Development and Validation of a Novel Gene Expression-Based Macrophage-Associated Marker Prognostic Score
Liza M Quintana, Andrew H Beck. Beth Israel Deaconess Medical Center, Boston, MA
Background: Tumor associated macrophages are involved in breast carcinogenesis; however, few macrophage-associated prognostic biomarkers have been identified. We sought to identity prognostic macrophage-associated markers and to develop a macrophage-associated marker prognostic score (MAMPS).
Design: We identified a list of 638 macrophage-associated markers using Ingenuity Pathway Analysis. We previously performed a meta-analysis across 11 microarray data sets (total of 20,827 genes and 2,123 patients) to estimate the association of each gene with survival in each of the four breast cancer molecular subtypes (Luminal A, Luminal B, Basal, Her2). In the current study, we focused our analysis on macrophage-associated markers showing a strong prognostic association (absolute value of Z statistic ≥ 3) in at least one breast cancer molecular subtype. Based on the genes identified, we computed a prognostic score (MAMPS) as the sum of the expression levels of the macrophage-related markers associated with decreased survival minus the sum of the expression levels of the macrophage-related markers associated with improved survival. We then evaluated the prognostic association of the MAMPS in patients from three independent validation data sets (n = 780).
Results: No macrophage-associated markers were identified at the significance threshold in Luminal A. In Luminal B, Her2 and Basal, we identified a total of 12 markers (11 associated with improved prognosis and 1 associated with poorer prognosis). These 12 markers were used to compute the MAMPS. In patients from the validation data sets, the MAMPS was significantly associated with recurrence free survival in Luminal B (Z=3.5, p = 0.0005), Basal (Z=3.3, p = 0.0009), and molecular Her2 (Z=2.1, p = 0.03) breast cancer cases, with no association in Luminal A (p>0.6). In a multivariate model including MAMPS and molecular subtype, MAMPS was a significant prognostic factor (Z=5.1, p = 3.0e-7), independent of molecular subtype.
Conclusions: The MAMPS is strongly associated with prognosis in Luminal B and Basal breast cancer with a weaker association in Her2 and no significant association in Luminal A. These findings provide new insights into tumor-associated macrophages in breast cancer and will facilitate the development of diagnostic and therapeutic strategies targeting macrophages in breast cancer.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 19, Monday Morning