A Beginner's Guide to Targeted Cancer Treatments and Cancer Immunotherapy E-Book

Elaine Vickers

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1067

Veröffentlichungsjahr: 2024

Beschreibung

Demystifying the science behind new cancer treatments

A clear and accessible guide written in everyday language for nurses and other healthcare professionals

A Beginner’s Guide to Targeted Cancer Treatments and Cancer Immunotherapy helps readers understand the science behind many of the newer drug treatments for cancer. Assuming only a basic familiarity with cell biology, this easy-to-digest guide describes how our increased understanding of cancer has been translated into the creation of new cancer treatments with a wide range of targets.

Gifted communicator and educator Dr. Elaine Vickers helps you understand the mechanisms of a wide range of individual targeted therapies and immunotherapies — enabling you to communicate effectively with your colleagues and patients. Concise chapters explain how new cancer drugs and immunotherapies work, discuss their benefits, identify their limitations, and more.

Now in its second edition, this popular handbook is fully revised to reflect the latest developments in targeted drug therapies and immunotherapies. Entirely new chapters on advancements in various immunotherapies are accompanied by more than 100 new and updated color illustrations.

• Provides an up-to-date overview of relevant treatment targets for all major cancer types, including hematological cancers
• Describes cancer biology and the relationship between cancer and the immune system
• Offers valuable insights into cell communication pathways as a common target
• Covers small molecule drugs, antibody-based treatments, and cellular therapies, including novel immunotherapies

A Beginner’s Guide to Targeted Cancer Treatments and Cancer Immunotherapy is a must-have resource for trainees, practicing nurses, and other healthcare professionals involved in the care of cancer patients, as well as non-specialists who encounter cancer data or cancer terminology in their field.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright Page

