Biomarkers in Cancer Screening and Early Detection

1 - Biomarkers in Cancer Screening and Early Detection [Seite 3]
2 - Contents [Seite 9]
3 - List of Contributors [Seite 11]
4 - Preface [Seite 15]
5 - PART I Foundations of Biomarker Research [Seite 17]
5.1 - 1 Nuts and Bolts of Biomarker Research [Seite 19]
5.1.1 - What is a biomarker? [Seite 19]
5.1.2 - Why biomarker research is imperative [Seite 20]
5.1.3 - A systematic approach to developing clinically useful biomarkers: important tools and infrastructure to address the challenges [Seite 22]
5.1.3.1 - NCIs Early Detection Research Network and the five-phase schema [Seite 22]
5.1.3.2 - The biospecimen-based assessment modality pathway [Seite 25]
5.1.4 - Regulatory systems in the United States [Seite 27]
5.1.5 - The changing landscape of biomarker research [Seite 27]
5.1.6 - References [Seite 28]
5.2 - 2 Cancer Genome Methylation: Biology, Biomarker and Therapeutic Opportunities [Seite 32]
5.2.1 - Introduction [Seite 32]
5.2.2 - DNA methylation mechanisms [Seite 33]
5.2.3 - DNA methylation and cancer [Seite 33]
5.2.4 - DNA methylation as cancer biomarker [Seite 36]
5.2.5 - Epigenetic therapeutics in cancer [Seite 37]
5.2.6 - Conclusion and perspectives [Seite 38]
5.2.7 - References [Seite 40]
5.3 - 3 MicroRNA Biomarkers for Early Detection of Cancer [Seite 43]
5.3.1 - Introduction [Seite 43]
5.3.2 - MicroRNA discovery and non-coding RNA types [Seite 43]
5.3.3 - MicroRNA biogenesis and mechanism of action [Seite 44]
5.3.4 - MicroRNAs act as oncogenes and tumor suppressor genes [Seite 44]
5.3.5 - MicroRNAs in cancer detection and prediction [Seite 45]
5.3.5.1 - MicroRNAs as risk indicators [Seite 45]
5.3.5.2 - MicroRNAs for detecting cancer and improving standard diagnostic tools [Seite 46]
5.3.5.3 - MicroRNAs in body fluids [Seite 46]
5.3.5.4 - Extracellular MicroRNAs as biomarkers of early detection [Seite 47]
5.3.5.5 - MicroRNAs in combination with other genomic and clinical indicators [Seite 47]
5.3.6 - New development of miRNA research [Seite 48]
5.3.7 - MicroRNA reproducibility and validation for cancer detection [Seite 48]
5.3.7.1 - Biological relevance [Seite 48]
5.3.7.2 - Analytical variability [Seite 48]
5.3.7.3 - Analytical standards [Seite 48]
5.3.8 - Summary [Seite 49]
5.3.9 - References [Seite 49]
5.4 - 4 Inflammation and Cancer [Seite 53]
5.4.1 - Background [Seite 53]
5.4.2 - Introduction: inflammation [Seite 53]
5.4.2.1 - Infection-induced inflammation [Seite 55]
5.4.2.2 - Inflammation in sterile tissue injury [Seite 55]
5.4.3 - Tumor-promoting inflammatory cells [Seite 56]
5.4.4 - Tumor-promoting inflammatory cytokines and chemokines [Seite 57]
5.4.5 - Molecular pathways and networks that regulate tumor promoting inflammation [Seite 58]
5.4.6 - Tumor-associated antigens and inflammation [Seite 59]
5.4.7 - Disease-associated antigens in immunosurveillance of cancer and inflammation [Seite 60]
5.4.8 - Preventing tumor-promoting inflammation by eliciting DAA specific immunity: example from inflammatory bowel disease (IBD) promoting colitis associated colon cancer (CACC) [Seite 61]
5.4.9 - References [Seite 62]
5.5 - 5 Exosomes: A Valuable Biomedical Tool in Biomarker Discovery and Development [Seite 66]
