Abstract 1963: Spatial patterns of microenvironmental biomarkers drive long-term breast cancer outcome
Authors: Nizzero Sara , Zhang Licheng , Xu Yitian , Pelaez-Soni Maria J. , Dogra Prashant , Menegaz Brian A. , Jordan Lee B. , Purdie Colin A. , Quinlan Philip R. , Nagi Chandandeep , Sepulveda Karla A. , Oertle Philipp , Appenzeller Tobias A. , Chen Shu-Hsia , Loparic Marko , Wang Zhihui , Cristini Vittorio , Plodinec Marija , Thompson Alastair M. 
Published: June 2022

Determining early biomarkers of long-term survival remain a significant challenge for solid tumors. Certain spatial patterns of immune and stroma cells within tumors have been correlated with treatment response across cancer types, including breast cancer. Mechanical and physical microenvironmental signatures have emerged as drivers of cancer aggressiveness and invasiveness. This suggests that physio/mechanical structures may drive the formation of favorable immune-tumor-stroma cell patterns. In this work, we use a novel 60-marker imaging mass cytometry panel that included 16 tumor markers, 20 immune markers and 24 microenvironmental markers to resolve spatial patterns of cells, mechanical, structural, and other biomarkers within 700 clinical tumor samples (tissue microarrays from untreated primary breast cancers). Table 1 Sample distribution, patients were also treated surgically.

Imaging and clinical data (eg. pathology, treatment, 10+ years survival) were integrated and analyzed to extract cell phenotypes, neighboring cells/markers and establish cell density, microenvironmental marker presence, and repeating spatial cell/marker patterns in all samples. Several markers showed significant increased expression in the survival group including CD3, CD44, CD20 for cellular markers, α-SMA, Pan-Cytokeratin, Cytokeratin 5, MMP2, LOX, and HIF1α for mechanical/microenvironmental markers. Conversely, breast cancer death samples exhibited upregulation of Na+/K+ ATPase, hCA9, and Ki67. Moreover, we identified that the co-localization of mechanical markers such as Integrin β1 and Plakoglobin is a signature of tumors with poor outcome, while the individual presence of either does not affect survival. For each of the cells/markers studied, we investigated functional relationships and identified clusters that drive survival such as Vimentin+/β-actin+ B cells, which suggests that the role of mechanics is critical to the tumor-controlling functions of immune cells.

Long-term survival Cohort Survival Breast cancer death N samples 174 113 Long-term disease status Disease-free 94% 14% Local reoccurrence 4% 59% Distant reoccurrence 2% 27% Treatment No adjuvant treatment 3% 10% Adj. radiation 3% 4% Adj. chemo 0% 4% Adj. endocrine 28% 7% Adj .rad + chemo 13% 30% Adj. rad + endocrine 25% 35% Adj. chemo + endocrine 6% 4% Adj. rad + chemo + endocrine 21% 6%

Citation Format: Sara Nizzero, Licheng Zhang, Yitian Xu, Maria J. Pelaez-Soni, Prashant Dogra, Brian A. Menegaz, Lee B. Jordan, Colin A. Purdie, Philip R. Quinlan, Chandandeep Nagi, Karla A. Sepulveda, Philipp Oertle, Tobias A. Appenzeller, Shu-Hsia Chen, Marko Loparic, Zhihui Wang, Vittorio Cristini, Marija Plodinec, Alastair M. Thompson. Spatial patterns of microenvironmental biomarkers drive long-term breast cancer outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1963.