Acknowledgments

Praise for the First Edition

About the Author

How to Use This Book

CHAPTER 1: An Introduction to Cancer Cell Biology and Genetics

1.1 INTRODUCTION

1.2 DNA DAMAGE IS THE CAUSE OF EVERY CANCER

1.3 THE DEFINING FEATURES (HALLMARKS) OF CANCER CELLS

1.4 VARIATION AMONG CANCER CELLS IN A SINGLE TUMOR

1.5 CANCER’S RELATIONSHIP WITH OUR IMMUNE SYSTEM

1.6 THE CANCER MICROENVIRONMENT

1.7 CANCER SPREAD/METASTASIS

1.8 CANCER STEM CELLS

1.9 UNIQUE PROPERTIES OF HEMATOLOGICAL CANCERS

1.10 OBSTACLES THAT PREVENT US FROM CURING CANCER

1.11 FINAL THOUGHTS

REFERENCES

CHAPTER 2: Monoclonal Antibodies and Small Molecules as Cancer Treatments

2.1 INTRODUCTION

2.2 ANTIBODY‐BASED CANCER TREATMENTS

2.3 SMALL MOLECULE CANCER TREATMENTS

2.4 TREATMENT COMBINATIONS

2.5 FINAL THOUGHTS

REFERENCES

CHAPTER 3: Treatments that Target Cell Communication

3.1 INTRODUCTION

3.2 GROWTH FACTOR‐CONTROLLED SIGNALING PATHWAYS

3.3 GROWTH FACTOR RECEPTORS IN CANCER

3.4 DRUGS THAT TARGET EGFR

3.5 DRUGS THAT TARGET HER2

3.6 DRUGS THAT BLOCK OTHER GROWTH FACTOR RECEPTORS

3.7 TARGETING THE MAPK SIGNALING PATHWAY

3.8 TARGETING THE PI3K/AKT/MTOR SIGNALING PATHWAY

3.9 TARGETING THE JAK‐STAT PATHWAY

3.10 BCR‐ABL INHIBITORS

3.11 FINAL THOUGHTS

REFERENCES

CHAPTER 4: More Targets and Treatments

4.1 ANGIOGENESIS INHIBITORS

4.2 ANTIBODY CONJUGATES

4.3 PARP INHIBITORS

4.4 CDK INHIBITORS AND OTHER CELL CYCLE‐TARGETED TREATMENTS

4.5 HEDGEHOG PATHWAY INHIBITORS

4.6 TARGETING EPIGENETIC ENZYMES

4.7 TARGETING CELL SURVIVAL

4.8 TARGETING B CELL RECEPTOR SIGNALING

4.9 NUCLEAR TRANSPORT INHIBITORS

4.10 PROTEASOME INHIBITORS

4.11 FINAL THOUGHTS

REFERENCES

CHAPTER 5: Immunotherapy with Checkpoint Inhibitors

5.1 THE IMPORTANCE OF T CELLS

5.2 AN INTRODUCTION TO IMMUNE CHECKPOINT INHIBITORS

5.3 HOW CHECKPOINT INHIBITORS WORK

5.4 LESSONS LEARNED FROM CHECKPOINT INHIBITOR TRIALS

5.5 WHY SOME PATIENTS BENEFIT FROM CHECKPOINT INHIBITORS AND OTHERS DON’T

5.6 BIOMARKERS OF RESPONSE TO CHECKPOINT INHIBITORS

5.7 CHECKPOINT INHIBITOR COMBINATIONS

5.8 NOVEL CHECKPOINT INHIBITORS AND ACTIVATORS

5.9 FINAL THOUGHTS

REFERENCES

CHAPTER 6: Other Forms of Immunotherapy

6.1 INTRODUCTION

6.2 NAKED ANTIBODIES THAT TRIGGER AN IMMUNE RESPONSE

6.3 IMMUNOMODULATORS AND CELMoDs

6.4 INTRODUCTION TO ADOPTIVE CELL THERAPIES

6.5 TUMOR‐INFILTRATING LYMPHOCYTE THERAPY

6.6 CAR T CELL THERAPY

6.7 TCR‐ENGINEERED T CELL THERAPY

6.8 CELL THERAPY WITH OTHER WHITE BLOOD CELLS

6.9 T CELL ENGAGERS

6.10 CANCER TREATMENT VACCINES

6.11 FINAL THOUGHTS

REFERENCES

CHAPTER 7: Treatments Relevant to Individual Cancer Types

7.1 INTRODUCTION

7.2 TREATMENTS FOR BREAST CANCER

7.3 TREATMENTS FOR BOWEL AND ANAL CANCERS

7.4 TREATMENTS FOR LUNG CANCER

7.5 TREATMENTS FOR PROSTATE, TESTICULAR, AND PENILE CANCERS

7.6 TREATMENTS FOR HEAD AND NECK CANCER

7.7 TREATMENTS FOR ESOPHAGEAL, GASTROESOPHAGEAL JUNCTION, AND STOMACH CANCERS

7.8 TREATMENTS FOR PANCREATIC, BILE DUCT, AND PRIMARY LIVER CANCERS

7.9 TREATMENTS FOR KIDNEY AND BLADDER CANCERS

7.10 TREATMENTS FOR OVARIAN CANCER

7.11 TREATMENTS FOR OTHER GYNAECOLOGICAL CANCERS

7.12 TREATMENTS FOR BRAIN AND CNS CANCERS

7.13 TREATMENTS FOR SKIN CANCER

7.14 TREATMENTS FOR B CELL AND T CELL LEUKEMIAS

7.15 TREATMENTS FOR NON‐HODGKIN LYMPHOMAS

7.16 TREATMENTS FOR HODGKIN LYMPHOMA AND MYELOMA

7.17 TREATMENTS FOR MYELOID CELL CANCERS

7.18 TREATMENTS FOR CHILDHOOD CANCERS

REFERENCES

Appendix

INFORMATION ON CELLS, DNA, GENES, AND CHROMOSOMES

Glossary of Terms

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 A selection of some of the most commonly mutated oncogenes, tumor...

Table 1.2 The expected incidence of various hematological cancers in the Un...

Table 1.3 Some of the common translocations found in hematological cancer c...

Chapter 2

Table 2.1 Examples of targets and uses of antibody‐based cancer treatments....

Table 2.2 Comparison of different types of kinase inhibitors.

Table 2.3 Kinase inhibitors used as cancer treatments and their targets.

Table 2.4 Small molecules with non‐kinase targets.

Chapter 3

Table 3.1 Some growth factor receptors implicated in cancer.

Table 3.2 Treatments that target EGFR.

Table 3.3 Comparison of first‐, second‐, and third‐generation EGFR kinase i...

Table 3.4 Treatments that target HER2 [87–93].

Table 3.5 Comparison of HER2‐targeted kinase inhibitors.

Table 3.6 Treatments that target growth factor receptors other than EGFR or...

Table 3.7 Cancers in which

NTRK

gene fusions are found.

Table 3.8 Summary of licensed drugs that block the MAPK pathway.

Table 3.9 Frequency and identity of

RAS

gene mutations in different cancer ...

Table 3.10 Frequency of

BRAF

gene mutations in a range of cancer types.

Table 3.11 Summary of B‐Raf inhibitors.

Table 3.12 Frequency of

PIK3CA

and

PTEN

gene mutations in various tumor typ...

Table 3.13 A selection of PI3K, AKT, and mTOR inhibitors that have made it ...

Table 3.14 Summary of selected PI3K inhibitors.

Table 3.15 Approved JAK inhibitors. Treatments licensed for people with can...

Table 3.16 A comparison of ATP‐competitive Bcr‐Abl inhibitors.

Chapter 4

Table 4.1 Angiogenesis inhibitors licensed for use against cancer in the Un...

Table 4.2 The key elements of ADCs and their properties.

Table 4.3 Properties of trastuzumab emtansine compared to trastuzumab derux...

Table 4.4 Current and emerging targets of antibody‐drug conjugates. Antibod...

Table 4.5 Characteristics of

BRCA

‐mutated cancers in mutation carriers.

Table 4.6 Summary of licensed PARP inhibitors as of March 2024 (listed in a...

Table 4.7 Cell cycle targets other than CDKs.

Table 4.8 Commonly altered epigenetic enzymes in cancer cells and some of t...

Table 4.9 Some Bcl‐2 family members cause apoptosis, while others protect a...

Table 4.10 BCR signaling in various B cell cancers.

Table 4.11 A comparison of BTK inhibitors.

Table 4.12 Licensed BTK inhibitors.

Table 4.13 A summary of the chemical and pharmacological properties of vari...

Chapter 5

Table 5.1 The location and role of CTLA‐4 depend on the T cell type.

Table 5.2 Approved CTLA‐4, PD‐1, and PD‐L1‐targeted antibodies.

Table 5.3 A summary of survival rates in checkpoint inhibitor clinical tria...

Table 5.4 Examples of clinical trials in which checkpoint inhibitor monothe...

Table 5.5 Previously untreated patients with advanced cancer derive more be...

Table 5.6 Data from five trials in which a PD‐1‐ or PD‐L1‐targeted checkpoi...

Table 5.7 Examples of biomarkers that could be used to predict benefit from...

Table 5.8 Data from five clinical trials in advanced kidney cancer [142–147...

Chapter 6

Table 6.1 Licensed monoclonal antibody therapies that trigger a cancer‐figh...

Table 6.2 Summary of the major mechanisms of action of ImiDs in the treatme...

Table 6.3 Results from the M14TIL trial, which compared TIL therapy to ipil...

Table 6.4 Licensed CAR T cell therapies.

Table 6.5 Examples of possible CAR T cell targets for other hematological c...

Table 6.6 Why CAR T cell therapy is effective against hematological cancers...

Table 6.7 Obstacles to the creation of CAR T cell therapy for solid tumors ...

Table 6.8 Strategies to create safe and effective CAR T cell therapies for ...