5.5.1 - Introduction [Seite 66]
5.5.2 - Biogenesis and characterization of exosomes [Seite 66]
5.5.3 - Diagnostic potential of exosomal RNA [Seite 68]
5.5.4 - Diagnostic potential of exosomal proteins [Seite 68]
5.5.5 - Role in immune regulation and tumor development [Seite 69]
5.5.6 - Exosomes from tumor cells [Seite 70]
5.5.7 - Recent developments in utilization of exosomes as biomarkers for cancer [Seite 70]
5.5.8 - Challenges in exosome utilization [Seite 72]
5.5.9 - Challenges in exosome-based diagnostics [Seite 73]
5.5.10 - Conclusion [Seite 73]
5.5.11 - References [Seite 74]
5.6 - 6 Epithelial-to-Mesenchymal Transition (EMT): Clinical Implications [Seite 80]
5.6.1 - Biology of epithelial-to-mesenchymal transition (EMT) [Seite 80]
5.6.2 - EMT: effects on cells and tissues [Seite 81]
5.6.3 - Induction of EMT: contribution of the tumor microenvironment [Seite 81]
5.6.4 - Stromal cells in tumors and their role in EMT induction [Seite 82]
5.6.4.1 - Macrophages [Seite 82]
5.6.4.2 - CD8T cells [Seite 83]
5.6.5 - Carcinoma-associated fibroblasts and endothelial cells [Seite 83]
5.6.6 - Epithelial-to-mesenchymal transition regulators [Seite 83]
5.6.6.1 - Transcription factors [Seite 83]
5.6.6.2 - MicroRNAs [Seite 84]
5.6.7 - Mesenchymal-to-epithelial transition (MET) [Seite 84]
5.6.8 - EMT: clinical implications [Seite 85]
5.6.9 - EMT and chemoresistance [Seite 86]
5.6.10 - Inhibition of EMT [Seite 86]
5.6.11 - Summary [Seite 87]
5.6.12 - Acknowledgements [Seite 87]
5.6.13 - References [Seite 87]
6 - PART II State-of-the-Science in Organ-Specific Biomarker Research [Seite 91]
6.1 - 7 Breast Cancer [Seite 93]
6.1.1 - Introduction [Seite 93]
6.1.2 - Genomic biomarkers of risk [Seite 93]
6.1.3 - Breast cancer development [Seite 94]
6.1.3.1 - Benign breast disease [Seite 94]
6.1.3.2 - Ductal carcinoma in situ (DCIS) [Seite 94]
6.1.3.3 - Lobular carcinoma in situ (LCIS) [Seite 95]
6.1.4 - Blood-based biomarkers for early detection [Seite 95]
6.1.4.1 - Current clinical practice [Seite 95]
6.1.4.2 - Protein biomarkers [Seite 97]
6.1.5 - The challenge of tumor heterogeneity [Seite 98]
6.1.5.1 - Autoantibodies [Seite 98]
6.1.5.2 - Glycosylation [Seite 98]
6.1.5.3 - Exosomes [Seite 99]
6.1.5.4 - Circulating tumor cells (CTC) [Seite 99]
6.1.5.5 - Cell-free DNA [Seite 99]
6.1.5.6 - microRNA [Seite 100]
6.1.5.7 - Prognostic tissue biomarkers of BBD and DCIS [Seite 100]
6.1.5.8 - Prognostic biomarkers of invasive carcinoma [Seite 101]
6.1.6 - Potential clinical applications of biomarkers for breast cancer [Seite 102]
6.1.6.1 - Improving risk assessment of healthy populations [Seite 102]
6.1.6.2 - Complementing mammographic screening [Seite 103]
6.1.7 - Summary [Seite 103]
6.1.8 - Conflict of interest [Seite 104]
6.1.9 - References [Seite 104]
6.2 - 8 Ovarian Cancer [Seite 109]
6.2.1 - Introduction [Seite 109]
6.2.2 - Origin of ovarian cancer [Seite 109]
6.2.2.1 - Ovarian surface [Seite 109]
6.2.2.2 - Secondary müllerian system [Seite 109]
6.2.2.3 - Fallopian tube [Seite 110]
6.2.2.4 - Endometriosis [Seite 110]
6.2.3 - Heterogeneity of epithelial ovarian cancer [Seite 111]
6.2.4 - Early detection of ovarian cancer [Seite 111]
6.2.4.1 - Challenges for early detection of ovarian cancer [Seite 112]
