Correlation of ⁶⁸Ga-FAPi-46 PET biodistribution with FAP expression by immunohistochemistry in patients with solid cancers: a prospective translational exploratory study

Abstract

Purpose: Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts confer treatment resistance, promote metastasis and immunosuppression. Because FAP is overexpressed in many cancers, radiolabeled molecules targeting FAP are studied for their use as pan-cancer theranostic agents. This study aims to establish the spectrum of FAP expression across various cancers by immunohistochemistry and to explore whether gallium-68 FAPi-46 (⁶⁸Ga-FAPi-46) PET biodistribution faithfully reflects FAP expression from resected cancer and non-cancer specimens. Methods: We conducted a FAP expression screening by using immunohistochemistry on a pan-cancer human tissue microarray (TMA) (141 patients, 14 different types of cancer) and an interim analysis of a prospective exploratory imaging trial in cancer patients. Volunteer patients underwent one whole body ⁶⁸Ga-FAPi-46 PET/CT scan and subsequently, surgical resection of their primary tumor and/or metastasis. ⁶⁸Ga-FAPi-46 PET maximum standardized uptake value (SUV_max and SUVmean) was correlated with FAP immunohistochemistry score in cancer and non-cancer tissues for each patient. Results: FAP was expressed across all 14 cancers types on TMA 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 following their ⁶⁸Ga-FAPi-46 PET/CT scan within a mean time interval of 16.1±14.4 days. ⁶⁸Ga-FAPi-46 SUVs and immunohistochemistry scores were higher in cancer than in normal tissue: mean SUV_max 7.7 vs 1.6 (p<0.001), mean SUVmean 6.2 vs 1.0 (p<0.001) and mean FAP immunohistochemistry score 2.8 vs 0.9 (p<0.001). FAP immunohistochemistry scores strongly correlated with ⁶⁸Ga-FAPi 46 SUV_max 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 pan-cancer imaging biomarker for FAP expression and stratification tool for FAP- targeted therapies.