Abstract 2436: Systematic computational analysis of histologic-genomic associations in triple-negative infiltrating ductal carcinomas of the breast
Authors: Amgad Mohamed , Kurkure Uday , Elfandy Habiba , Khallaf Hagar H. , Gutman David A. , Moreno Carlos S. , Barnes Michael , Cooper Lee A. 
Published: August 2019

Background: Triple-negative breast cancer (TNBC) is characterized by rapid progression and lack of therapeutic targets. There is a pressing need for in-depth characterization of the biological correlates (and potential prognostic biomarkers) in TNBC. We performed a systematic analysis of genomic correlates of histologic markers of tumor aggressiveness and immune infiltration in 125 infiltrating ductal TNBC patients from The Cancer Genome Atlas.

Methods: Fully-convolutional networks of the VGG16-FCN8 architecture were trained to classify various tissue regions in H&E slides (0.956 AUC on unseen slides), and morphologic descriptors of tumor aggressiveness, invasion, and immune infiltration were extracted from predictions. Expression levels of 17,052 genes were entered into sample purity-adjusted linear regression models, and a Gene Set Enrichment Analysis was performed using the model coefficients to find gene set-level associations.

Results: Significant associations are summarized in Table 1. Expression of mTOR pathway genes (especially HIGD1C and PDE6H) is positively associated with large, dense tumor nests with a smooth tumor-stroma boundary. Boundary complexity is also positively associated with the oxidant stress response of NFE2L2. In contrast, some genes downregulated by the TGF-β pathway (including FGF6, PSG2 and CHRNG) are associated with a large tumor nest phenotype. The cell cycle regulator E2F1 (through PRM1, KRT72, and DBF4) is associated with dense immune infiltration, a known marker of good prognosis, and also small tumor nest size.

Conclusion: mTOR and NFE2L2-mediated mechanisms are significantly associated with features of tumor aggressiveness in TNBC, while E2F and some TGF-β targets are associated with morphological markers of less aggressive tumors. Further research is needed to elucidate the biological basis of these associations and their potential significance in therapeutic targeting of TNBC.

Table 1:Significant histologic-genomic associations in infiltrating-ductal TNBC.Histologic phenotype (feature description)Enriched gene set (MSigDB Oncogenic Signatures)Gene set descriptionNES(P-value, FDR)Leading-edge genesTumor nest size (Mean tumor nest area)TGFB_UP.V1_DNGenes down-regulated by TGFB11.55(p&lt;0.001, FDR=0.036)FGF6; PSG2; CHRNGTumor-stroma interface (non-)complexity (mean solidity of tumor nests)NFE2L2.V2Genes upregulated with knockout of NFE2L2 gene (involved in oxidant stress response and inflammation)-1.51(p&lt;0.001, FDR=0.027)DEFB119; CNTNAP5; SCGB1D1MTOR_UP.V1_DNGenes downregulated by everolimus (an mTOR inhibitor)1.43(p=0.0017, FDR= 0.094)HIGD1CSmall, solitary tumor nestsE2F1_UP.V1_UPGenes up-regulated when E2F1 is over-expressed (cell cycle regulation)1.48(p&lt;0.001, FDR&lt;0.001)PRM1MTOR_UP.V1_DNGenes downregulated by everolimus (an mTOR inhibitor)-1.50(p=0.0027, FDR= 0.079)PDE6H; HIGD1CSmall tumor nests with abundant surrounding immune infiltration (a spatial descriptor meant to capture immune success)E2F1_UP.V1_UPGenes up-regulated when E2F1 is over-expressed.(cell cycle regulation)1.55(p&lt;0.001, FDR= 0.0019)PRM1; KRT72; DBF4

Citation Format: Mohamed Amgad, Uday Kurkure, Habiba Elfandy, Hagar H. Khallaf, David A. Gutman, Carlos S. Moreno, Michael Barnes, Lee A. Cooper. Systematic computational analysis of histologic-genomic associations in triple-negative infiltrating ductal carcinomas of the breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2436.