6.2.4.2 - Two-stage screening strategies [Seite 113]
6.2.4.3 - Enhancing the first stage of a two-stage screening strategy [Seite 114]
6.2.4.4 - Enhancing the second stage of two-stage screening [Seite 117]
6.2.5 - References [Seite 117]
6.3 - 9 Esophageal Cancer Biomarkers [Seite 120]
6.3.1 - Introduction [Seite 120]
6.3.2 - Molecular alterations in pre-malignant and malignant disease of the esophagus [Seite 121]
6.3.3 - Early detection markers for Barretts esophagus (BE) [Seite 122]
6.3.3.1 - Somatic mutations [Seite 122]
6.3.3.2 - Aberrantly methylated genes [Seite 122]
6.3.3.3 - miRNA [Seite 123]
6.3.3.4 - Protein biomarkers [Seite 126]
6.3.4 - Biomarkers for predicting the risk of progression of BE to EAC [Seite 126]
6.3.5 - Biomarkers for prognosis and disease recurrence [Seite 127]
6.3.6 - Biomarkers to predict treatment response [Seite 127]
6.3.7 - Obstacles to the discovery of useful biomarkers for BE and esophageal cancer [Seite 129]
6.3.8 - Conclusions [Seite 129]
6.3.9 - Acknowledgements [Seite 129]
6.3.10 - References [Seite 129]
6.4 - 10 Predictive Biomarkers for Therapy in Adenocarcinoma of the Upper Digestive Tract [Seite 134]
6.4.1 - Introduction [Seite 134]
6.4.2 - Importance of biomarkers in adenocarcinoma of the upper digestive tract (UDT) [Seite 134]
6.4.3 - Predictive biomarkers in UDT adenocarcinoma [Seite 135]
6.4.3.1 - Excision repair cross-complementing 1 (ERCC1) [Seite 135]
6.4.3.2 - NF-KB [Seite 135]
6.4.3.3 - TP53 [Seite 136]
6.4.3.4 - Chemotherapy-associated metabolism genes [Seite 136]
6.4.3.5 - ATP-binding cassette transporters (ABC transporters) [Seite 136]
6.4.3.6 - MicroRNA [Seite 137]
6.4.3.7 - Germline alterations (single nucleotide polymorphisms (SNPs)) [Seite 137]
6.4.3.8 - Biomarker signatures [Seite 137]
6.4.4 - Currently targeted biomarkers in UDT adenocarcinoma [Seite 139]
6.4.4.1 - Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER 2) [Seite 139]
6.4.4.2 - Vascular endothelial growth factor (VEGF) [Seite 139]
6.4.4.3 - Other targets under development [Seite 140]
6.4.5 - New horizons in predictive biomarkers for adenocarcinoma of the UDT [Seite 140]
6.4.6 - Conclusions [Seite 141]
6.4.7 - References [Seite 141]
6.5 - 11 Pancreatic Cancer [Seite 146]
6.5.1 - Introduction [Seite 146]
6.5.2 - Diagnostic markers [Seite 147]
6.5.2.1 - CA19-9 for PDA [Seite 147]
6.5.2.2 - Other markers for PDA [Seite 149]
6.5.2.3 - Markers for cystic lesions [Seite 149]
6.5.3 - Prognostic markers [Seite 150]
6.5.3.1 - CA19-9 for PDA [Seite 150]
6.5.3.2 - Investigational markers for PDA [Seite 151]
6.5.4 - Predictive markers [Seite 152]
6.5.4.1 - Investigational markers for PDA [Seite 152]
6.5.5 - Future directions [Seite 153]
6.5.6 - References [Seite 153]
6.6 - 12 Colon Cancer [Seite 157]
6.6.1 - Importance of colorectal cancer screening [Seite 157]
6.6.2 - Current screening modalities [Seite 157]
6.6.3 - Desirable properties of biomarkers for screening/early detection of colorectal cancer [Seite 158]
6.6.4 - Biomarker discovery, verification and validation [Seite 159]
6.6.5 - Stool-based biomarkers [Seite 160]
6.6.5.1 - Microbiome [Seite 160]
6.6.6 - Blood-based biomarkers [Seite 161]
6.6.6.1 - Proteins [Seite 161]
