Cancer of the Breast

1. Introduction 2. Figure 1.1 3. Cancer Genes and Their Mutations 4. Identification of Cancer Genes 5. Cancer Gene Discovery by Sequencing Candidate Gene Families 6. Mutational Analysis of Exomes Using Sanger Sequencing 7. Next-Generation Sequencing and Cancer Genome Analysis 8. Whole-Genome Analysis Utilizing Second-Generation Sequencing 9. Whole-Exome Analysis Utilizing Second-Generation Sequencing 10. Figure 1.2 11. Table 1.1: Comparative Analysis of Next-Generation Sequencing Platforms 12. Figure 1.3 13. Figure 1.4 14. Figure 1.5 15. Somatic Alteration Classes Detected by Cancer Genome Analysis 16. Figure 1.6 17. Pathway-Oriented Models of Cancer Genome Analysis 18. Passenger and Driver Mutations 19. Figure 1.7 20. Figure 1.8 21. Figure 1.9 22. Table 1.2: Computational Tools and Databases Useful for Cancer Genome Analyses 23. Networks of Cancer Genome Projects 24. The Genomic Landscape of Cancers 25. Integrative Analysis of Cancer Genomics 26. Table 1.3: Useful Information for the Description and Management of Cancer 27. The Cancer Genome and the New Taxonomy of Tumors 28. Figure 1.10 29. Cancer Genomics and Drug Resistance 30. Perspectives of Cancer Genome Analysis 31. Acknowledgments 32. References 33. Chapter 2: Hallmarks of Cancer: An Organizing Principle for Cancer Medicine 34. Introduction 35. Hallmark Capabilities, in Essence 36. Sustaining Proliferative Signaling 37. Evading Growth Suppressors 38. Resisting Cell Death 39. Enabling Replicative Immortality 40. Inducing Angiogenesis 41. Activating Invasion and Metastasis 42. Reprogramming Energy Metabolism 43. Evading Immune Destruction 44. Figure 2.1 45. Two Ubiquitous Characteristics Facilitate the Acquisition of Hallmark Capabilities 46. An Enabling Characteristic: Genome Instability and Mutation 47. An Enabling Characteristic: Tumor-Promoting Inflammation 48. Figure 2.2 49. The Constituent Cell Types of the Tumor Microenvironment 50. Cancer-Associated Fibroblasts 51. Endothelial Cells 52. Pericytes 53. Immune Inflammatory Cells 54. Stem and Progenitor Cells of the Tumor Stroma 55. Heterotypic Signaling Orchestrates the Cells of the Tumor Microenvironment 56. Coevolution of the Tumor Microenvironment During Carcinogenesis 57. Cancer Cells, Cancer Stem Cells, and Intratumoral Heterogeneity 58. Figure 2.3 59. Figure 2.4 60. Figure 2.5 61. Figure 2.6 62. Therapeutic Targeting of the Hallmarks of Cancer 63. Figure 2.7 64. Conclusion and a Vision for the Future 65. Acknowledgment 66. References 67. Chapter 3: Molecular Methods in Cancer 68. Applications of Molecular Diagnostics in Oncology 69. Table 3.1: Genomic Alterations as Putative Predictive Biomarkers for Cancer Therapy 70. Figure 3.1 71. Figure 3.2 72. The Clinical Molecular Diagnostics Laboratory: Rules and Regulations 73. Specimen Requirements for Molecular Diagnostics 74. Molecular Diagnostics Testing Process 75. Figure 3.3 76. Technologies 77. Polymerase Chain Reaction 78. Targeted Mutation Analysis Methods 79. Whole Genome Analysis Methods 80. Table 3.2: Molecular Methods in Oncology 81. Figure 3.4 82. Figure 3.5 83. Figure 3.6 84. Figure 3.7 85. Figure 3.8 86. Figure 3.9 87. Figure 3.10 88. References 89. Part Ii: Etiology and Epidemiology of Cancer. Section 1: Etiology of Cancer 90. Chapter 4: Tobacco 91. Introduction 92. Epidemiology of Tobacco and Cancer 93. Tobacco Use Behaviors 94. Evolution of Tobacco Products 95. Table 4.1: Level of Evidence for Smoking-Attributable Cancers According to the United States Office of the Surgeon General by Cancer Site and Yearly Smoking-Attributable Mortality at Sites with Available Estimates, United States, 2004 96. Carcinogens in Tobacco Products and Processes of Cancer Development 97. Compounds of Particular Concern 98. How Tobacco Use Leads to Cancer 99. Table 4.2: Carcinogens in Tobacco and Tobacco Smoke Identified as Harmful and Potentially Harmful by the U.S. Food and Drug Administration, with International Agency for Research on Cancer Carcinogenecity (IARC) Classifications as of 2013 100. Table 4.3: Commonly Used Biomarkers of Exposure to Carcinogens in Tobacco Smoke 101. Table 4.4: Key Pathways and Processes Where Selected Smoke Constituents Are Activated and Detoxified 102. References 103. Chapter 5: Oncogenic Viruses 104. Principles of Tumor Virology 105. Table 5.1: Oncogenic Viruses 106. Papillomaviruses 107. Polyomaviruses 108. History 109. Merkel Cell Polyomavirus 110. Other Human Polyomaviruses 111. Figure 5.1 112. Epstein-Barr Virus 113. Kaposi’s Sarcoma Herpesvirus 114. History and Epidemiology 115. Kaposi’s Sarcoma-Associated Herpesvirus in Kaposi’s Sarcoma 116. Lymphoproliferative Disorders 117. Figure 