Table 6.9 Some properties of T cell engagers reflect their different designs...

Table 6.10 A selection of T cell engagers (approved or in trials) that conn...

Table 6.11 A comparison of CAR T cells and TCR T cells with T cell engagers...

Table 6.12 Properties of tumor‐associated antigens and tumor‐specific antig...

Chapter 7

Table 7.1 Cancer type‐agnostic approvals [1, 2].

Table 7.2 A summary of treatment approaches relevant to different breast ca...

Table 7.3 Targets and treatments for hormone‐sensitive breast cancer.

Table 7.4 Targets and treatments for HER2‐positive breast cancer.

Table 7.5 Targets and treatments for triple‐negative breast cancer.

Table 7.6 A summary of treatment approaches relevant for people with bowel c...

Table 7.7 Targets and treatments for people with MSS bowel cancer.

Table 7.8 Targets and treatments for MSI or

POLE

‐mutant bowel cancer.

Table 7.9 A summary of relevant treatment approaches for NSCLC, with or with...

Table 7.10 Targets and treatments for people with NSCLC with an actionable m...

Table 7.11 Targets and treatments for people with NSCLC that are not known t...

Table 7.12 A summary of treatment approaches relevant to prostate cancer.

Table 7.13 Targets and treatments for hormone‐sensitive prostate cancer.

Table 7.14 Targets and treatments for castration‐resistant prostate cancer....

Table 7.15 A summary of treatment approaches relevant to head and neck squam...

Table 7.16 Targets and treatments for people with head and neck squamous cel...

Table 7.17 Targets and treatments for people with thyroid cancer.

Table 7.18 A summary of the treatment approaches relevant to esophageal, gas...

Table 7.19 Targets and treatments for esophageal cancer, GEJ cancer, or sto...

Table 7.20 A summary of treatment approaches relevant to pancreatic ductal a...

Table 7.21 Targets and treatments for pancreatic ductal adenocarcinoma.

Table 7.22 Targets and treatments for primary liver cancer.

Table 7.23 Targets and treatments for bile duct cancer.

Table 7.24 A summary of treatment approaches relevant for clear cell renal c...

Table 7.25 Targets and treatments for clear cell renal cell carcinoma.

Table 7.26 Targets and treatments for urothelial carcinoma.

Table 7.27 A summary of treatment approaches relevant to serous ovarian canc...

Table 7.28 Targets and treatments for high‐grade serous ovarian cancer.

Table 7.29 Targets and treatments for low‐grade serous ovarian cancer.

Table 7.30 A summary of treatment approaches relevant to endometrial, cervic...

Table 7.31 Targets and treatments for endometrial cancer.

Table 7.32 Targets and treatments for cervical cancer.

Table 7.33 A summary of treatment approaches relevant to glioblastoma and ot...

Table 7.34 Targets and treatments for glioblastoma.

Table 7.35 Targets and treatments for non‐glioblastoma brain and other CNS t...

Table 7.36 A summary of treatment approaches relevant to melanoma and non‐me...

Table 7.37 Targets and treatments for melanoma skin cancer.

Table 7.38 Targets and treatments for non‐Melanoma skin cancer.

Table 7.39 A summary of treatment approaches relevant for B cell ALL and CLL...

Table 7.40 Targets and treatments for B cell ALL.

Table 7.41 Targets and treatments for CLL.

Table 7.42 A summary of treatment approaches relevant to NHL.

Table 7.43 Targets and treatments for B cell NHL.

Table 7.44 Targets and treatments for T cell NHL.

Table 7.45 A summary of treatment approaches relevant to Hodgkin lymphoma an...

Table 7.46 Targets and treatments for Hodgkin lymphoma.

Table 7.47 Targets and treatments for myeloma.

Table 7.48 A summary of treatment approaches relevant to myeloid cell cancer...

Table 7.49 Targets and treatments for AML.

Table 7.50 Targets and treatments for MDS.

Table 7.51 Targets and treatments for CML.

Table 7.52 Targets and treatments for MPNs (other than CML).

Table 7.53 Targets and treatments for childhood cancers.

List of Illustrations

Chapter 1

Figure 1.1 Gene mutations cause the production of faulty proteins. Chromosom...

Figure 1.2 Some of the causes of DNA damage.

Figure 1.3 DNA damage can come in many forms. Deletions, amplifications, and...

Figure 1.4 A chromosome translocation. Two chromosomes (colored turquoise an...

Figure 1.5 The TMPRSS2‐ERG gene fusion often found in prostate cancer cells...

Figure 1.6 A chromosome insertion – part of one chromosome is inserted into ...

Figure 1.7 Chromosome deletions and inversions. (a) In a chromosome deletion...

Figure 1.8 Gene amplification. The cell accidentally makes extra copies of a...

Figure 1.9 Point mutations. A point mutation (shown by a red star) is when o...

Figure 1.10 The mutations found in a person’s cancer cells are a record of a...

Figure 1.11 A series of mutations leads to bowel cancer [5]. (a) Orderly, we...

Figure 1.12 Genome instability causes intratumoral heterogeneity. (a) In a n...

Figure 1.13 Cells use MHC class 1 proteins to display their inner workings t...

Figure 1.14 T cells are activated by dendritic cells. There are three signal...

Figure 1.15 The Cancer‐Immunity Cycle. (a) Tumors contain living cance...

Figure 1.16 Elimination, equilibrium, and escape. In the initial elimination...

Figure 1.17 The cancer microenvironment contains many different types of cel...

Figure 1.18 The influence of various infiltrating white blood cells on patie...

Figure 1.19 Cancer angiogenesis. (a) A cluster of cancer cells is too far aw...

Figure 1.20 The microenvironment of non‐small cell lung cancer (NSCLC)

Figure 1.21 The pancreatic cancer microenvironment can protect cancer cells ...

Figure 1.22 The path to metastasis. (a) A primary tumor containing many diff...