6.6.6.2 - Mass spectrometry protein profiling [Seite 161]
6.6.6.3 - Circulating tumor DNA [Seite 162]
6.6.6.4 - Methylated DNA [Seite 162]
6.6.6.5 - mRNAs [Seite 162]
6.6.6.6 - MicroRNAs (miRNAs) [Seite 162]
6.6.6.7 - Metabolomics [Seite 163]
6.6.7 - Urine-based biomarkers [Seite 163]
6.6.7.1 - DNA [Seite 163]
6.6.7.2 - Metabolomics [Seite 163]
6.6.7.3 - Proteins [Seite 164]
6.6.8 - Conclusion [Seite 164]
6.6.9 - References [Seite 164]
6.7 - 13 Prognostic and Predictive Biomarkers for Colorectal Cancer [Seite 167]
6.7.1 - Introduction [Seite 167]
6.7.2 - Definitions and types of biomarkers [Seite 167]
6.7.3 - Biomarkers of colorectal cancers (CRCS) [Seite 168]
6.7.3.1 - Race/ethnicity-based biomarkers [Seite 168]
6.7.3.2 - Exosomes as biomarkers [Seite 168]
6.7.3.3 - The metabolome as a source of biomarkers for CRCs [Seite 170]
6.7.3.4 - The kinome [Seite 171]
6.7.3.5 - miRNAs as biomarkers [Seite 171]
6.7.3.6 - Genetic alterations as biomarkers [Seite 172]
6.7.3.7 - Companion diagnostics [Seite 173]
6.7.4 - Challenges and future directions [Seite 173]
6.7.5 - Acknowledgements [Seite 174]
6.7.6 - References [Seite 174]
6.8 - 14 Early Detection of Lung Cancer [Seite 179]
6.8.1 - Introduction [Seite 179]
6.8.2 - The clinical context of early detection of lung cancer [Seite 180]
6.8.3 - Current status of early detection biomarkers for lung cancer [Seite 181]
6.8.3.1 - Tissue-based biomarkers [Seite 181]
6.8.3.2 - Biofluids-based markers [Seite 184]
6.8.4 - Current challenges in improving lung cancer diagnosis [Seite 191]
6.8.5 - Conclusions and future clinical perspectives [Seite 193]
6.8.6 - Acknowledgment [Seite 194]
6.8.7 - References [Seite 194]
6.9 - 15 Commonalities in Lung Cancer and COPD [Seite 201]
6.9.1 - Introduction [Seite 201]
6.9.2 - Natural history of COPD and lung cancer [Seite 202]
6.9.2.1 - Chronic obstructive lung disease (COPD) [Seite 202]
6.9.2.2 - Lung cancer [Seite 202]
6.9.3 - Potential link between COPD and lung cancer [Seite 203]
6.9.4 - Commonalities in the molecular pathogenesis of lung cancer and COPD [Seite 204]
6.9.4.1 - Inflammation [Seite 204]
6.9.4.2 - Molecular field of injury [Seite 205]
6.9.4.3 - Genetics [Seite 206]
6.9.4.4 - Epigenetic modifications [Seite 207]
6.9.5 - Challenges and future directions [Seite 208]
6.9.6 - References [Seite 209]
6.10 - 16 Prostate Cancer [Seite 213]
6.10.1 - Introduction [Seite 213]
6.10.2 - US Food and Drug Administration (FDA) approved/cleared clinical diagnostic tests [Seite 214]
6.10.2.1 - [-2]proPSA and the Phi index [Seite 215]
6.10.2.2 - Prostate Cancer Antigen 3 (PCA3) [Seite 216]
6.10.3 - Clinical Laboratory Improvement Amendments (CLIA) and Laboratory Developed Test (LDT) [Seite 216]
6.10.3.1 - TMPRSS2-ERG [Seite 217]
6.10.3.2 - Oncotype Dx [Seite 217]
6.10.3.3 - Prolaris Score [Seite 218]
6.10.3.4 - Prostarix [Seite 218]
6.10.3.5 - 4K Score [Seite 218]
6.10.4 - References [Seite 219]
7 - PART III Biomarkers, Screening and Precision Health: Implications for Public Health [Seite 223]
7.1 - 17 Improving the Clinical Validity of Biomarker Research in Cancer Detection [Seite 225]
7.1.1 - Background, purpose and organization [Seite 225]
7.1.2 - Distinguishing clinical validity from analytical validity and clinical utility [Seite 225]
