Abstract P2-09-14: Immunogenomic pathway and survival analysis in breast cancers based on tumor location and molecular subtypes
Authors: Shen Y , Shyu C-R , Mitchem JB , Ding F , Shajahan-Haq AN 
Published: May 2019

Introduction: Most breast tumors respond poorly to immunotherapy. Triple-negative breast cancer (TNBC) breast tumors are thought to be more immunogenic than other breast cancer subtypes (luminal A/B or HER2+). Increased immune response in TNBC are characterized by high levels of tumor infiltrating T lymphocyte (TIL) composition that would predict excellent response to immune checkpoint blockade. For all breast cancers, tumors appear more commonly in the upper outer quadrant. However, it is not clear whether expression of immune response genes vary with tumor location among the subtypes. Here, we hypothesized that by analyzing differential gene expression associated with immune response pathways among molecular subtypes of breast cancer such as luminal A/B, HER2+ or TNBC, we can identify targetable pathways to improve therapy with breast cancer.

Methods: Using the Cancer Genome Atlas (TCGA) dataset, we have identified 918 breast cancer tumor samples and compared RNAseq gene expression based on molecular subtypes and anatomic locations of biopsies (i.e., right, left, lower inner quadrant, lower outer quadrant, upper inner quadrant or upper outer quadrant). Genes with significantly different expression (p&lt;0.01) were selected for survival analysis. R, Reactome Pathway Browser were used to retrieve and analyze data.

Results: In TNBC, tumors from lower outer quadrant, lower inner quadrant demonstrated significantly higher CD8B mRNA expression compared with luminalA/B and HER2 (p=2.93E-04, 2.73E-04) from same locations. CD8B mRNA was not significantly higher in TNBC tumors of other sites compared with luminalA/B and HER2. However, pathway/genes associated with CTL function remained significantly different between the different sites for TNBC compared with other subtypes. The metastasis suppressor gene, CD82, was significantly higher in TNBC samples from the right side (p=4.83E-05), lower outer quadrant (p=4.33E-05), lower inner quadrant (p=3.32E-03) and upper inner quadrant (p=4.51E-07), but this gene was not significantly expressed in the upper outer region, where tumors are prevalent.

From immune pathway analysis, genes involved in the antigen activates B cell receptor pathway (p&lt;0.05) were associated with overall survival (OS) in right and left sided Luminal A/B and HER2 tumors and right sided TNBC tumors. Finally, genes from pathway involved in immune-regulatory interactions between a lymphoid and a non-lymphoid cells were associated with OS in lower outer quadrant, upper outer quadrant tumors in luminal A/B and HER2 cases and right sided tumors in TNBC (p&lt;0.05).

Conclusion: While previous studies have reported that tumor infiltrating lymphocytes and lymphoid aggregates in tumors are associated with survival, following more complex analysis, we reveal novel genes and immune pathways that demonstrate improved survival prediction in the TCGA dataset for breast cancers. Furthermore, as expected, we confirm that different immune pathways are associated with survival in luminalA/B, HER2 and TNBC tumors. Our findings demonstrate the importance of a patient-centered approach to the treatment of patients with breast cancer.

Citation Format: Shen Y, Shyu C-R, Mitchem JB, Ding F, Shajahan-Haq AN. Immunogenomic pathway and survival analysis in breast cancers based on tumor location and molecular subtypes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-14.