Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging

• Published in: British journal of cancer Vol. 127; no. 1; pp. 145 - 155
• Main Authors: Strating, Esther, Wassenaar, Emma, Verhagen, Mathijs, Rauwerdink, Paulien, van Schelven, Susanne, de Hingh, Ignace, Rinkes, Inne Borel, Boerma, Djamila, Witkamp, Arjen, Lacle, Miangela, Fodde, Riccardo, Volckmann, Richard, Koster, Jan, Stedingk, Kris, Giesel, Frederik, de Roos, Remmert, Poot, Alex, Bol, Guus, Lam, Marnix, Elias, Sjoerd, Kranenburg, Onno
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2022; Nature Publishing Group
• Subjects: 631/67/2321; 692/4028/67/1504/1885; Biomedical and Life Sciences; Biomedicine; Cancer Research; Colorectal cancer; Colorectal carcinoma; Drug Resistance; Epidemiology; Fibroblast activation protein; Fibroblasts; Medical prognosis; Metastases; Metastasis; Molecular Medicine; mRNA; Oncology; Patients; Peritoneum; Positron emission tomography; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-01748-z

Background
In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.
Methods
To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3–5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM;
n
 = 59). Molecular imaging was performed using the
68
Ga-DOTA-FAPI-46 PET tracer.
Results
Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (
P
 = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.
Conclusion
FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.