7.1.3 - Internal validity and external validity [Seite 226]
7.1.4 - Past lessons: CEA blood test for colon cancer [Seite 226]
7.1.5 - Recent lessons: proteomics blood tests for ovarian cancer [Seite 226]
7.1.5.1 - Initial promising claims [Seite 227]
7.1.5.2 - Later promising claims lead to an NCI study to assess clinical validity [Seite 227]
7.1.5.3 - NCIs study to assess clinical validity [Seite 227]
7.1.5.4 - Thinking big: using banked specimens in both discovery and validation [Seite 228]
7.1.6 - Practical issues I: how validity "gets in" to a study (design and conduct) and is measured (interpretation and reporting) [Seite 229]
7.1.6.1 - Design [Seite 229]
7.1.6.2 - Conduct [Seite 230]
7.1.6.3 - Interpretation [Seite 230]
7.1.6.4 - Reporting [Seite 230]
7.1.7 - Practical issues II: how "valid" does a study need to be? And "when" or at what stage or phase is validity important - early (discovery) or late ("validation")? [Seite 230]
7.1.7.1 - Principles [Seite 231]
7.1.7.2 - Importance [Seite 231]
7.1.7.3 - Challenge of addressing bias in observational research [Seite 231]
7.1.7.4 - Confusion caused by terminology: the "validation study" [Seite 232]
7.1.7.5 - "Validity" of discovery research [Seite 232]
7.1.8 - Lessons for the future [Seite 233]
7.1.9 - References [Seite 233]
7.2 - 18 Cancer Overdiagnosis, Ramifications and Research Strategies [Seite 236]
7.2.1 - What is overdiagnosis? [Seite 236]
7.2.2 - Population-level data supporting the overdiagnosis [Seite 237]
7.2.3 - Evidence for overdiagnosis from screening at individual disease sites [Seite 238]
7.2.3.1 - Neuroblastoma [Seite 238]
7.2.3.2 - Breast cancer [Seite 238]
7.2.3.3 - Lung cancer [Seite 240]
7.2.3.4 - Prostate cancer [Seite 240]
7.2.3.5 - Thyroid cancer [Seite 241]
7.2.3.6 - Cancer of the kidney and renal pelvis [Seite 241]
7.2.3.7 - Melanoma [Seite 241]
7.2.3.8 - Overdiagnosis of non-invasive, premalignant lesions [Seite 241]
7.2.4 - Why does overdiagnosis matter and what can we do about it? [Seite 242]
7.2.5 - References [Seite 243]
7.3 - 19 Predictive Markers and Driver Genes From Treatment Trials: Potential Utility For Early Diagnosis [Seite 247]
7.3.1 - Introduction [Seite 247]
7.3.2 - Common predictive markers [Seite 248]
7.3.3 - Minimally invasive technologies [Seite 248]
7.3.4 - Mutational landscape of driver genes in cancer [Seite 248]
7.3.5 - What are the predictive markers that are most likely to be useful for early diagnosis? [Seite 252]
7.3.6 - The PI3K/AKT/PTEN pathway [Seite 252]
7.3.7 - The RAS/RAF/MAPK/ERK pathway [Seite 254]
7.3.7.1 - KRAS [Seite 254]
7.3.7.2 - BRAF [Seite 254]
7.3.7.3 - NRAS [Seite 254]
7.3.8 - TP53 [Seite 255]
7.3.9 - c-KIT [Seite 256]
7.3.10 - IDH1/2 [Seite 256]
7.3.11 - DNMT3A [Seite 257]
7.3.12 - Summary [Seite 257]
7.3.13 - References [Seite 258]
7.4 - 20 Statistical Consideration in Predictive and Prognostic Markers [Seite 261]
7.4.1 - Introduction [Seite 261]
7.4.2 - Biomarker identification and validation [Seite 262]
7.4.2.1 - Prognostic biomarkers versus predictive biomarkers [Seite 262]
7.4.2.2 - Biomarker trials [Seite 263]
7.4.2.3 - Model development [Seite 264]
7.4.2.4 - Regularized least squares regression models [Seite 265]