5.2 118. Animal and Human Retroviruses 119. Human T-Cell Leukemia Virus Epidemiology 120. Human T-Cell Leukemia Virus Molecular Biology 121. Clinical Characteristics and Treatment of HTLV-Associated Malignancies 122. Figure 5.3 123. Hepatitis Viruses 124. Conclusion 125. References 126. Chapter 6: Inflammation 127. Introduction 128. Figure 6.1 129. Molecular Basis of Inflammation 130. Role of Inflammation in Transformation 131. Role of Inflammation in Survival 132. Role of Inflammation in Proliferation 133. Role of Inflammation in Invasion 134. Role of Inflammation in Angiogenesis 135. Role of Inflammation in Metastasis 136. Epigenetic Changes and Inflammation 137. Role of Inflammation in Cancer Diagnosis 138. Inflammation and Genomics 139. Inflammation and Targeted Therapies 140. Conclusions 141. References 142. Chapter 7: Chemical Factors 143. Introduction 144. The Nature of Chemical Carcinogens: Chemistry and Metabolism 145. Table 7.1: Known Chemical Carcinogens in Humansa 146. Animal Model Systems and Chemical Carcinogenesis 147. Molecular Epidemiology, Chemical Carcinogenesis, and Cancer Risk in Human Populations 148. Aristolochic Acid and Urothelial Cancers as a Model for Identifying Human Carcinogens 149. Figure 7.1 150. References 151. Chapter 8: Physical Factors 152. Introduction 153. Ionizing Radiation 154. Mechanisms of Damage Induction 155. Cellular Responses 156. Cancer Risks 157. Figure 8.1 158. Figure 8.2 159. Ultraviolet Light 160. Mechanisms of Damage Induction 161. Cellular Responses 162. Cell Death 163. Cancer Risks 164. Nonmelanoma Skin Cancer 165. Melanoma 166. Photoimmunosuppression 167. Figure 8.3 168. Radiofrequency and Microwave Radiation 169. Electromagnetic Fields 170. Asbestos 171. Nanoparticles 172. References 173. Chapter 9: Dietary Factors 174. Introduction 175. Methodologic Challenges 176. The Role of Individual Food and Nutrients in Cancer Etiology 177. Other Foods and Nutrients 178. Dietary Patterns 179. Diet during the Early Phases of Life 180. Diet after a Diagnosis of Cancer 181. Summary 182. Limitations 183. Future Directions 184. Recommendations 185. References 186. Chapter 10: Obesity and Physical Activity 187. Introduction 188. Breast Cancer 189. Colon and Rectal Cancer 190. Endometrial Cancer 191. Adenocarcinoma of the Esophagus 192. Kidney/Renal Cell Cancer 193. Pancreatic Cancer 194. Gallbladder Cancer 195. Non-Hodgkin Lymphoma 196. Prostate Cancer 197. Lung Cancer 198. Ovarian Cancer 199. Conclusions 200. Table 10.1: Summary of the Strength of the Observational Epidemiologic Evidence for Physical Activity as a Protective Factor and Obesity as a Risk Factor for Cancer, By Type of Cancer 201. References 202. Section 2: Epidemiology of Cancer 203. Chapter 11: Epidemiologic Methods 204. Introduction 205. Figure 11.1 206. Analytical Studies 207. Interpretation of Epidemiologic Findings 208. Cancer Outcomes Research 209. Molecular Epidemiology 210. References 211. Chapter 12: Trends in United States Cancer Mortality 212. Introduction 213. Cancer Surveillance Systems 214. Making Sense of Cancer Trends 215. Trends in Cancer Risk Factors and Screening 216. Table 12.1: Trends in Risk Factors and Cancer Screening Practices in the United States, 1990–2010a 217. Cancer Incidence and Mortality 218. Lung Cancer 219. Colorectal Cancer 220. Breast Cancer 221. Prostate Cancer 222. Other Cancers 223. Table 12.2: Trends in Age-Adjusted Cancer Incidence Rates in the United States by Cancer Site, 1990–2010a 224. Figure 12.1 225. Table 12.3: Trends in Age-Adjusted Cancer Mortality Rates in the United States by Cancer Site, 1990–2010a 226. Predicting Future Cancer Trends 227. References 228. Part Iii: Cancer Therapeutics 229. Chapter 13: Essentials of Radiation Therapy 230. Introduction 231. Biologic Aspects of Radiation Oncology 232. Radiation-Induced DNA Damage 233. Cellular Responses to Radiation-Induced DNA Damage 234. Chromosome Aberrations Result from Faulty DNA Double-Strand Break Repair 235. Membrane Signaling 236. The Effect of Radiation on Cell Survival 237. Figure 13.1 238. Figure 13.2 239. Figure 13.3 240. Figure 13.4 241. Figure 13.5 242. Figure 13.6 243. Figure 13.7 244. Figure 13.8 245. Figure 13.9 246. Figure 13.10 247. Factors That Affect Radiation Response 248. The Fundamental Principles of Radiobiology 249. Figure 13.11 250. Drugs That Affect Radiation Sensitivity 251. Radiation Physics 252. Physics of Photon Interactions 253. Photon Beam Generation and Treatment Delivery 254. Treatment Beam Characteristics and Dose-Calculation Algorithms 255. Figure 13.12 256. Figure 13.13 257. Figure 13.14 258. Figure 13.15 259. Figure 13.16 260. Figure 13.17 261. Figure 