Figure 1.23 The epithelial‐to‐mesenchymal transition (EMT). (a) ...

Figure 1.24 Diagram of hematopoiesis showing the cell of origin of common he...

Figure 1.25 The maturation and activation of B cells is a multistep process....

Figure 1.26 As we age, our tissues become a patchwork of colonies of mutated...

Figure 1.27 Intratumoral heterogeneity is an obstacle to effectiveness of ta...

Figure 1.28 The proportion of clonal vs. subclonal mutations influences the ...

Chapter 2

Figure 2.1 Some important milestones in the development of non‐surgical canc...

Figure 2.2 Overlap between targeted therapies and immunotherapies. Some trea...

Figure 2.3 Some of the targets of the targeted cancer treatments covered in ...

Figure 2.4

Antibodies are made by specialized B cells called plasma cells

. (...

Figure 2.5 Antibodies are large proteins constructed from four separate piec...

Figure 2.6 Different types of antibodies used as cancer treatments. The scie...

Figure 2.7

Antibody segments can be rearranged to create new structures

. (a)

Figure 2.8 An antibody’s effectiveness can be improved by tweaking its struc...

Figure 2.9 An antibody‐based treatment’s overall impact is a combination of ...

Figure 2.10 Antibodies can block growth factor receptors and the pathways un...

Figure 2.11 Conjugated antibodies can deliver chemotherapy, radioactivity, o...

Figure 2.12 Mechanism of action of antibody‐drug conjugates (ADCs). (a...

Figure 2.13 Antibodies can kill cancer cells by attracting white blood cells...

Figure 2.14 Antibody‐based cancer treatments can create a T cell‐mediated re...

Figure 2.15 A small molecule drug’s effectiveness depends both on the drug a...

Figure 2.16 Kinases are catalysts that attach phosphates to other proteins a...

Figure 2.17 Growth factor receptors are kinases. Growth factor receptors are...

Figure 2.18 Many kinase inhibitors work by mimicking the shape of ATP in som...

Figure 2.19 Different types of kinase inhibitors and the way they work. (a) ...

Figure 2.20 Cell communication pathways involve lots of kinases. Growth fact...

Figure 2.21 Targets of small molecule‐ and antibody‐based cancer treatments...

Chapter 3

Figure 3.1 Our cells respond to a wide range of short‐range and long‐range s...

Figure 3.2 Growth factor receptors are activated by growth factors. (a) Cell...

Figure 3.3 Growth factors can have a variety of different impacts on cells.

Figure 3.4 Growth factor receptors phosphorylate each other only when growth...

Figure 3.5 Some of the many proteins and pathways activated by growth factor...

Figure 3.6 Growth factor receptors are overactive in cancer cells for a vari...

Figure 3.7 All four EGF receptors can pair up to create homo‐ and heterodime...

Figure 3.8 Comparison of panitumumab and cetuximab. Both treatments are mono...

Figure 3.9 Cetuximab’s mechanisms of action. (a) Cetuximab prevents li...

Figure 3.10 Reasons for resistance to EGFR‐targeted antibodies in bowel canc...

Figure 3.11 Structure of the

EGFR

gene and how it relates to EGFR protein. T...

Figure 3.12 Location of mutations in the EGFR gene that cause overactivity o...

Figure 3.13 Reasons for resistance to osimertinib in EGFR‐mutated NSCLC...

Figure 3.14 Mechanisms of action of HER2‐targeted antibodies. (a) Tras...

Figure 3.15 HER2‐positive cancers have extra copies of the HER2 gene and/or ...

Figure 3.16 Some reasons for resistance to HER2‐targeted antibodies in breas...

Figure 3.17 The structure of FLT3 showing the impact of internal tandem dupl...

Figure 3.18 Fundamentals of the MAPK pathway. (a) Paired‐up growth factor re...

Figure 3.19 Ras proteins are active when bound to GTP. When growth factor re...

Figure 3.20 The V600E (and V600K) mutant versions of B‐Raf are active as mon...

Figure 3.21 The Raf inhibitor paradox. (a) In healthy cells, most Raf protei...

Figure 3.22 Some of the most common reasons for resistance to B‐Raf inhibito...

Figure 3.23 The basics of the PI3K/AKT/mTOR signaling pathway. (a) As with t...

Figure 3.24 PI3K comes in various forms. There are numerous versions of the ...

Figure 3.25 The location of mutations in the PIK3CA gene found in various so...

Figure 3.26 The basics of the JAK‐STAT signaling pathway. (a) In the a...

Figure 3.27 The mechanisms of action of ATP‐competitive vs. allosteric Bcr‐A...

Chapter 4

Figure 4.1 A summary of some of the functions of VEGF and its importance as ...

Figure 4.2 Longitudinal illustration of a tumor blood vessel. Healthy blood ...

Figure 4.3 Mechanism of action of various angiogenesis inhibitors. (a) Bevac...

Figure 4.4 Structure of aflibercept (ziv‐aflibercept). Aflibercept is ...

Figure 4.5 Mutations in VHL trigger angiogenesis. (a) In healthy cells, and ...

Figure 4.6 Various reasons for resistance to angiogenesis inhibitors. (a) So...

Figure 4.7 Scientists are improving ADCs by making a number of changes.

Figure 4.8 Function of PARP enzymes. (a) PARP detects a single‐strand break ...

Figure 4.9 Mechanisms of action of PARP inhibitors. (a) PARP inhibitors prev...

Figure 4.10 The path from

BRCA

gene mutations to cancer. (a) If a person is ...

Figure 4.11 PARP inhibitors kill cells that are missing one of their BRCA pr...

Figure 4.12 Roughly half of high‐grade serous ovarian cancers can’t perform ...

Figure 4.13 People with HR‐deficient cancers benefit more from PARP inhibito...

Figure 4.14 The cell cycle in a human cell. (a) The first stage in the cell ...

