Supplementary Table S16: Results from the gene set enrichment analysis of 28 different immune signatures across the METABRIC-set 15 (MC subtypes) classification. Supplementary Table S17: Table representing the copy number status of the five genes part of the MAPK inactivation score across the METABRIC-set 15 (MC subtypes) classification. Supplementary Table S18: Output of the multivariable logistic regression analysis for the MC6 and the BL1 subtype in Sanofi Phase II. Supplementary Table S19: Output of the multivariable logistic regression analysis for the MC6 and the BL1 subtype in Sanofi Phase III. Supplementary Table S20: Results from the drug screen performed between MC6 and non-MC6 TNBC cell lines.
ARTICLE ABSTRACT
The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1, and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors (∼50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.