13.18 262. Treatment Planning 263. Figure 13.19 264. Figure 13.20 265. Figure 13.21 266. Other Treatment Modalities 267. Table 13.1: Common Isotopes for Brachytherapy Treatment 268. Clinical Applications of Radiation Therapy 269. Treatment Intent 270. Fractionation 271. Adverse Effects 272. Table 13.2: Radiation Tolerance Doses for Normal Tissues 273. Principles of Combining Anticancer Agents with Radiation Therapy 274. Figure 13.22 275. References 276. Chapter 14: Cancer Immunotherapy 277. Introduction 278. Human Tumor Antigens 279. Cancer/Germ-Line Antigens 280. Melanocyte Differentiation Antigens 281. Overexpressed Gene Products 282. Mutated Gene Products Recognized by CD8+ and CD4+ T Cells 283. Antigens Identified in Viral-Associated Cancers 284. Figure 14.1 285. Figure 14.2 286. Human Cancer Immunotherapies 287. Nonspecific Approaches to Cancer Immunotherapy 288. Checkpoint Modulators 289. Active Immunization Approaches to Cancer Therapy (Cancer Vaccines) 290. Adoptive Cell Transfer Immunotherapy 291. Genetic Modification of Lymphocytes for Use in Adoptive Cell Therapy: Basic Principles and Applications to Solid Tumors 292. Genetic Modification of Lymphocytes to Treat Hematologic Malignancies 293. Chimeric Antigen Receptors 294. Chimeric Antigen Receptors and T-Cell Receptors Targeting Hematologic Antigens Other than CD19 295. T-Cell Gene Therapy in the Setting of Allogeneic Hematopoietic Stem Cell Transplantation 296. Table 14.1: Three Main Approaches to Cancer Immunotherapy 297. Figure 14.3 298. Figure 14.4 299. Table 14.2: Experience with Therapeutic Cancer Vaccines 300. Figure 14.5 301. Figure 14.6 302. Table 14.3: Cell Transfer Therapy 303. Figure 14.7 304. Figure 14.8 305. Table 14.4: Surgery Branch, National Cancer Institute Program for the Application of Cell Transfer Therapy to a Wide Variety of Human Cancers 306. Table 14.5: Hematologic Antigens Targeted by Genetically-Modified T-Cells 307. Figure 14.9 308. References 309. Chapter 15: Pharmacokinetics and Pharmacodynamics of Anticancer Drugs 310. Introduction 311. Figure 15.1 312. Pharmacokinetic Concepts 313. Absorption 314. Disposition 315. Dose Proportionality 316. Figure 15.2 317. Pharmacodynamic Concepts 318. Table 15.1: Examples of Systemic Exposure as a Pharmacodynamic Marker of Anticancer Drug Effects 319. Variability in Pharmacokinetics/Pharmacodynamics 320. Body Size and Body Composition 321. Age 322. Pathophysiologic Changes 323. Sex Dependence 324. Drug Interactions 325. Inherited Genetic Factors 326. Figure 15.3 327. Table 15.2: Effect of Food on Exposure to Select Oral Anticancer Agents 328. Table 15.3: Effects of Common Herbal Products on Exposure to Anticancer Agents 329. Figure 15.4 330. Dose-Adaptation Using Pharmacokinetic/Pharmacodynamic Principles 331. References 332. Chapter 16: Pharmacogenomics 333. Introduction 334. Table 16.1: Clinical Examples of Genotype-Guided Cancer Chemotherapy 335. Pharmacogenomics of Tumor Response 336. Pathway Directed Anticancer Therapy 337. Application of Genomewide Gene Expression Profiling to Guide Therapy 338. Genetic-Guided Therapy Practical Issues in Somatic Analysis 339. Figure 16.1 340. Figure 16.2 341. Pharmacogenomics of Chemotherapy Drug Toxicity 342. Thiopurine Methyltransferase 343. Dihydropyrimidine Dehydrogenase (DPD) 344. Cytochrome P450 2D6 345. Figure 16.3 346. Conclusions and Future Directions 347. References 348. Chapter 17: Alkylating Agents 349. Perspectives 350. Chemistry 351. Figure 17.1 352. Classification 353. Alkyl Sulfonates 354. Aziridines 355. Triazines 356. Nitrogen Mustards 357. Nitrosoureas 358. Table 17.1: Major Classes of Clinically Useful Alkylating Agents 359. Table 17.2: Dose and Schedules of Clinically Useful Alkylating Agents 360. Clinical Pharmacokinetics/Pharmacodynamics 361. Figure 17.2 362. Therapeutic Uses 363. Toxicities 364. Complications with High-Dose Alkylating Agent Therapy 365. Alkylating Agent–Steroid Conjugates 366. Drug Resistance and Modulation 367. Recent Developments 368. References 369. Chapter 18: Platinum Analogs 370. Introduction 371. History 372. Platinum Chemistry 373. Platinum Complexes after Cisplatin 374. Carboplatin 375. Oxaliplatin 376. Nedaplatin and Lobaplatin 377. Newer Platinum Structures 378. Figure 18.1 379. Mechanism of Action 380. Cellular Responses to Platinum-Induced DNA Damage 381. Is DNA the Only Target? 