Figure 4.15 Chemotherapies often kill cells that are at certain stages of th...

Figure 4.16 The cell cycle is controlled by CDKs, cyclins, and CDK inhibitor...

Figure 4.17 CDKs phosphorylate RB. (a) In a cell that isn’t multiplying, RB ...

Figure 4.18 Reasons why CDKs are overactive and E2F proteins are uncontrolle...

Figure 4.19 Combined hormone therapy + CDK4/6 inhibitor therapy for the trea...

Figure 4.20 Mechanisms of resistance to CDK4/6 inhibitors. (a) CDK4/6 inhibi...

Figure 4.21 The basics of the hedgehog signaling pathway. (a) In the absence...

Figure 4.22 Epigenetic modifications to DNA and histone proteins alter the a...

Figure 4.23 The relationship between gene mutations and epigenetic alteratio...

Figure 4.24 Cells can trigger their own death using a process called apoptos...

Figure 4.25 Bcl‐2 protects cells from apoptosis. (a) BAX and BAK cause...

Figure 4.26 Bcl‐2 inhibitors mimic the BH3‐only domain. (a) Some...

Figure 4.27 The B cell receptor (BCR). The BCR is made up of an antibody (al...

Figure 4.28 Signaling pathways activated by BCRs. When a B cell’s BCRs are a...

Figure 4.29 Exportin‐1 transports cargo proteins out of the nucleus via the ...

Figure 4.30 Proteasomes are our cells’ recycling units. Proteasomes play...

Figure 4.31 Protein destruction by a proteasome. (a) Proteasomes destroy pro...

Figure 4.32 Possible reasons why proteasome inhibitors kill cancer cells. Th...

Chapter 5

Figure 5.1 Immunotherapies that create or boost cancer‐fighting T cells...

Figure 5.2 T cells have a wide range of (a) stimulatory and (b) inhibitory c...

Figure 5.3 CTLA‐4 has opposite effects on different types of T cells.

Figure 5.4 Cytotoxic T cells (CTLs) are suppressed and more likely to die wh...

Figure 5.5 CTLA‐4 targeted antibodies affect both CTLs and regulatory T cell...

Figure 5.6 PD‐1 and PD‐L1 antibodies increase the activity of CTLs in periph...

Figure 5.7 The number and activity of cancer‐specific cytotoxic T cells (CTL...

Figure 5.8 An outline of the design and results of the SWOG S1801 clinical t...

Figure 5.9 There are many different patterns of response and resistance to c...

Figure 5.10 Results from an imaginary trial in which 30 people with advanced...

Figure 5.11 Mutations and other defects in cancer cells affect whether the p...

Figure 5.12 Tumors can be categorized according to the white blood cells fou...

Figure 5.13 Prevalence of MSI in various cancer types. The data are taken fr...

Figure 5.14 PD‐L1 is found on various cell types and can be present or absen...

Figure 5.15 There is no correlation between TMB and PD‐L1 levels in a tumor...

Figure 5.16 The two main strategies to improve outcomes with checkpoint inhi...

Figure 5.17 Examples of antibodies that block a range of inhibitory checkpoi...

Figure 5.18 Examples of antibodies that act as activators (agonists) for a r...

Figure 5.19 My interpretation of the Gartner Hype Cycle and its relevance fo...

Chapter 6

Figure 6.1 Introducing TIL therapy, CAR T cell therapy, and TCR T cell thera...

Figure 6.2 Creating an effective TIL therapy product. Using the method illus...

Figure 6.3 A basic outline of the CAR T cell therapy process. The goal of CA...

Figure 6.4 CAR proteins and CAR T cells. (a) CAR proteins are constructed fr...

Figure 6.5 Properties of CAR protein targets. Abbreviations: CAR – chimeric ...

Figure 6.6 Some of the reasons why patients might not benefit from CAR T cel...

Figure 6.7 CAR T cells tend to multiply to higher levels, and be detectable ...

Figure 6.8 Activated CAR T cells indirectly cause CRS. Activated CAR T cells...

Figure 6.9 Activated CAR T cells indirectly cause ICANS by releasing cytokin...

Figure 6.10 Some of the ways CAR T cell therapy is being improved. Abbreviat...

Figure 6.11 Comparing the structure of a conventional CAR protein with a uni...

Figure 6.12 Comparing a CAR T cell with a TCR T cell. (a) A CAR T cell has t...

Figure 6.13 Similarities and differences between an antibody (right) and a T...

Figure 6.14 Targets for TCR T cells are peptide antigens displayed by MHC pr...

Figure 6.15 TCR will only connect with its target antigen if it is displayed...

Figure 6.16 A common design for a T cell engager. This layout is called a Bi...

Figure 6.17 Blinatumomab attaches to CD19 and CD3. CD19 is found on the surf...

Figure 6.18 A few examples of the enormous number of different T cell engage...

Figure 6.19 A so‐called ImmTAC protein made from a soluble TCR and an scFv...

Figure 6.20 The basic idea of most cancer treatment vaccines. The vaccine is...

Figure 6.21 Dendritic cell vaccines. To create such a vaccine, dendritic cel...

Figure 6.22 Creating a personalized mRNA treatment vaccine. The process begi...

Figure 6.23 Mechanism of action of T‐VEC, an oncolytic virus cancer treatmen...

Chapter 7

Figure 7.1 Different proportions of breast cancers are HR‐ or v‐positive, or...

Figure 7.2 Some of the mutations found in the cancer cells of people with ad...

Figure 7.3 Targetable mutations in adenocarcinoma NSCLC. A pie‐chart showing...

Guide

Cover Page

Table of Contents

Title Page

Copyright Page

Acknowledgments

Praise for the First Edition

About the Author

How to Use This Book

Begin Reading

Appendix

Glossary of Terms

Index

WILEY END USER LICENSE AGREEMENT

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A Beginner's Guide to Targeted Cancer Treatments and Cancer Immunotherapy

SECOND EDITION

Elaine Vickers

This second edition first published 2025© 2025 John Wiley & Sons Ltd

Edition HistoryJohn Wiley & Sons Ltd (1e, 2018)

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The right of Elaine Vickers to be identified as the author of this work has been asserted in accordance with law.

