Pan-cancer association between increased iron utilization and poor prognosis highlights potential of transferrin receptor-targeting therapies in multiple tumor types.
Authors: Trabolsi Asaad , Arumov Artavazd , Yin Jun , Halmos Balazs , Brodskiy Pavel , Oberley Matthew James , Hoon Dave S. B. , Liu Stephen V. , Wei Shuanzeng , Kang Irene , Schatz Jonathan Harry 
Published: June 2022

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Background: The cell-surface transferrin receptor TFR1 imports iron-bound transferrin into cells via clathrin-mediated endocytosis. Tumors require constitutive iron import to drive proliferation, and several studies establish TFR1 as a target able to facilitate intracellular delivery of cytotoxic therapeutic molecules. Our own work previously revealed association between high expression of TFRC, the gene encoding TFR1, and high risk for poor outcome in diffuse large B-cell lymphoma (DLBCL). We showed therapetuic targeting of TFR1 in DLBCL results in significant anti-tumor benefit. Systematic analysis of TFRC expression as a prognostic marker across tumor types, however, has not been investigated. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. Overall survival (OS) was calculated from date of tissue collection to last contact from insurance claims data and employed Kaplan-Meier analysis by Wilcoxon statistics, with p < 0.05 defined as significant. Results: Amongst 47 cancer types included, colorectal cancer (CRC) displayed the highest level of TFRC mRNA, followed by gastric cancer. In an all-tumor cohort (n = 93248), patients with higher TFRC expression (cutoff = median) had significantly worse OS (HR = 1.348, 95% CI [1.317-1.38], p < 0.00001). This was statistically significant in 23 individual tumor types. Drilling down further, TFRC adverse prognostic value was mainly driven by cohorts with larger number of samples in the database, including non-small cell lung cancer (n = 17309), CRC (n = 12860), breast cancer (n = 8632), ovarian carcinoma (n = 7998), uterine neoplasms (n = 6097), prostate adenocarcinoma (n = 3411), glioblastoma (n = 2821), gastric cancer (n = 1579), and others. Surprisingly, TFRC overexpression correlated with improved outcome in vulvar squamous cell carcinoma (VSCC, n = 297). TFRC was found to be most prognostic in prostate adenocarcinoma with median OS 1139 days in pts with high vs 3230 days in pts with low TFRC (HR = 2.556, 95% CI [2.213-2.951], p < 0.00001). Conclusions: Our study is the first to combine modern molecular profiling with a large cohort of clinical tissue samples to reveal a prognostic role for TFRC expression in a variety of solid tumor types. We found TFRC overexpression to be prognostic in a large proportion of histologies, though surprisingly association with improved OS in VSCC. Highest expression occured in CRC and gastric cancer, diseases with needs for new therapies. A number of TFR1-targeting therapeutics are currently at various stages of development, and warrant further investigation in disease cohorts identified from our study.