382. Mechanisms of Resistance 383. Reduced Accumulation 384. Inactivation 385. Increased DNA Repair 386. Autophagy 387. Increased DNA Damage Tolerance 388. Figure 18.2 389. Clinical Pharmacology 390. Pharmacokinetics 391. Pharmacodynamics 392. Pharmacogenomics 393. Table 18.1: Comparative Parmacokinetics of Platinum Analogs After Bolus or Short Intravenous Infusion 394. Formulation and Administration 395. Toxicity 396. Cisplatin 397. Carboplatin 398. Oxaliplatin 399. Table 18.2: Toxicity Profiles of Platinum Analogs in Clinical Use 400. References 401. Chapter 19: Antimetabolites 402. Antifolates 403. Mechanism of Action 404. Mechanisms of Resistance 405. Clinical Pharmacology 406. Toxicity 407. Table 19.1: Antimetabolites: Indications, Doses and Schedules, and Toxicities 408. 5-Fluoropyrimidines 409. Mechanism of Action 410. Mechanisms of Resistance 411. Clinical Pharmacology 412. Biomodulation of 5-FU 413. Toxicity 414. Figure 19.1 415. Table 19.2: Toxicities of Different Forms of 5-FU 416. Capecitabine 417. Cytarabine 418. Gemcitabine 419. Mechanism of Action 420. Mechanisms of Resistance 421. Clinical Pharmacology 422. Toxicity 423. Figure 19.2 424. 6-Thiopurines 425. Fludarabine 426. Cladribine 427. Clofarabine 428. References 429. Chapter 20: Topoisomerase Interactive Agents 430. Classification, Biochemical, and Biologic Functions of Topoisomerases 431. Classification of Topoisomerases 432. Biochemical Characteristics and Cleavage Complexes of the Different Topoisomerases 433. Differential Topoisomerization Mechanisms: Swiveling Versus Strand Passage, DNA Versus RNA Topoisomerases 434. Table 20.1: Classification of Human Topoisomerases and Topoisomerase Inhibitors 435. Figure 20.1 436. Topoisomerase Inhibitors as Interfacial Poisons 437. Topoisomerase Inhibitors Act as Interfacial Inhibitors by Binding at the Topoisomerase–DNA Interface and Trapping Topoisomerase Cleavage Complexes 438. Top1cc-Targeted Drugs (Camptothecin and Noncamptothecin Derivatives) Kill Cancer Cells by Replication Collisions 439. Cytotoxic Mechanisms of Top2cc-Targeted Drugs (Intercalators and Demethyl Epipodophyllotoxins) 440. Figure 20.2 441. Topoisomerase I Inhibitors: Camptothecins and Beyond 442. Irinotecan 443. Topotecan 444. Camptothecin Conjugates and Analogs 445. Noncamptothecin Topoisomerase I Inhibitors 446. Figure 20.3 447. Table 20.2: U.S. Food and Drug Administration–Approved Camptothecin Analogs 448. Table 20.3: Topoisomerase I Inhibitors in Development 449. Topoisomerase II Inhibitors: Intercalators and Nonintercalators 450. Doxorubicin 451. Liposomal Doxorubicin 452. Daunorubicin 453. Epirubicin 454. Idarubicin 455. Cardiac Toxicity of Anthracyclines 456. Anthracenediones 457. Dactinomycin 458. Epipodophyllotoxins 459. Etoposide 460. Teniposide 461. Table 20.4: U.S. Food And Drug Administration–Approved Topoisomerase II Inhibitors in Clinical Use 462. Therapy-Related Secondary Acute Leukemia 463. Future Directions 464. References 465. Chapter 21: Antimicrotubule Agents 466. Microtubules 467. Figure 21.1 468. Taxanes 469. Mechanism of Action 470. Clinical Pharmacology 471. Drug Interactions 472. Toxicity 473. Table 21.1: Antimicrotubule Agents: Dosages and Toxicities 474. Vinca Alkaloids 475. Microtubule Antagonists 476. Mitotic Motor Protein Inhibitors 477. Mechanisms of Resistance to Microtubule Inhibitors 478. References 479. Chapter 22: Kinase Inhibitors as Anticancer Drugs 480. Introduction 481. Table 22.1: Kinase Inhibitors: Approved or Anticipated Approval In 2014 482. Early Successes: Targeting Cancers with Well-Known Kinase Mutations (BCR-ABL, KIT, HER2) 483. The Serendipity of Unexpected Clinical Responses: EGFR in Lung Cancer 484. A Mix of Science and Serendipity: PDGF Receptor–Driven Leukemias and Sarcoma 485. Exploiting the New Paradigm: Searching for Other Kinase-Driven Cancers 486. Rounding Out the Treatment of Myeloproliferative Disorders: JAK2 and Myelofibrosis 487. BRAF Mutant Melanoma: Several Missteps Before Finding the Right Inhibitor 488. Getting It Right: ALK and Lung Cancer 489. Extending the Model to RET Mutations in Thyroid Cancer: Clinical Responses, But Why? 490. FLT3 Inhibitors in Acute Myeloid Leukemia: Did the Genomics Mislead Us? 491. Kidney Cancer: Targeting the Tumor and the Host With Mammalian Target of Rapamycin and VEGF Receptor Inhibitors 492. Other Indications for mTOR Inhibitors: Breast Cancer and Tuberous Sclerosis Complex Mutant Cancers 493. Figure 22.1 494. Figure 22.2 495. Directly Targeting the PI3K Pathway 496. Combinations of Kinase Inhibitors to Induct Response and Prevent Resistance 497. Speculations on the Future Role of Kinase Inhibitors in Cancer Medicine 498. References 499. Chapter 23: Histone Deacetylase Inhibitors and Demethylating Agents 500. Introduction 501. Epigenetic Abnormalities and Gene Expression Changes in Cancer 502. Abnormal Gene Silencing 503. Chromatin in Gene Regulation 504. Enzymes Regulating DNA Methylation and Histone Acetylation 