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Limit of Liability/Disclaimer of WarrantyThe contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication DataNames: Vickers, Elaine (Elaine Ruth), author.Title: A beginner’s guide to targeted cancer treatments and cancer immunotherapy / Elaine Vickers.Description: Second edition. | Hoboken, NJ, USA : Wiley, 2025. | Includes bibliographical references and index.Identifiers: LCCN 2024029662 (print) | LCCN 2024029663 (ebook) | ISBN 9781119834069 (pb) | ISBN 9781119834076 (adobe pdf) | ISBN 9781119834083 (epub)Subjects: MESH: Neoplasms–drug therapy | Molecular Targeted Therapy–methodsClassification: LCC RC271.C5 V53 2024 (print) | LCC RC271.C5 (ebook) | DDC 616.99/406–dc23/eng/20240708LC record available at https://lccn.loc.gov/2024029662LC ebook record available at https://lccn.loc.gov/2024029663

Cover Design: WileyCover Image: © Juan Gaertner/Shutterstock

Acknowledgments

Firstly, and most importantly, I am enormously indebted to Kathleen Killen, who I met through her work at Cancer Research UK. Kat contacted me at the end of 2022, offering her proofreading skills as a medical writer, and she has contributed enormously to this edition. Not only has Kat scrutinized every word on every page, legend, footnote, and table, but she has also made many valuable contributions to the consistency, accuracy, and inclusivity of the content.

I would also like to thank everyone else who has offered their advice and reviewed and critiqued this edition. They are: Maggie Uzzell, Joanne Bird, Anne Croudass, Karen Turner, Ben Hood, Chloe Beland, Miranda Payne, Nick Duncan, Clayton Wong, and Philip Dean.

As with the first edition, special thanks go to Ruth McLaren. Ruth was the person who first suggested I should teach nurses and other health professionals as my full‐time occupation. Without her, my business and my book might never have happened.

Praise for the First Edition

“I wish this book had existed when I began my career in oncology research. It gives an excellent background to proteins within cancer cells and healthy cells as well as microenvironment differences in cancers. Reading this book gave me even deeper insight into some of the studies I had previously worked on. The writing style and presentation of material is very easy to follow and well organized.”

–Dr Ben Hood, Cancer Research Consultant Nurse, Sir Bobby Robson Cancer Trials Research Centre

“Well done on such a massive undertaking and a really, really useful book. I've learned a lot as I've read it.”

–Dr Sue Brook, Associate Medical Director, Ellipses Pharma

“Very impressive! Supportively written, this will become the “go‐to book” for any health care professional wanting information on targeted treatments in cancer.”

–Daniel Collins, Deputy Chief Pharmacist, Liverpool Women’s NHS Foundation Trust

“As a healthcare professional, I need to know how the drugs I administer to my patients are acting in the body, how they are designed to fight cancer, and to be able to answer the sometimes‐difficult questions that patients ask. This book helps me to do this with confidence. It is complicated in parts because the science is complicated, but written in a way that all those working in the field of cancer care will be able to understand, with knowledge that they can apply to practice. Fabulous illustrations throughout the book and a very logical format make this text accessible to all.”

–Nikki Hayward, Skin Cancer CNS team lead, Buckinghamshire Healthcare NHS Trust

“What an amazing achievement! Patients and healthcare professionals will be delighted to discover a book that makes incomprehensible concepts accessible, interesting, and logical.”

–Heather Phillips, Research Delivery Manager, NIHR

“Really wonderful, so nicely written, exactly what I had been looking for. We are in the very early stages of developing an NIH/NCI grant proposal related to technology that helps clinicians easily align their patients' variants with potential treatment options, and Dr. Vickers' book was absolutely invaluable at opening my eyes to the complexity and the possibilities.”

–Bob Dolin, Senior Informaticist, Elimu Informatics

I recommend this book to all of my students who wish to further develop their knowledge of some of the targeted therapies used to treat cancer. The book is well written which strengthens its use as a reference and it is also a book which readers can use to check their understanding of these treatments. It contains excellent illustrations.

–Maggie Uzzell, The Royal Marsden School

About the Author

Elaine Vickers has been a cancer educator and writer for over twenty years. Since setting up her company, Science Communicated Ltd (sciencecommunicated.co.uk), Elaine has developed a wide range of study days, courses, and teaching materials that explain cancer biology and the science behind targeted cancer treatments and immunotherapies.

Each year, Elaine teaches hundreds of cancer nurses, doctors, and allied cancer professionals working in the United Kingdom. She also presents a regular program of in‐person study days for the Royal Marsden Conference Centre in London and speaks at numerous cancer conferences in the United Kingdom and Europe. In recent years, Elaine has expanded her reach by delivering online courses and creating educational videos and webinars. She has also worked with an animator to create animations that explain cancer and cancer treatments.

Elaine has a degree in Medical Science from the University of Birmingham and a PhD in Molecular Biology from the University of Manchester. Her goal is to unravel the complexities of cancer biology and new cancer treatments and make these topics interesting and accessible to nonscientists.

Elaine considers herself incredibly lucky to live in Manchester with her husband Rowan and her little dog CJ.

How to Use This Book

I wrote the first edition of this book when I couldn’t find a resource that would cover all the topics I was teaching on without overwhelming the reader with scientific detail. I felt what was missing was a single book that brought together sufficient information on cancer biology to explain the promise and the limitations of the latest cancer treatments.

Since the first edition was published in 2018, a lot has changed, particularly in the realm of immunotherapy. Thus, in this edition, I have expanded the early chapters to incorporate greater detail on the relationship between cancer and our immune system. I have also vastly expanded the information on immunotherapy. In this edition, immune checkpoint inhibitors have their own chapter. I also devote a second chapter to explanations of the science behind many other immunotherapy approaches.

