast cancer (TNBC) is described by lack of ER and PR expression and HER2 overexpression. This subgroup has no targeted therapies and its prognosis its worse than other breast cancer subtypes. The Cancer Stem Cell hypothesis lies in two ideas; first, that breast cancers can initiate in different cell types, which can be any epithelial stem cells or any of their progeny, and, that this original cell will give the tumor a specific molecular profile. Our work proposes a division in molecular groups of TNBC looking for this tissue of origin molecular profile through gene expression data and probabilistic graphical models analyses. Material and methods: TNBC gene expression data was obtained from GSE31519 (n=494). 2000 most variable genes were selected for subsequent analysis. A functional network was built using a probabilistic graphical model approach. Functional nodes were defined, and its function was explored by Gene Ontology using DAVID. Then, a new molecular classification was generated using the activity of functional nodes and k-means. Subgroups were characterized and compared with previous TNBC molecular classifications. Results: Probabilistic graphical models defined a functional structure comprising 27 functional nodes. We found some Luminal, some Basal and a claudin-enriched node. Based on these nodes molecular subgroups were defined, following the cancer stem cell hypothesis. Thus, four subtypes: (Luminal Androgen receptor (LAR), basal, claudin-low and claudin-high were defined matching tumor origin characteristics with those in the actual tumor sample. Tumors with low expression of claudins (CLDN-low subtype) had been differentiated in the first steps of the mammary epithelial development. Tumors with high expression of claudins (CLDN-High) had been originated at the second step of the development. Next step in the development are basal-epithelial cells, which will generate Basal subtype of TNBC. And finally, the last step in development is the differentiation to luminal cell, which is the origin of the Luminal subtype. Immune status, determined by immune functional nodes, showed prognostic value (p>0.05). Finally, we compared our classification with previous ones defined by Lehmann, Burstein and the PAM50. Conclusion: Functional networks can provide a relevant molecular knowledge which complements the TNBC classification. From this approach we establish a new classification taking into account the cancer stem cell hypothesis. Besides, this deep knowledge will allow a more accurate prediction of outcome and can also be used for diagnostic purposes and therapy selection. Citation Format: Zamora-Aunon P, Trilla-Fuertes L, Diaz-Almiron M, Gamez-Pozo A, Prado-Vazquez G, Zapater-Moros A, Llorente-Armijo S, Gaya Romero F, Espinosa Arranz E, Fresno-Vara JA. Triple negative breast cancer classification according to cancer stem cell hypothesis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-07-07.