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

Esther Strating, Emma Wassenaar, Mathijs Verhagen, Paulien Rauwerdink, Susanne van Schelven, Ignace de Hingh, Inne Borel Rinkes, Djamila Boerma, Arjen Witkamp, Miangela Lacle, Riccardo Fodde, Richard Volckmann, Jan Koster, Kris Stedingk, Frederik Giesel, Remmert de Roos, Alex Poot, Guus Bol, Marnix Lam*, Sjoerd Elias*Onno Kranenburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 68Ga-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. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)145-155
Number of pages11
JournalBritish Journal of Cancer
Volume127
Issue number1
Early online date16 Mar 2022
DOIs
Publication statusPublished - 1 Jul 2022

Bibliographical note

Funding Information:
This work was supported by Health Holland (grant number LSHM18010).

Publisher Copyright:
© 2022, The Author(s).

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