505. Reversal of Layers of Gene Silencing 506. DNA Methyltransferase Inhibitors 507. Figure 23.1 508. Figure 23.2 509. Table 23.1: Small Molecules Targeting Epigenetic Abnormalities in Clinical Development 510. Histone Deacetylase Inhibitors 511. Epigenetic Therapy for Hematologic Malignancies 512. New Aproaches to Epigenetic Therapy 513. References 514. Chapter 24: Proteasome Inhibitors 515. Biochemistry of the Ubiquitin-Proteasome Pathway 516. Proteasome Inhibitors 517. Chemical Classes of Proteasome Inhibitors in Clinical Development 518. Preclinical Activity of Proteasome Inhibitors 519. Pharmacokinetics and Pharmacodynamics of Proteasome Inhibitors in Animals 520. Table 24.1: Proteasome Inhibitors in Clinical Development 521. Proteasome Inhibitors in Cancer 522. References 523. Chapter 25: Poly (ADP-ribose) Polymerase Inhibitors 524. Introduction 525. Cellular DNA Repair Pathways 526. The Development of PARP Inhibitors 527. BRCA1 and BRCA2 Mutations and DNA Repair 528. PARP-1 Inhibition as a Synthetic Lethal Therapeutic Strategy for the Treatment of BRCA-Deficient Cancers 529. Initial Clinical Results Testing Synthetic Lethality of PARP Inhibitors and BRCA Mutation 530. Table 25.1: PARP Inhibitors in Late Stage Clinical Development 531. The Use of PARP Inhibitors in Sporadic Cancers 532. Mechanisms of Resistance to PARP Inhibitors 533. Prospects 534. References 535. Chapter 26: Miscellaneous Chemotherapeutic Agents 536. Homoharringtonine and Omacetaxine 537. L-Asparaginase 538. Bleomycin 539. Procarbazine 540. Vismodegib 541. Ado-Trastuzumab Emtansine 542. Sirolimus and Temsirolimus 543. Everolimus 544. Thalidomide, Lenalidomide, and Pomalidomide 545. Thalidomide 546. Lenalidomide 547. Pomalidomide 548. Table 26.1: Miscellaneous Chemotherapeutic Agents 549. Table 26.2: U.S. Food And Drug Administration Hematology Oncology Drug Approvals 2010–2013 550. References 551. Chapter 27: Hormonal Agents 552. Introduction 553. Table 27.1: Overview of Major Hormonal Agents Used in Cancer 554. Selective Estrogen Receptor Modulators 555. Tamoxifen 556. Pharmacology 557. Toremifene 558. Pharmacology 559. Raloxifene 560. Pharmacology 561. Fulvestrant 562. Pharmacology 563. Figure 27.1 564. Figure 27.2 565. Aromatase Inhibitors 566. Letrozole and Anastrozole 567. Exemestane 568. Side Effects of Exemestane 569. Pharmacology 570. Figure 27.3 571. Gonadotropin-Releasing Hormone Analogs 572. Gonadotropin-Releasing Hormone Antagonists 573. Antiandrogens 574. Novel Antiandrogens 575. Other Sex Steroid Therapies 576. Other Hormonal Therapies 577. References 578. Chapter 28: Antiangiogenesis Agents 579. Introduction 580. Understanding the Angiogenic Process 581. Angiogenic Switch and Regulatory Proteins 582. Endogenous Inhibitors of Angiogenesis 583. Table 28.1: Examples of Endogenous Inhibitors of Angiogenesis 584. Drug Development of Angiogenesis Inhibitors 585. Rationale for Antiangiogenic Therapy 586. Modes of Action of Antiangiogenic Agents 587. Table 28.2: Antiangiogenic Agents that Have Received U.S. Food and Drug Administration Approval for Cancer Treatment 588. Table 28.3: Examples of Drugs that Possess Antiangiogenic Activity or Inhibit Angiogenesis as a Secondary Function 589. Clinical Utility of Approved Antiangiogenic Agents in Cancer Therapy 590. Combination Therapies 591. Biomarkers of Antiangiogenic Therapy 592. Resistance to Antiangiogenic Therapy 593. References 594. Chapter 29: Monoclonal Antibodies 595. Introduction 596. Table 29.1: FDA Approved Antibodies for the Treatment of Cancer 597. Immunoglobulin Structure 598. Structural and Functional Domains 599. Figure 29.1 600. Modified Antibody-Based Molecules 601. Table 29.2: Rules for Naming MAb for the Treatment of Cancer 602. Factors Regulating Antibody-Based Tumor Targeting 603. Unconjugated Antibodies 604. Cell-Mediated Cytotoxicity 605. Complement-Dependent Cytotoxicity 606. Figure 29.2 607. Altering Signal Transduction 608. Immunoconjugates 609. Antibodies Approved for Use in Solid Tumors 610. Antibodies Used in Hematologic Malignancies 611. Conclusion 612. References 613. Chapter 30: Assessment of Clinical Response 614. Introduction 615. From Calipers and Rulers in Lymphoma to the Bidimensional World Health Organization Criteria 616. Table 30.1: Key Features of Response Criteria 617. Figure 30.1 618. Assessing Response 619. Alternate Response Criteria 620. Severity-Weighted Assessment Tool Score in Cutaneous T-Cell Lymphoma 621. Pathologic Complete Response in Breast Cancer 622. Computed Tomography-Based Tumor Density 623. FDG-PET 624. Serum Biomarkers of Response 625. Circulating Tumor Cells and Circulating Tumor DNA 626. Table 30.2: Alternate