RANK-C Expression Sensitizes ER-Negative, EGFR-Positive Breast Cancer Cells to EGFR-Tyrosine Kinase Inhibitors (TKIs).

BACKGROUND: We have previously shown that overexpression of RANK-c in ER-negative breast cancer cell lines attenuates aggressive properties of cancer cells, partially through a RANK-c/EGFR interaction. EGFR inhibition through TKIs in breast cancer has been tested in triple-negative disease settings with limited clinical benefit for patients. Here we test if expression of RANK-c in ER-negative breast cancer cells in conjunction with treatment with TK inhibitors (erlotinib or gefitinib) can affect survival and colony-forming capacity of cancer cells. METHODS: Stably expressing MDA-MB-231-RANK-c and SKBR3-RANK-c cells were employed to test proliferation and colony formation in the presence of TKIs. In addition, Western blot analysis was performed to dissect EGFR related signaling cascades upon TK inhibition in the presence of RANK-c. RESULTS: Interestingly the two RANK-c expressing, ER-negative cells lines presented with a distinct phenotype concerning TKI sensitivity upon treatment. MDA-MB-231-RANK-c cells had a higher sensitivity upon gefitinib treatment, while erlotinib decreased the proliferation rate of SKBR3-RANK-c cells. Further, colony formation assays for MDA-MB-231-RANK-c cells showed a decrease in the number and size of colonies developed in the presence of erlotinib. In addition, RANK-c seems to alter signaling through EGFR after TKI treatment in a cell type-specific manner. CONCLUSIONS: Our results indicate that ER-negative breast cancer cells that express RANK-c alter their sensitivity profile against tyrosine kinase inhibitors (erlotinib and gefitinib) in a cell type-specific and culture substrate-dependent manner.

PIOS (Patras Immunotherapy Score) Score Is Associated with Best Overall Response, Progression-Free Survival, and Post-Immunotherapy Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer (NSCLC) Treated with Anti-Program Cell Death-1 (PD-1) Inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the therapeutic management of advanced non-small cell lung cancer (aNSCLC) over the last decade. However, there is an unmet need for clinically useful biomarkers in this patient subgroup. The aim of this study was to combine baseline clinical characteristics of aNSCLC patients, in the form of a scoring system, and to investigate its predictive and prognostic value in NSCLC patients treated with ICIs. A total of 112 patients with advanced (stages IIIA to IV) NSCLC, treated with nivolumab or pembrolizumab, were enrolled in this study. Patras Immunotherapy Score (PIOS) was developed based on four of the studied parameters (performance status (PS), body mass index (BMI), age, and lines of treatment (LOT), which were incorporated into our formula (PS × BMI/ LOT × age). PIOS score was strongly associated with best overall responses (BOR), with those patients having benefit/good response (stable disease (SD) or partial (PR) or complete response (CR), achieving a higher score compared to patients who developed progressive disease (PD) (p < 0.001). Furthermore, PIOS score was associated with progression-free survival (PFS), since high-score patients had longer PFS (p < 0.001, hazard ratio (HR) = 0.469). Moreover, PIOS was associated with post-immunotherapy overall survival (OS), with high-score patients having improved OS (log-rank p = 0.019). This study suggests that a combination of baseline parameters, which give rise to PIOS score, may predict the best response of NSCLC patients treated with anti-program cell death -1 (PD-1) monotherapy as well as it may have a potent prognostic value for PFS and post immunotherapy OS.