As with the first edition, although I have called this book “A Beginner’s Guide …” I do include a lot of science. I also don’t try to hide the complexity of the subjects I am attempting to describe. However, I hope that by providing illustrations and including lots of background information in the first two chapters, you can follow the rest of the book.

You’ll also notice that I don’t describe any advances in radiotherapy or surgery, and I provide very little information on chemotherapy and hormone therapy. I made this choice because I am a molecular biologist, and I wanted to focus my attention on where I feel I have the most to offer: explaining the science behind targeted therapies and immunotherapies for cancer.

One challenge I had when writing this book was the rapid pace of cancer research and drug development. Although I have done my best to provide up‐to‐date information, this will no doubt be quickly eroded by the creation of new treatments and new approvals in the months and years to come. I apologize if any drug or bit of science you are interested in – from a professional or personal standpoint – isn’t included. I hope that because I have focused on the mechanisms of action of new treatments rather than their stage of development, you will find this book relevant to you.

Another decision I made when writing the book was to provide only passing information on the degree of benefit offered by the treatments mentioned. I made this choice because the difference a treatment makes is context‐ and disease‐specific. For example, a treatment that provides only a modest extension in survival times in people with relapsed, advanced disease may be able to cure people who have early‐stage, newly diagnosed disease. As a molecular biologist interested in explaining how treatments work, I decided this level of detail was beyond the scope of this book. For similar reasons, I don’t generally provide information about which countries a treatment is licensed in or for which patients.

I have presumed that when you open this book, you will be approaching the subject from one of four perspectives:

Because you’re interested in

a specific treatment

and want to learn more about it. If that’s the case, you might want to start with the index and look it up by name.

Because you’re involved in caring for people affected by a

certain type of cancer

and want to know about the relevant treatments. If so, you might wish to turn to chapter seven first.

Because you’d like to know about treatments that

have a specific target

, such as CDK inhibitors, or that

have a particular mechanism

, such as vaccine‐based treatments. If that’s you, then

chapters 3

–

6

will likely contain the information you’re after.

Or, if you’re relatively new to the topics covered in this book, I would advise you to begin at the beginning and go from there!

Whatever your reason for reading this book, my sincere hope is that you will find it useful and interesting.

CHAPTER 1An Introduction to Cancer Cell Biology and Genetics

IN BRIEF

I find it impossible to describe how targeted cancer treatments work without mentioning what it is they target. And when I try to explain what it is they target, I find myself going back to the beginning and explaining where cancers come from, what faults they contain, and why they behave as they do. And, to explain that, I need to explain concepts such as DNA damage, oncogenes, tumor suppressor genes, and the hallmarks of cancer cells.

In recent years, we’ve also made great progress in using a patient’s immune system to treat cancer using immunotherapy. When explaining how immunotherapies work, I find it useful to offer at least a brief description of our immune system and the ways in which cancer cells and white blood cells interact. Armed with this knowledge, various strategies to use the immune system to destroy cancer cells begin to make sense.

In this chapter, my goal is to bring together much of this background knowledge. I hope it will provide you with a useful foundation that enables you to understand individual targeted therapies and immunotherapies that I mention in later chapters.

First, I run through the causes and consequences of DNA mutations in cells. I describe how even just a handful of mutations can force a healthy cell to become a cancer cell.

I also describe the cancer microenvironment – the cells and structures that cancer cells live alongside, including white blood cells of our immune system. Cancer cells have the ability to exploit their local environment and, in many instances, manipulate it. I explain what impact this has when doctors come to treat people with the disease.

In addition, I tackle topics such as genome instability and intratumoral heterogeneity. Perhaps these are topics that right now don’t mean anything to you, and you’re unsure of why you need to know about them. But it’s only through understanding these concepts that you can appreciate the limitations of targeted (and standard) cancer treatments and grasp the potential of immunotherapy. It is also important to understand why cancer spreads and how cancers evolve and change over time.

I then turn my attention to the unique properties of hematological cancers. I describe some of the types of mutation that drive their behavior and talk about why these mutations occur. I also explain their greater vulnerability to immunotherapy compared to solid tumors.

Finally, I wrap up the chapter with a brief overview of why cancer is so difficult to treat successfully and why so many people currently cannot be cured.

1.1 INTRODUCTION

This book is about the science that lies behind targeted cancer treatments and cancer immunotherapies. Almost without exception, these treatments work by attaching to, or blocking the actions of, proteins. So, to understand these treatments, it’s first of all essential to understand what proteins are, how they work, and how the proteins found inside and on the surface of cancer cells differ from their healthy counterparts.

For this to make sense to you, I need to explain the different types of DNA damage that cancer cells contain, because a cell’s DNA is its instruction manual telling it how to make proteins. If we know what DNA damage a cell contains, this will tell us what faulty proteins it’s making. And if we know what faulty proteins it’s making, we will have a better idea of which treatments might work against it.

So, this chapter contains lots of information about cancer cells, DNA, and proteins. However, even in this chapter, I’ve made some assumptions about what you do and don’t know. For example, I’ve assumed that you have a rough idea of what DNA is and how cells use their DNA to make proteins. If you’re not familiar with these concepts, I would recommend first taking a look at the Appendix, which contains a list of reading materials about cells, DNA, chromosomes, genes, and proteins. When you’ve had a look at that, you’ll be ready to read further.

This chapter doesn’t exclusively focus on individual cancer cells and their faults.

AbbreviationCancer cells don’t live alone, nor are tumors a homogenous mass of identical cancer cells. Instead, cancer cells live among other types of cells, such as fibroblasts, fat cells, and numerous types of white blood cells. This composition changes over time and also in response to treatment. In addition, cancer cells themselves evolve and change over time, and this has an enormous impact on the effectiveness, or not, of many treatments.