Response Criteria: Biomarkers 627. Determining Outcome 628. Overall Response Rate, Duration of Response, and Stable Disease 629. Progression-Free Survival, Time to Progression, and Time to Treatment Failure 630. Overall Survival 631. Kaplan–Meier Plots 632. Hazard Ratios 633. Forest Plots 634. Beyond Dichotomized Data 635. Table 30.3: A Comparison of Important Cancer Approval Endpoints 636. Figure 30.2 637. Figure 30.3 638. Figure 30.4 639. Figure 30.5 640. References 641. Part Iv: Cancer Prevention and Screening 642. Chapter 31: Tobacco Use and the Cancer Patient 643. Introduction 644. Neurobiology of Tobacco Dependence 645. Tobacco Use Prevalence and the Evolution of Tobacco Products 646. Tobacco Use by the Cancer Patient 647. The Clinical Effects of Smoking on the Cancer Patient 648. Addressing Tobacco Use by the Cancer Patient 649. National Oncology Association Statements and Clinical Practice Guidelines 650. Smoking Cessation Guidelines 651. Implementing Smoking Cessation Into Clinical Practice 652. Pharmacologic Treatment for Smoking Cessation 653. Empirically Tested Cessation Interventions with Cancer Patients 654. Current Tobacco Assessment and Cessation Support by Oncologists 655. Examples of Model Tobacco Treatment Programs 656. Figure 31.1 657. Table 31.1: Additional Tobacco Cessation Resources for Patients and Cliniciansa 658. Table 31.2: Select Treatment Strategies Used for Tobacco Cessation Treatments 659. Table 31.3: First-Line Pharmacotherapy Agents for the Treatment of Nicotine Depedence 660. Table 31.4: Attributes of Prototypical Tobacco Treatment Programs 661. Future Considerations 662. References 663. Chapter 32: Role of Surgery in Cancer Prevention 664. Introduction 665. Patients at High Risk for Breast Cancer 666. Identification of Patients at Risk 667. Surgical Issues and Technique 668. Table 32.1: Hereditary Carcinoma Syndromes Including Breast Cancer 669. Hereditary Diffuse Gastric Cancer 670. Figure 32.1 671. Figure 32.2 672. Surgical Prophylaxis of Hereditary Ovarian and Endometrial Cancer 673. Hereditary Ovarian Cancer (BRCA1, BRCA2) 674. Figure 32.3 675. Hereditary Endometrial Cancer (Lynch Syndrome) 676. Gynecologic Cancer Risk in Very Rare Hereditary Cancer Syndromes 677. Multiple Endocrine Neoplasia Type 2 678. Gene Carriers 679. RET Genotype-Phenotype Correlations 680. Risk-Reducing Thyroidectomy in RET Mutation Carriers 681. Follow-up 682. Conclusions 683. Table 32.2: Clinical Features of Sporadic Medullay Thyroid Carcinoma, Multiple Endocrine Neoplasia 2A, Multiple Endocrine Neoplasia 2B, and Familial Medullay Thyroid Carcinoma 684. Figure 32.4 685. Figure 32.5 686. Familial Adenomatous Polyposis, MYH-Associated Poluposis, and Lynch Syndrome 687. Familial Adenomatous Polyposis 688. MYH-Associated Polyposis 689. Lynch Syndrome 690. Figure 32.6 691. Table 32.3: The Revised Bethesda Guidelines for Testing Colorectal Tumors for Microsatellite Instability 692. Table 32.4: Prophylactic Total Abdominal Colectomy and Ileorectal Anastomosis for Lynch Syndrome Patients without Cancer 693. References 694. Chapter 33: Cancer Risk Reducing Agents 695. Why Cancer Prevention as a Clinical Oncology Discipline 696. Figure 33.1 697. Defining Cancer Risk–Reducing Agents (Chemoprevention) 698. Identifying Potential Cancer Risk–Reducing Agents 699. Table 33.1: Molecular Mechanisms Common to Transforming Cells and Potential Preventive Interventions 700. Preclinical Development of Cancer Risk–Reducing Agents 701. Biochemical Prescreening Assays 702. In Vitro Efficacy Models 703. Preclinical In Vivo Models for Cancer Risk–Reducing Agent Efficacy Testing 704. Table 33.2a: Chemical Carcinogenesis Models Used for Screening of Cancer Risk–Reducing Agents for Common Epithelial Neoplasms in Animals 705. Table 33.2b: Selected Transgenic Animal Models for Carcinogenesis Evaluation 706. Clinical Development of Cancer Risk–Reducing Agents 707. Special Features of Cancer Risk–Reducing Agent Development 708. Biomarkers as Cancer Risk–Reducing Agent Targets and Efficacy End Points 709. Phases of Cancer Risk–Reducing Agent Development 710. Table 33.3: Common Intraepithelial Neoplasias 711. Table 33.4: Characteristics of Biomarkers for Use as End Points in Cancer Risk–Reducing Agent Efficacy Assessment 712. Micronutrients 713. Definition 714. Retinoids, Carotenoids, and Antioxidant Nutrients 715. Summary and Conclusion: Micronutrients 716. Table 33.5: Larger, Randomized Trials of Retinoids in Human Cancer Risk Reduction with Cancer Outcomesa,b 717. Table 33.6: Randomized Trials of Antioxidant Nutrients in Human Cancer Risk Reduction with Cancer Outcomesa 718. Anti-Inflammatory Drugs 719. Mechanism 720. Epidemiology 721. Evidence in Preclinical In Vivo Carcinogenesis Models 722. Clinical Trials 723. Table 33.7: Summary of Clinical Trials of Nonsteroidal Anti-Inflammatory Drugs as Colorectal Cancer Risk–Reducing Agents 724. Epigenetic Targeting Agents (Selective Estrogen Receptor Modulators, 5α-Steroid Reductase Inhibitors, Polyamine Inhibitors) 725. Selective Estrogen Receptor Modulators 726. 