Correlation of 68Ga-FAPi-46 PET Biodistribution with FAP Expression by Immunohistochemistry in Patients with Solid Cancers: Interim Analysis of a Prospective Translational Exploratory Study

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 SUV_max and SUV_mean 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 SUV_max 7.7 versus 1.6 (P < 0.001), mean SUV_mean 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 SUV_max and SUV_mean: 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.

Keywords: 68Ga-FAPi-46; PET/CT; cancer; fibroblast activation protein; immunohistochemistry.

Graphical abstract

FIGURE 1.

FAP expression by immunohistochemistry in 14 cancer types and normal tissues (TMA analysis). (A) Quantification of FAP expression per cancer type. FAP intensity was evaluated using semiquantitative visual scoring system that accounts for staining intensity (0, negative; 1, weak; 2, strong). (B) FAP immunohistochemistry expression on representative tissue core from indicated cancer or normal tissue type.

FIGURE 2.

Matched ⁶⁸Ga-FAPI-46 PET/CT and immunohistochemistry results for patient 10, 56-y-old woman with sigmoid colon adenocarcinoma who underwent colorectal anterior resection (ypT4b N0 M0). In area corresponding to resected mass as shown by yellow arrows (PET maximum-intensity projection [A], axial CT [B, top], axial PET/CT [B, middle], and axial PET [B, bottom]), ⁶⁸Ga-FAPi-46 PET/CT showed intense uptake (SUV_max, 15.9; SUV_mean, 12.8). FAP immunohistochemistry on representative histologic sections demonstrated absent to weak FAP expression seen predominantly as vessel endothelial cell staining in normal tissue (C, top) and strong FAP expression in intratumoral and peritumoral stromal (C, bottom). White arrows depict normal region resected.

FIGURE 3.

FAP immunohistochemistry (IHC) score with ⁶⁸Ga-FAPi-46 PET SUV_max (A) and SUV_mean (B) in cancer and tumor-adjacent non-cancer tissues. Each bar represents mean with SD.

FIGURE 4.

Correlation between FAP immunohistochemistry (IHC) score and ⁶⁸Ga-FAPi-46 PET SUV_max (A) and SUV_mean (B) across cancer and tumor-adjacent non-cancer tissues. r = 0.781 in A (95% CI, 0.376–0.936; P < 0.001) and r = 0.783 in B (95% CI, 0.379–0.936; P < 0.001).