Abstract 962: Oncodrivers expression analysis in primary tumors: potential for development of targeted immunotherapies for triple negative breast cancer (TNBC)
Authors: Garg Saurabh K. , Champion Nicholas T. , Basu Amrita , Whiting Junmin , Sun Weihong , Hoover Susan , Czerniecki Brian J. 
Published: April 2023

Background and significance: Lack of targets, aggressive course, resistance to treatment and poor prognosis are typical characteristics of TNBC. Like other breast cancer (BC) types, TNBC cells are also dependent on oncodrivers that potentiate the malignancy by inducing proliferation. This dependency makes oncodrivers the target of choice for new BC therapies. Here, we focus on cellular distribution of HER3, EGFR, and MET in TNBC tumors. Analysis of oncodrivers expression along with immune cell landscape in TNBC tumors pre- and post-chemotherapy will help in understanding the interaction between immune response and oncodrivers status and how that correlates with therapeutic response(s) in patients to design future clinical trial using targeted immunotherapy.Methods: In an IRB-approved study, immunohistochemistry was performed using tissue microarray (TMA) on surgical blocks from a cohort of 90 TNBC patients. Two separate multiplex panels: (1) Oncodrivers (HER3, EGFR & MET); (2) Immune cells (CD4, CD8, CD20, CD56, CD45, & PD1) were used. Subsequently, oncodrivers expression was correlated to immune infiltration, clinical responses, and survival by reviewing the pathological data.

Results: We analyzed total 208 QC-passed TMA cores. Irrespective of clinical outcome, EGFR (41.13% vs 15.09%, p&lt;0.0001) and MET (35.67% vs 11.61%, p&lt;0.0001) showed increase in the number of positive cells in tumor as compared to benign tissue. Curiously, limited expression of HER3 was significantly lower in stromal tissue (1.62% vs 0.59%, p=0.026). The distribution of MET and EGFR showed a significant correlation (r=0.32, p&lt;0.0001) whereas HER3 expression was mutually exclusive to either MET (r=-0.006, p=0.931) or EGFR (r=-0.07, p=0.291). Analysis of clinical and pathological data demonstrated that HER3 expression was higher in patients treated with neoadjuvant chemotherapy (2.95% versus 0.79%, p=0.004). There was higher expression of HER3 in node positive disease (p=0.013) and MET in node negative disease (p=0.004). There was no change in expression between pre- and post-chemotherapy samples for MET (p=0.097) and EGFR (p=0.754). Interestingly, the intermediate strength of EGFR expression was significantly associated with favorable overall survival in patients treated with neoadjuvant chemotherapy (univariate Cox model, N=13, HR=0.28, p=0.024). Analysis of immune infiltrate showed a significant correlation between CD45 and EGFR (r=0.379, p&lt;0.001) as well as MET (r=0.443, p&lt;0.001).

Conclusion: EGFR and MET overexpressed in tumor tissue of TNBC specimens while smaller proportion of HER3+ cells were limited to tumor as compared to stroma. HER3 appears to be altered by neoadjuvant chemotherapy. EGFR and MET expression correlated with CD45+ immune cells. To this end, HER3, EGFR, and MET remain viable options as potential targets for dendritic cell tumor vaccines.

Citation Format: Saurabh K. Garg, Nicholas T. Champion, Amrita Basu, Junmin Whiting, Weihong Sun, Susan Hoover, Brian J. Czerniecki. Oncodrivers expression analysis in primary tumors: potential for development of targeted immunotherapies for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 962.