5α-Steroid Reductase Inhibitors 727. Table 33.8: Phase III, Randomized, Controlled Clinical Trials of SERMs for the Prevention of Breast Cancer 728. Table 33.9: Phase III, Randomized, Controlled Clinical Trials of Aromatase Inhibitors for the Prevention of Breast Cancer 729. Table 33.10: Phase III, Randomized, Controlled Clinical Trials of 5α-Steroid Reductase Inhibitors for the Prevention of Prostate Cancer 730. Signal Transduction Modifiers 731. Difluoromethylornithine 732. Statins 733. Bisphosphonates 734. Metformin 735. Diet-Derived Natural Products 736. Table 33.11: Summary of Clinical Trials of Difluoromethylornithine as a Cancer Risk–Reducing Agent 737. Table 33.12: Selected Diet-Derived Natural Products with Cancer Risk–Reducing Activity 738. Anti-Infectives 739. Multiagent Approaches to Cancer Risk Reduction 740. References 741. Chapter 34: Cancer Screening 742. Introduction 743. Performance Characteristics 744. Table 34.1: Performance Characteristics of a Screening Test 745. Table 34.2: Positive Predictive Value Given Varying Sensitivity and Specificity and Prevalence 746. Assessing Screening Tests and Outcomes 747. Screening Test Results 748. Assessing Screening Outcomes 749. Figure 34.1 750. Figure 34.2 751. Problems with Randomized Trials 752. Screening Guidelines and Recommendations 753. Table 34.3: Screening Recommendations for Normal-Risk Asymptomatic Subjects 754. Breast Cancer 755. Effectiveness of Breast Cancer Screening 756. Screening Women Age 40 to 49 757. Screening Women at High Risk 758. Breast Density 759. Ductal Carcinoma In Situ 760. Harms 761. Recommendations 762. Table 34.4: Randomized Controlled Trials 763. Colon Cancer Screening 764. Current Recommendations 765. Table 34.5: Colon Cancer Screening Recommendations for People with Familial or Inherited Risk 766. Other Cancers of the Gastrointestinal Tract 767. Gynecologic Cancer 768. Lung Cancer Screening 769. Prostate Cancer Screening 770. Skin Cancer Screening 771. References 772. Chapter 35: Genetic Counseling 773. Introduction 774. Table 35.1: How to Find a Genetic Counselor for Your Patient 775. Who Is a Candidate for Cancer Genetic Counseling? 776. Table 35.2: Risk Factors that Warrant Genetic Counseling for Hereditary Cancer Syndromes 777. Components of the Cancer Genetic Counseling Session 778. Issues in Cancer Genetic Counseling 779. Recent Advances and Future Directions 780. References 781. Part V: Cancer of the Breast 782. Chapter 36: Molecular Biology of Breast Cancer 783. Introduction 784. Genetics of Breast Cancer 785. Figure 36.1 786. Hereditary Breast Cancer 787. High-Penetrance, Low-Frequency Breast Cancer Predisposition Genes 788. Moderate-Penetrance, Low-Frequency Breast Cancer Predisposition Genes 789. Low-Penetrance, High-Frequency Breast Cancer Predisposition Genes and Loci 790. Microsatellite Instability in Breast Cancer 791. MicroRNA and Cancer Susceptibility 792. Table 36.1: Breast Cancer Susceptibility Genes and Loci 793. Table 36.2: High Penetrance: Modifiers of BRCA1/2 794. Somatic Changes in Breast Cancer 795. Transcriptional Profiling of Breast Cancer 796. Epigenetics of Breast Cancer 797. Protein/Pathway Alterations 798. Estrogen Receptor Pathway 799. Therapeutic Targets in Breast Cancer 800. Figure 36.2 801. Summary 802. References 803. Chapter 37: Malignant Tumors of the Breast 804. Introduction 805. Anatomy of the Breast 806. Figure 37.1 807. Risk Factors for Breast Cancer 808. Familial Factors 809. Inherited Predisposition to Breast Cancer 810. Hormonal Factors 811. Dietary and Lifestyle Factors 812. Benign Breast Disease 813. Breast Density 814. Environmental Factors 815. Table 37.1: Factors Suggestive of BRCA1 or BRCA2 Mutation 816. Table 37.2: Magnitude of Risk of Known Breast Cancer Risk Factors 817. Management of the High-Risk Patient 818. Table 37.3: American Cancer Society Guidelines for Magnetic Resonance Imaging Screening 819. Table 37.4: A Comparison of Tamoxifen Chemoprevention Studies 820. Table 37.5: Outcome of Tamoxifen Chemoprevention Studies 821. Table 37.6: Outcome of Bilateral Prophylatic Mastectomy in High-Risk Women 822. Diagnosis and Biopsy 823. Table 37.7: Indications for Surgical Biopsy After Core Needle Biopsy 824. Lobular Carcinoma in Situ 825. Ductal Carcinoma in Situ 826. Treatment