Christine E Mona1,2,3, Matthias R Benz4,2, Firas Hikmat4, Tristan R Grogan5, Katharina Lueckerath4,2,3, Aria Razmaria4, Rana Riahi6, Roger Slavik4, Mark D Girgis7, Giuseppe Carlucci4,2, Kimberly A Kelly8, Samuel W French2,6, Johannes Czernin4,2,3, David W Dawson2,6, Jeremie Calais1,2,3. 1. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California; jcalais@mednet.ucla.edu cmona@mednet.ucla.edu. 2. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California. 3. Institute of Urologic Oncology, UCLA, Los Angeles, California. 4. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California. 5. Department of Medicine Statistics Core, David Geffen School of Medicine, UCLA, Los Angeles, California. 6. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California. 7. Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California; and. 8. Department of Biomedical Engineering, University of Virginia School of Engineering and Applied Sciences, and Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.
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.
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.
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