TY - JOUR
T1 - Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging
AU - Strating, Esther
AU - Wassenaar, Emma
AU - Verhagen, Mathijs
AU - Rauwerdink, Paulien
AU - van Schelven, Susanne
AU - de Hingh, Ignace
AU - Rinkes, Inne Borel
AU - Boerma, Djamila
AU - Witkamp, Arjen
AU - Lacle, Miangela
AU - Fodde, Riccardo
AU - Volckmann, Richard
AU - Koster, Jan
AU - Stedingk, Kris
AU - Giesel, Frederik
AU - de Roos, Remmert
AU - Poot, Alex
AU - Bol, Guus
AU - Lam, Marnix
AU - Elias, Sjoerd
AU - Kranenburg, Onno
N1 - Funding Information:
This work was supported by Health Holland (grant number LSHM18010).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
KW - Colorectal Neoplasms/diagnostic imaging
KW - Fibroblasts/pathology
KW - Gallium Radioisotopes/therapeutic use
KW - Humans
KW - Neoplasm Recurrence, Local
KW - Peritoneal Neoplasms
KW - Positron Emission Tomography Computed Tomography/methods
KW - Positron-Emission Tomography
UR - http://www.scopus.com/inward/record.url?scp=85126332005&partnerID=8YFLogxK
U2 - 10.1038/s41416-022-01748-z
DO - 10.1038/s41416-022-01748-z
M3 - Article
C2 - 35296803
SN - 0007-0920
VL - 127
SP - 145
EP - 155
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 1
ER -