Abstract
Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts confer treatment resistance and promote metastasis and immunosuppression. Because FAP is overexpressed in many cancers, radiolabeled molecules targeting FAP are studied for their use as pancancer theranostic agents. This study aimed to establish the spectrum of FAP expression across various cancers by immunohistochemistry and to explore whether 68Ga FAP inhibitor (FAPi)-46 PET biodistribution faithfully reflects FAP expression from resected cancer and non-cancer specimens. Methods: We conducted a FAP expression screening using immunohistochemistry on a pancancer human tissue microarray (141 patients, 14 different types of cancer) and an interim analysis of a prospective exploratory imaging trial in cancer patients. Volunteer patients underwent 1 whole-body 68Ga-FAPi-46 PET/CT scan and, subsequently, surgical resection of their primary tumor or metastasis. 68Ga-FAPi-46 PET SUVmax and SUVmean was correlated with FAP immunohistochemistry score in cancer and tumor-adjacent non-cancer tissues for each patient. Results: FAP was expressed across all 14 cancer types on tissue microarray with variable intensity and frequency, ranging from 25% to 100% (mean, 76.6% ± 25.3%). Strong FAP expression was observed in 50%-100% of cancers of the bile duct, bladder, colon, esophagus, stomach, lung, oropharynx, ovary, and pancreas. Fifteen patients with various cancer types (colorectal [n = 4], head and neck [n = 3], pancreas [n = 2], breast [n = 2], stomach [n = 1], esophagus [n = 2], and uterus [n = 1]) underwent surgery after their 68Ga-FAPi-46 PET/CT scan within a mean interval of 16.1 ± 14.4 d. 68Ga-FAPi-46 SUVs and immunohistochemistry scores were higher in cancer than in tumor-adjacent non-cancer tissue: mean SUVmax 7.7 versus 1.6 (P < 0.001), mean SUVmean 6.2 versus 1.0 (P < 0.001), and mean FAP immunohistochemistry score 2.8 versus 0.9 (P < 0.001). FAP immunohistochemistry scores strongly correlated with 68Ga-FAPi 46 SUVmax and SUVmean: r = 0.781 (95% CI, 0.376-0.936; P < 0.001) and r = 0.783 (95% CI, 0.379-0.936; P < 0.001), respectively. Conclusion: In this interim analysis of a prospective exploratory imaging trial, 68Ga-FAPi-46 PET biodistribution across multiple cancers strongly correlated with FAP tissue expression. These findings support further exploration of FAPi PET as a pancancer imaging biomarker for FAP expression and as a stratification tool for FAP-targeted therapies.
Highlights
Fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts and is a key player in tumor progression [1]
We present here the results of an interim analysis that was mandated by the University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center (JCCC) Internal Scientific Peer Review Committee (ISPRC) and Data Safety Monitoring Board (DSMB) after completed enrollment of 15 patients
Of the 114 positive tumors, FAP expression was stromal in 108/114, epithelial in 1/114, and mixed in 5/114 of cases (Lung cancer (N=1), Ovarian cancer (N=1), Oropharynx (N=1), Pancreatic (N=1) and Uterine cancer (N=1))
Summary
Fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts and is a key player in tumor progression [1]. High FAP expression is almost exclusively restricted to cancer-associated fibroblasts and serves as an independent negative prognostic factor for multiple types of cancers [2]. Targeting the enzymatic activity of FAP with antibodies does not yield beneficial clinical effects [6,7]. FAP-targeting ligands (FAPi) labeled with Positron Emission Tomography (PET) imaging (e.g., Gallium-68, Fluor-18 for Positron Emission Tomography; PET) and therapeutic (e.g., Lutetium-177, Yttrium-90) radioisotopes have been introduced [8,9]. High tumor uptake observed with FAPi PET imaging in various cancers suggests promising potential of radiolabeled FAPi compounds for diagnostic and therapeutic applications [10]
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