Host Inflammation and Breast Cancer Molecular Subtypes: Results from a TCGA Sub-Analysis
Kimberly H Allison, Yunn-Yi Chen, Susan C Lester, Nicole B Johnson, Rachel E Factor, Gary MK Tse, Sandra J Shin, David A Eberhard, Puay Hoon Tan, Stuart J Schnitt, Laura C Collins, Kristin C Jensen, Konstanty Korski, Fredrick M Waldman, Andrew H Beck. Cancer Genome Atlas (TCGA) Breast Cancer Expert Pathology Committee, Bethesda, MD
Background: Tumor-associated inflammation is highly variable between patients. The association of tumor molecular and pathological characteristics with host immune response is not well understood. Utilizing inflammation scores on the histology of breast cancer samples submitted for comprehensive molecular analyses for The Cancer Genome Atlas (TCGA), we examined associations between host inflammation and breast cancer molecular and pathologic features.
Design: Experts in breast pathology reviewed the digital slides of breast cancer samples submitted for comprehensive molecular profiling to the TCGA and scored each case for the level of inflammation present (high/moderate vs mild/minimal). We tested pairwise associations between host inflammation and molecular subtypes (DNA copy-number, RNA expression, RPPA defined subtypes, miRNA subtypes, methylation subtypes) and pathological features by performing Chi-Square analyses. Multiple hypothesis testing correction was performed using the Bonferroni method.
Results: Morphological features (including inflammation) were scored by pathological review of 309 breast cancer cases that underwent molecular profiling as part of TCGA. The strongest associations were seen between inflammation and the methylation subtypes (p = 4E-10), with 66% of methylation cluster 5 cases showing at least moderate inflammation, compared with only 16% of non-cluster 5 cases. Inflammation also was strongly associated with the PAM-50 molecular subtypes (p = 6E-9), with 67% of Basal molecular subtype cases showing at least moderate inflammation, compared with only 9% of Luminal A, 25% of Luminal B, and 42% of HER2-enriched cases. Inflammation was strongly associated with breast cancer Nottingham grade, with 51%, 18%, and 15% of cases showing inflammation among grade 3, 2, and 1 cases respectively (p = 1.9e-7). Mitotic activity and nuclear pleomorphism were both strongly associated with inflammation(p = 3.3E-8 and 2.0E-5, respectively); however, there was no significant association of inflammation with pathological assessment of tubule formation (p=0.40).
Conclusions: In this integrative analysis of breast cancer molecular profiling data with histopathological analysis of cancer-associated inflammation, we identify strong associations between breast cancer molecular and pathological features and the host inflammatory response. These associations provide new insights into breast cancer molecular and morphologic factors driving tumor-associated inflammation.
Tuesday, March 5, 2013 8:15 AM
Proffered Papers: Section B, Tuesday Morning