TABLE OF CONTENTS
ACKNOWLEDGMENTS ... iii TABLE OF CONTENTS ... vi LIST OF ABBREVIATIONS ... ix THESIS SUMMARY ... 1 RÉSUMÉ DE THÈSE ... 2 1. GENERAL INTRODUCTION ... 31.1 Metastatic colorectal cancer ... 3
1.1.1 Epidemiology ... 3
1.1.2 Treatments ... 3
1.1.3 Substantial burden for healthcare systems ... 7
1.2 Prognostic and predictive biomarkers ... 8
1.2.1 Definitions ... 8
1.2.2 Biomarkers in mCRC ... 9
1.2.2.1 Prognostic biomarkers ... 9
1.2.2.1.1 Clinical and biological biomarkers ... 9
1.2.2.1.2 Metabolic imaging biomarkers ... 10
a. Volume-based PET parameters ... 10
1) The interest of the volume-based PET parameters ... 10
2) Definitions of the volume-based PET parameters ... 11
3) Segmentation methods of the volume-based PET parameters ... 12
4) Prognostic role of these volume-based PET parameters ... 14
1.2.2.1.3 Circulating biomarkers ... 16
a. Conventional tumor markers ... 16
b. Liquid biopsy ... 17
1) ctDNA versus tumor tissue biopsy for RAS profiling in mCRC ... 18
2) Applications of liquid biopsies (cfDNA/ctDNA) in mCRC ... 20
3) Estimation of prognosis by cfDNA ... 21
1.2.2.1.4 Molecular biomarkers ... 22
a. KRAS mutations ... 22
1.2.2.2 Predictive biomarkers ... 25
1.2.2.2.1 Imaging biomarkers ... 25
a. Morphologic imaging ... 25
1) Conventional radiologic response criteria... 25
2) Other radiologic response criteria ... 26
b. Functional imaging ... 27
1) Dynamic contrast-enhanced MRI ... 28
2) Diffusion-weighted MRI ... 29
c. Metabolic imaging ... 30
1) Definitions ... 30
2) PET standardization ... 32
3) PET criteria for treatment response assessment ... 34
1.2.2.2.2 Circulating biomarkers ... 39
a. Conventional tumor markers ... 39
b. Liquid biopsy ... 40
1) ctDNA to monitor the efficacy of therapies ... 40
2) ctDNA to select patients eligible for anti-EGFR rechallenge therapy ... 40
1.2.2.2.3 Molecular biomarkers ... 41
1.2.3 Risk scoring systems in mCRC ... 44
1.3 Justification of this thesis ... 46
1.4 Hypothesis of this thesis and related points of investigation ... 47
1.4.1 Hypothesis ... 47
1.4.2 Main points of investigation to test this hypothesis ... 47
1.4.2.1 Investigations related to prognostic biomarkers ... 47
1.4.2.2 Investigations related to predictive biomarkers ... 48
1.4.2.3 Investigations related to the combination of biomarkers ... 48
1.5 Clinical trials used in this thesis ... 49
2. STUDIES ... 54
2.1 Study on baseline whole-body metabolically active tumor volume and total lesion glycolysis as 18F-FDG PET/CT-based prognostic biomarkers in chemorefractory metastatic colorectal cancer ... 54
2.3 Study on baseline 18F-FDG PET/CT-based whole-body metabolically active tumor volume and early metabolic response as prognostic and predictive biomarkers in metastatic colorectal cancer patients under first or last-line of treatment (paper in process of
submission) ... 80
2.4 Study on early and late metabolic response assessments using 18F-FDG PET/CT in chemorefractory metastatic colorectal cancer patients under targeted therapy ... 110
2.5 Studies on prognostic scores combining baseline 18F-FDG PET/CT-based whole-body metabolically active tumor volume, clinical parameters, as well as circulating cell-free DNA in metastatic colorectal cancer ... 121
3. GENERAL DISCUSSION AND PERSPECTIVES ... 128
3.1 Prognostic biomarkers ... 128
3.1.1 Baseline WB-MATV/TLG biomarkers ... 128
3.1.2 Baseline cfDNA biomarker ... 134
3.2 Predictive biomarkers ... 137
3.2.1 Early mR ... 137
3.2.2 Comparison of the different mR methods ... 141
3.3 Combination of biomarkers ... 142
3.3.1 Combination of prognostic biomarkers ... 142
3.3.2 Combination of prognostic and predictive biomarkers ... 143
3.4 New parameters ... 144
3.5 Future perspectives ... 145
3.5.1 PET-driven therapeutic strategies ... 147
3.5.1.1 Design of one trial that would demonstrate the clinical utility of using the early mR in liver-limited mCRC patients (REGAIN study) ... 147
4. GENERAL CONCLUSIONS ... 149
MAIN RESULTS OF THIS THESIS ... 150
SUPPLEMENTAL FIGURE ... 152
SUPPLEMENTAL TABLE ... 153