7.4.2.5 - Model validation and evaluation [Seite 265]
7.4.3 - Biomarker discover: challenges and obstacles [Seite 266]
7.4.3.1 - Data torture and multiple comparison problem [Seite 266]
7.4.3.2 - Statistical power [Seite 267]
7.4.3.3 - Reproducibility and generalizability [Seite 268]
7.4.4 - Discussion [Seite 268]
7.4.5 - References [Seite 269]
7.5 - 21 Clinical Validation of Molecular Biomarkers in Translational Medicine [Seite 272]
7.5.1 - Translational relevance [Seite 272]
7.5.2 - Introduction [Seite 272]
7.5.3 - Validation of biomarkers [Seite 273]
7.5.4 - Three stages of validation [Seite 274]
7.5.4.1 - Stage 1: identification, characterization, and evaluation (ICE) [Seite 275]
7.5.4.2 - Stage 2: data and model testing (DMT) [Seite 276]
7.5.4.3 - Stage 3: replication of results (ROR) [Seite 277]
7.5.5 - Issues related to validating biomarkers [Seite 277]
7.5.5.1 - Biomarker datasets [Seite 277]
7.5.5.2 - Statistical model instability [Seite 278]
7.5.5.3 - Clinical events [Seite 279]
7.5.5.4 - Combining molecular biomarkers [Seite 279]
7.5.5.5 - Time denomination of the biomarker [Seite 280]
7.5.6 - Conclusion [Seite 280]
7.5.7 - References [Seite 280]
7.6 - 22 Cancer Biomarker Assays: Performance Standards [Seite 283]
7.6.1 - Introduction [Seite 283]
7.6.2 - Assay development: analytical performance [Seite 283]
7.6.2.1 - General considerations [Seite 283]
7.6.2.2 - Precision [Seite 284]
7.6.2.3 - Trueness [Seite 284]
7.6.2.4 - Analytical sensitivity [Seite 285]
7.6.2.5 - Specificity and analytical interference [Seite 286]
7.6.2.6 - Carryover [Seite 287]
7.6.3 - Assay development: clinical performance [Seite 287]
7.6.3.1 - General considerations [Seite 287]
7.6.3.2 - Intended use [Seite 287]
7.6.3.3 - Clinical sensitivity and specificity [Seite 287]
7.6.3.4 - ROC analysis [Seite 288]
7.6.3.5 - Positive and negative predictive values [Seite 288]
7.6.4 - Conclusions [Seite 289]
7.6.5 - List of abbreviations [Seite 289]
7.6.6 - Competing interests [Seite 289]
7.6.7 - Authors contributions [Seite 289]
7.6.8 - References [Seite 289]
7.7 - 23 Bioethics and Cancer Biomarker Research [Seite 293]
7.7.1 - Introduction [Seite 293]
7.7.2 - What is bioethics? [Seite 293]
7.7.3 - Bioethics, ethics and the validation of cancer biomarkers [Seite 294]
7.7.4 - Case study: prostate specific antigen [Seite 294]
7.7.5 - Bioethical conclusions about validation [Seite 295]
7.7.6 - Data protection, confidentiality and the return of research results [Seite 296]
7.7.7 - Conclusions [Seite 297]
7.7.8 - References [Seite 297]
7.8 - 24 Colon Cancer Screening [Seite 299]
7.8.1 - Introduction [Seite 299]
7.8.1.1 - Molecular pathogenesis of colorectal cancer [Seite 299]
7.8.2 - Current screening practice methodologies: approaches and limitations [Seite 300]
7.8.2.1 - Screening modalities [Seite 300]
7.8.2.2 - Screening recommendations according to risk stratification [Seite 303]
7.8.3 - Adoption of biomarkers in current screening practice: challenges and limitations [Seite 307]
7.8.3.1 - Fecal markers [Seite 307]
7.8.3.2 - Serum markers [Seite 308]
7.8.4 - Summary [Seite 309]
7.8.5 - References [Seite 309]
8 - Index [Seite 313]
9 - Supplemental Images [Seite 321]
10 - EULA [Seite 337]