Chiara Maria Lavinia Loeffler1, Nadina Ortiz Bruechle2, Max Jung2, Lancelot Seillier2, Michael Rose2, Narmin Ghaffari Laleh1, Ruth Knuechel2, Titus J Brinker3, Christian Trautwein1, Nadine T Gaisa4, Jakob N Kather5. 1. Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany. 2. Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany. 3. Digital Biomarkers for Oncology Group (DBO), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany. Electronic address: ngaisa@ukaachen.de. 5. Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany; Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR) inhibitor treatment has become the first clinically approved targeted therapy in bladder cancer. However, it requires previous molecular testing of each patient, which is costly and not ubiquitously available. OBJECTIVE: To determine whether an artificial intelligence system is able to predict mutations of the FGFR3 gene directly from routine histology slides of bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: We trained a deep learning network to detect FGFR3 mutations on digitized slides of muscle-invasive bladder cancers stained with hematoxylin and eosin from the Cancer Genome Atlas (TCGA) cohort (n = 327) and validated the algorithm on the "Aachen" cohort (n = 182; n = 121 pT2-4, n = 34 stroma-invasive pT1, and n = 27 noninvasive pTa tumors). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the area under the receiver operating curve (AUROC) for mutation detection. Performance of the deep learning system was compared with visual scoring by an uropathologist. RESULTS AND LIMITATIONS: In the TCGA cohort, FGFR3 mutations were detected with an AUROC of 0.701 (p < 0.0001). In the Aachen cohort, FGFR3 mutants were found with an AUROC of 0.725 (p < 0.0001). When trained on TCGA, the network generalized to the Aachen cohort, and detected FGFR3 mutants with an AUROC of 0.625 (p = 0.0112). A subgroup analysis and histological evaluation found highest accuracy in papillary growth, luminal gene expression subtypes, females, and American Joint Committee on Cancer (AJCC) stage II tumors. In a head-to-head comparison, the deep learning system outperformed the uropathologist in detecting FGFR3 mutants. CONCLUSIONS: Our computer-based artificial intelligence system was able to detect genetic alterations of the FGFR3 gene of bladder cancer patients directly from histological slides. In the future, this system could be used to preselect patients for further molecular testing. However, analyses of larger, multicenter, muscle-invasive bladder cancer cohorts are now needed in order to validate and extend our findings. PATIENT SUMMARY: In this report, a computer-based artificial intelligence (AI) system was applied to histological slides to predict genetic alterations of the FGFR3 gene in bladder cancer. We found that the AI system was able to find the alteration with high accuracy. In the future, this system could be used to preselect patients for further molecular testing.
BACKGROUND: Fibroblast growth factor receptor (FGFR) inhibitor treatment has become the first clinically approved targeted therapy in bladder cancer. However, it requires previous molecular testing of each patient, which is costly and not ubiquitously available. OBJECTIVE: To determine whether an artificial intelligence system is able to predict mutations of the FGFR3 gene directly from routine histology slides of bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: We trained a deep learning network to detect FGFR3 mutations on digitized slides of muscle-invasive bladder cancers stained with hematoxylin and eosin from the Cancer Genome Atlas (TCGA) cohort (n = 327) and validated the algorithm on the "Aachen" cohort (n = 182; n = 121 pT2-4, n = 34 stroma-invasive pT1, and n = 27 noninvasive pTa tumors). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the area under the receiver operating curve (AUROC) for mutation detection. Performance of the deep learning system was compared with visual scoring by an uropathologist. RESULTS AND LIMITATIONS: In the TCGA cohort, FGFR3 mutations were detected with an AUROC of 0.701 (p < 0.0001). In the Aachen cohort, FGFR3 mutants were found with an AUROC of 0.725 (p < 0.0001). When trained on TCGA, the network generalized to the Aachen cohort, and detected FGFR3 mutants with an AUROC of 0.625 (p = 0.0112). A subgroup analysis and histological evaluation found highest accuracy in papillary growth, luminal gene expression subtypes, females, and American Joint Committee on Cancer (AJCC) stage II tumors. In a head-to-head comparison, the deep learning system outperformed the uropathologist in detecting FGFR3 mutants. CONCLUSIONS: Our computer-based artificial intelligence system was able to detect genetic alterations of the FGFR3 gene of bladder cancer patients directly from histological slides. In the future, this system could be used to preselect patients for further molecular testing. However, analyses of larger, multicenter, muscle-invasive bladder cancer cohorts are now needed in order to validate and extend our findings. PATIENT SUMMARY: In this report, a computer-based artificial intelligence (AI) system was applied to histological slides to predict genetic alterations of the FGFR3 gene in bladder cancer. We found that the AI system was able to find the alteration with high accuracy. In the future, this system could be used to preselect patients for further molecular testing.
Authors: Chiara Maria Lavinia Loeffler; Nadine T Gaisa; Hannah Sophie Muti; Marko van Treeck; Amelie Echle; Narmin Ghaffari Laleh; Christian Trautwein; Lara R Heij; Heike I Grabsch; Nadina Ortiz Bruechle; Jakob Nikolas Kather Journal: Front Genet Date: 2022-02-16 Impact factor: 4.599
Authors: Frederik Wessels; Max Schmitt; Eva Krieghoff-Henning; Jakob N Kather; Malin Nientiedt; Maximilian C Kriegmair; Thomas S Worst; Manuel Neuberger; Matthias Steeg; Zoran V Popovic; Timo Gaiser; Christof von Kalle; Jochen S Utikal; Stefan Fröhling; Maurice S Michel; Philipp Nuhn; Titus J Brinker Journal: PLoS One Date: 2022-08-17 Impact factor: 3.752