PD64: Kidney Cancer: Basic Research & Pathophysiology III
PD64-03: Uncovering Intra-tumor AXL Expression Heterogeneity and Outcomes in Clear Cell Renal Cell Carcinoma: Comprehensive Analysis for Primary and Metastatic lesion.
Introduction: AXL is the TAM family of receptor tyrosine kinases targeted by a new approved Cabozantinib in renal cell carcinoma (RCC). A growing body of evidence suggests a relationship between AXL expression levels and RCC prognosis. However, intra-tumor heterogeneity is a big problem in RCC. Herein we uncover an intra-tumor heterogeneity for AXL expression in clear cell RCC (ccRCC) specimens across primary and metastatic lesions, shedding light on optimal Cabozantinib treatments in future practice.
Methods: The study included 152 ccRCC surgically-treated specimens, in which 105 were from primary lesions and 47 from metastases. To uncover intra-tumor heterogeneity for AXL expression in ccRCC, we histologically extracted center of tumor (CT) and invasive margin (IM) in pairs for all cases. Notably, cell-by-cell AXL expression analysis was immunohistochemically conducted by the virtual slide scanner and automatic single-cell count system. We defined the median values of AXL-positive cell number in primary lesions as the cut-off for high-/low-AXL expression.
Results: The median follow-up period was 99 months. In 105 cases of ccRCC, AXL expression levels in CT and IM each significantly predict overall survival (OS) following surgery (Figure A). However, considering the spatial AXL distribution, AXL expression levels were high in both CT and IM in 44 cases (H/H group, 42%), and low in both the CT and IM in 44 cases (L/L group, 42%). The remaining 17 cases were either CT or IM high and either low (H/L group, 16%). Thus, AXL expression levels in CT and IM did not always match. Kaplan-Meier curves for OS in these 3 groups (i.e., H/H, L/L, and H/L groups) revealed that they were divided into 3 prognostic groups with statistical differences (Figure B). Conduction comprehensive analysis for primary and metastatic lesions, AXL expression levels was high in both CT and IM in 30 cases (64%) of 47 metastases. This ratio was much higher than that of primary lesions, rather the tendency was remarkable with metastasis to bone (n = 17). In 13 cases of excised primary lesions and matched metastasis, AXL expression levels were increased in 11 metastases compared to matched primary lesions.
Conclusions: We revealed intra-tumor AXL expression heterogeneity, and spatial AXL expression levels affects OS in ccRCC. The levels of AXL expression was increased in metastases, and site-specific differences of AXL expression levels were evident. Our study may depict potential candidates for clinically targeting AXL e.g., Cabozantinib treatments in ccRCC. Source of