of the Breast 827. Treatment of the Axilla 828. Endocrine Therapy 829. Table 37.8: Randomized Trials of Excision with or without Radiotherapy in Ductal Carcinoma In Situ 830. Staging 831. Tumor, Node, and Metastases Definitions 832. Table 37.9: American Joint Committee on Cancer Staging 833. Pathology of Breast Cancer 834. Local Management of Invasive Cancer 835. Breast-Conserving Therapy 836. Risk Factors for Local Recurrence Following Conservative Surgery and Radiation Therapy 837. Preservation of a Cosmetically Acceptable Breast 838. Guidelines for Patient Selection 839. Absolute and Relative Contraindications to Breast-Conserving Therapy (National Comprehensive Cancer Network 2014) 840. Preoperative Systemic Therapy for Operable Cancer 841. Conservative Surgery Without Radiation Therapy 842. Hypofractionated Whole-Breast and Accelerated Partial-Breast Irradiation 843. Toxicities of Breast Radiotherapy 844. Mastectomy 845. Table 37.10: Ten-Year Local Recurrence Rates in Recent National Surgical Adjuvant Breast and Bowel Project Trials 846. Figure 37.2 847. Figure 37.3 848. Table 37.11: Trials of Tamoxifen with or without Radiotherapy After Breast-Conserving Therapy 849. Table 37.12: Five-Year Rates of Local Recurrence in Tamoxifen with or without Radiotherapy Trials 850. Table 37.13: Common Reproductive Options After Mastectomy 851. Figure 37.4 852. Management of the Axilla 853. Table 37.14: Accuracy of Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Patients with Lymph Node Involvement at Presentation 854. Table 37.15: Recent Trials of Axillary Management 855. Postmastectomy Radiation Therapy 856. Table 37.16: Five-Year Local-Regional Recurrence Rates and Fifteen-Year Breast Cancer Mortality Rates in the Three Groups for Patients Randomly Assigned to Postmastectomy Radiation Therapy or Not 857. Prognostic and Predictive Factors in Breast Cancer 858. Other Factors 859. Molecular and Genomic Factors 860. Table 37.17: Association of Clinicopathologic Features of Breast Cancer with Intrinsic Subtype 861. Adjuvant Systemic Therapy 862. Adjuvant Endocrine Therapy 863. Adjuvant Chemotherapy 864. Adjuvant Trastuzumab Therapy for HER2-Overexpressing Breast Cancer 865. Table 37.18: Overview of Adjuvant Treatment Approaches in Breast Cancer 866. Table 37.19: Major Studies Comparing Adjuvant Therapy Incorporating Aromatase Inhibitors with Five Years of Tamoxifen 867. Table 37.20: Adjuvant Trials of Trastuzumab 868. Integration of Multimodality Primary Therapy 869. Table 37.21: International Recommendations for Adjuvant Chemotherapy 870. Follow-Up for Breast Cancer Survivors 871. Table 37.22: Breast Cancer Follow-Up 872. Special Therapeutic Problems 873. Management of Local-Regional Recurrence 874. Metastatic Disease 875. Endocrine Therapy for Metastatic Breast Cancer 876. Chemotherapy for Metastatic Breast Cancer 877. Anti-HER2 Therapy for Metastatic Breast Cancer 878. Emerging Options for BRCA1- or BRCA2-Associated Breast Cancer 879. Treatment of Special Metastatic Sites in Patients with Breast Cancer 880. Table 37.23: Endocrine Therapies for Metastatic Breast Cancer 881. Table 37.24: Common Chemotherapy Agents and Combinations for Advanced Breast Cancer 882. References 883. Chapter 38: Genetic Testing in Breast Cancer 884. Introduction 885. Identification of High-Risk Individuals 886. Genetic Testing 887. BRCA1 and BRCA2 888. Description 889. Identifying BRCA1/2 Carriers 890. Cancer Risks 891. Management 892. Psychosocial Considerations 893. Table 38.1: BRCA1/2 Cancer Risks 894. Table 38.2: National Comprehensive Cancer Network Guidelines for Management of BRCA1/2 Carriers 895. TP53 896. Description 897. Identifying Li-Fraumeni Syndrome 898. Cancer Risks 899. Psychosocial Issues 900. Table 38.3: Tumors Reported to Be Associated with Li-Fraumeni Syndrome 901. Table 38.4: Clinical Criteria for Classic Li-Fraumeni Syndrome 902. Cowden Syndrome (Phosphate and Tensin Homolog) 903. Description 904. Diagnostic Criteria Testing Criteria 905. Identifying Cowden Syndrome 906. Cancer Risks 907. Management 908. Psychosocial Issues 909. Table 38.5: National Comprehensive Cancer Network Guidelines (V.1.2016): Testing Criteria for Cowden Syndrome 910. Table 38.6: Cancer Risks Associated with Cowden Syndrome 911. Table 38.7: National Comprehensive Cancer Network Guidelines (V.1.2016) for Cowden Syndrome Management 912. Other Genetic Mutations and Breast Cancer 913. STK11 914. CDH1 915. Table 38.8: Clinical Criteria for Peutz-Jeghers Syndrome and Hereditary Diffuse Gastric Cancer Syndrome 916. Moderate- and Low-Penetrance Breast Cancer Genes 917. Conclusion 918. References 919. Appendix 920. Remarks 921. Glossary