Abstract B49: The association between IKKα, immunologic markers, and clinical outcomes in patients with ER-positive tamoxifen-treated breast cancer
Authors: Khongthong Phungern , Bennett Linsay , Quinn Jean , Mallon Elizabeth , Roseweir Antonia , Edwards Joanne 
Published: March 2020

Background: Endocrine therapy is the standard of care for patients with estrogen receptor (ER)-positive breast cancer. However, endocrine therapy resistance is still a significant challenge for clinical practice. Nuclear factor Kappa B (NF-KB) is one of the most extensively studied pathways that has been demonstrated as a critical component in the endocrine resistance mechanism. In addition, NF-KB is a crucial factor that induces PD-L1 stabilization, resulting in enhancement of tumor immune evasion and potentially leading to endocrine therapy resistance. Studies that investigate correlations between NF-KB pathway and immunologic markers are limited. Therefore, the present study aims to examine the association between IKKα, a critical kinase in the NF-KB pathway, PD-1/PD-L1, and clinical outcomes in patient with ER-positive tamoxifen-treated breast cancer.

Methods: Immunohistochemistry was performed to examine IKKα, IKKα phosphorylated at threonine 23 (p-IKKαT23) or serine 176 (p-IKKαS176), PD-L1, and PD-1 on a tissue microarray of the patients with early-stage ER-positive breast cancer. The median value was used as the cut-off point to determine low or high expression. Kaplan-Meier curves and log-rank analysis were used to analyze an association between these markers and clinical outcomes in terms of cancer-specific survival (CSS), recurrence-free survival (RFS), and recurrence on tamoxifen (RoT).

Result: A total of 392 patients were included. High cytoplasmic IKKα was significantly associated with decreased CSS (p=0.012), RFS (p=0.005), and RoT (p=0.010). High nuclear p-IKKα S176 was significantly associated with decrease RoT (p=0.010). High nuclear p-IKKαT23 was significantly associated with decreased CSS (p=0.023), RFS (p=0.036), and RoT (p=0.015). High PD-L1 on tumor cells was significantly associated with decreased CSS (p&lt;0.001), RFS (p=0.001), and RoT (p&lt;0.001). Interestingly, high expression of PD-1 on TIL significantly associated with improved CSS (p=0.001), RFS (p=0.003), and RoT (p = 0.005). Assessing combined expression of high cytoplasmic IKKα and PD-L1 showed associations with decreased CSS (p&lt;0.001), decreased RFS (p&lt;0.001), and decreased RoT (p&lt;0.001). Combined high expression of nuclear p-IKKαT23 and PD-L1 was association with decreasde CSS (both low vs. both high, HR 4.632[1.744-12.303], p=0.001).

Conclusion: Increased expression of cytoplasmic and phosphorylated IKKα, as well as PD-L1 was significantly associated with poor clinical outcomes. However, increased PD-1 was associated with improved outcomes. In addition, combined high expression of cytoplasmic IKKα or nuclear p-IKKαT23 and PD-L1 was also significantly associated with poor clinical outcomes, indicating that in the tumor cell, activation of NF-kB pathway together with activation of PD-L1 provide additional prognosis that associates with decreased clinical outcomes and therefore could be employed as a prognostic marker.

Citation Format: Phungern Khongthong, Linsay Bennett, Jean Quinn, Elizabeth Mallon, Antonia Roseweir, Joanne Edwards. The association between IKKα, immunologic markers, and clinical outcomes in patients with ER-positive tamoxifen-treated breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B49.