Peripheral Blood Glucocorticoid Receptor α/β (GRα/GRβ) Ratio Predicts Response to Pemetrexed-Based Chemotherapy in Non-Squamous NSCLC: A Prospective Cohort Study

Bahareh Forouzani-Haghighi,1 Alireza Rezvani,2 Bita Geramizadeh,3 Elaheh Esfandiari,3 Mehdi Ghasemian,4 Afsaneh Vazin1 1Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 2Hematology Research Center, Stem Cells Research Institute, Shiraz University of Medical Sciences, Shiraz, Iran; 3Transplant Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran; 4Trauma Research Centre, Shahid Rajaee Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, IranCorrespondence: Afsaneh Vazin, Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran, Email [email protected]: This study evaluated whether the glucocorticoid receptor α/β (GRα/GRβ) mRNA expression ratio in peripheral blood mononuclear cells (PBMCs) can serve as a predictive biomarker for treatment response and survival in patients with non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed-based chemotherapy.Methods: Thirty-five patients with confirmed non-squamous NSCLC were prospectively enrolled and received platinum–pemetrexed chemotherapy with standard dexamethasone premedication. Quantitative PCR was used to measure GRα and GRβ mRNA levels in PBMCs, and patients were categorized into high- and low-ratio groups based on the median GRα/GRβ value. Tumor response was assessed per RECIST 1.1 criteria, and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression methods.Results: Compared with the high-ratio group, patients in the low GRα/GRβ group had a higher response rate (82.4% vs 44.4%, p = 0.035), greater tumor shrinkage (55% vs 42%, p = 0.027), and more pronounced lymph node regression (p = 0.039). Median PFS was longer in the low-ratio group (5.5 vs 3.5 months; log-rank p = 0.031; adjusted HR = 0.72, 95% CI: 0.53– 0.91), whereas the OS benefit seen in unadjusted analysis (14.0 vs 11.6 months; log-rank p = 0.042) was not significant after adjustment.Conclusion: A lower GRα/GRβ ratio in PBMCs was suggestively associated with improved tumor response and PFS in this small, exploratory cohort. However, the limited sample size, lack of an independent validation cohort, reliance on PBMC-derived measurements, potential confounding factors, and absence of multiple comparisons adjustment warrant cautious interpretation. These results should be considered hypothesis-generating, and validation in larger, multicenter, and adequately powered studies—including paired PBMC–tumor analyses—is essential before clinical implementation.Plain Language Summary: Lung cancer is one of the most common and serious cancers worldwide. A type called non-small cell lung cancer (NSCLC) is often treated with a chemotherapy drug named pemetrexed, but not all patients respond equally to this treatment.This study explored whether a blood-based biological marker could help predict how patients respond to pemetrexed. We focused on a protein called the glucocorticoid receptor (GR), which exists in two forms—GR-alpha (GRα) and GR-beta (GRβ). These forms influence how the body responds to dexamethasone, a medicine commonly given before chemotherapy.We measured GRα and GRβ levels in immune cells from patients’ blood, known as peripheral blood mononuclear cells (PBMCs), and calculated their ratio. Patients with a lower GRα/GRβ ratio had better treatment responses, greater tumor shrinkage, and longer progression-free survival than those with a higher ratio.However, this was a small study with only 35 patients, conducted at a single medical center, and without an independent validation group. Measuring GR in blood cells may not perfectly reflect tumor biology, and other factors such as medications, dexamethasone dose differences, or health conditions could have influenced the results.These findings are preliminary but suggest that the GRα/GRβ ratio in blood could become a simple, noninvasive tool to help guide treatment choices for NSCLC patients. Larger, multi-center studies that also compare blood and tumor measurements are needed to confirm these results before clinical use. Keywords: chemotherapy resistance, biomarker stratification, dexamethasone premedication, thymidylate synthase, personalized oncology