In this chapter, I’ll also provide you with some background information about how cancer cells relate to, and influence, our immune system. Why it is, for example, that in some people their immune system reacts strongly against their cancer cells, while in another person their immune system seems to essentially shrug its shoulders and carry on as normal. I’ll also pay special attention to T lymphocytes (T cells), which are at the heart of many different forms of immunotherapy.

Some of the information in this chapter is relevant to all cancers, wherever they occur in the body and whatever type of cell they developed from. However, there are some features of hematological cancers (such as leukemias and lymphomas) that set them apart from solid tumors like breast or bowel cancer. Some of this difference comes down to the mutations that drive hematological cancers, but some of it is due to their accessibility to drugs, and to healthy white blood cells.

Along with the chapter that follows (which is all about the two main groups of cancer treatments in this book: monoclonal antibodies and kinase inhibitors), this chapter hopefully provides you with all the background information you need to make sense of the rest of this book.

1.2 DNA DAMAGE IS THE CAUSE OF EVERY CANCER

Our cells’ DNA is essentially a huge instruction manual telling our cells what proteins to make, how to make them, when to make them, what to do with them, and when to destroy them. In turn, the proteins our cells make dictate their behavior. For this reason, if you damage a cell’s DNA, it is likely to make the wrong, or damaged, versions of proteins, leading to abnormal behavior (see Figure 1.1).

Cancer starts to develop when a single cell accumulates DNA damage to several important genes. This damage causes the cell to make faulty proteins that force it to behave abnormally. To result in cancer, the cell also needs to overcome whatever hostile forces are exerted by its environment and by neighboring cells. Thankfully, this normally doesn’t happen. Instead, a cell that finds its DNA damaged usually tries to repair the damage, or it self‐destructs through a process called apoptosis.1Or, if the cell doesn’t kill itself, it’s usually kept in check by its environment or destroyed by white blood cells. But, if a damaged cell survives, and if it avoids or overcomes its hostile neighbors, it might ultimately multiply and cause us to develop cancer.

Figure 1.1 Gene mutations cause the production of faulty proteins. Chromosomes are long lengths of DNA found inside the nucleus of each cell. Within our chromosomes are regions of DNA called genes. These are stretches of DNA that contain the instructions to make proteins. If a gene is affected by a mutation (represented by a lightning bolt), the cell might then make a faulty protein. In this example, the faulty protein is a cell surface receptor that gives the cell a continuous signal to grow and multiply.

Over the past 40 years or so, scientists have been gradually uncovering which gene mutations cause cancer. Genes only take up about 1%–2% or so of our cells’ total DNA, so it’s this DNA they have focused on [1]. (What exactly the rest of our cells’ DNA is for is a matter of continued debate among scientists.)

Box 1.1 The names of genes and their proteins

As you read this book, you might notice that protein names are written normally but that gene names are written in italics. For example, the HER2 gene contains the instructions for making HER2 protein. You might also notice that sometimes the gene and the protein have different names. An example of this is the TP53 gene, which contains the instructions for making a protein called p53. It’s also possible for a gene to contain the instructions for making more than one protein. For instance, the CDKN2A gene (sometimes referred to as the CDKN2A locus) contains the instructions for making several proteins, two of which are called p16INK4a and p14ARF.

To add to the confusion, some genes and proteins have more than one name. For example, the HER2 gene is also called ERBB2 and NEU. The reasons behind the various names often have a lot to do with what organism or group of cells the gene/protein was discovered in; if it’s similar to another gene/protein that has already been discovered; what role the gene/protein is thought to play in the cells or organism it was found in; and whether or not abnormalities in the gene/protein cause disease. For example, HER2 stands for “human epidermal growth factor receptor‐2,” because it’s similar in structure to HER1 (although we usually refer to HER1 as the EGF receptor or EGFR). HER2 is also called ERBB2 because a very similar gene, called ERBB, was discovered in a disease‐causing virus called the avian erythroblastosis virus. HER2 is also called NEU because a faulty version of it can cause a cancer called neuroblastoma in rodents.

A final point to note is that gene names are often written in capital letters, whereas protein names aren’t. But this convention isn’t always adhered to.

Through initiatives such as The Cancer Genome Atlas [2] and the International Cancer Genome Consortium [3], hundreds of scientists have amassed an incredible catalog of information about the thousands of different DNA mutations cancer cells contain [4, 5]. They’ve also discovered that different types of cancer differ from one another in terms of the mutations they contain and the treatments they respond to. In addition to these differences, we know that important similarities can exist between cancers that arise in different organs. For example, the cancer cells of some breast cancers overproduce2 a protein called HER2, and the same is true of the cancer cells in some stomach cancers and other cancer types [6].

Because there’s lots I want to say about the DNA mutations found in cancer cells, I’m going to split it up into different topics. First, I’ll talk about what causes the DNA mutations found in cancer cells (Section 1.2.1). Then I’ll describe what types of mutation occur (see Section 1.2.2), how the number and pattern of mutations in cancer cells varies (see Section 1.2.3), and which mutations have the greatest effect on cell behavior (see Section 1.2.4). Then I’ll talk about some of the most common gene mutations in cancer cells and what impact they have (Section 1.2.5).

All this information is gradually helping scientists create the new, more targeted cancer treatments described in this book.

1.2.1 Causes of DNA Mutations

There are many different reasons why our cells’ DNA gets damaged. Much of this damage is natural and unavoidable, whereas some of it is down to our lifestyle, behaviors, exposures, geographical location, and even local customs.3 We can also inherit damaged DNA from our parents. Depending on what sort of data scientists look at (e.g., whether they examine individual cells or whole organs or tissues, or look at populations of people in different countries), they end up drawing very different conclusions about what proportion of cancers could be avoided [7–10]. So, although I’ve listed some of the causes of DNA damage later, and in Figure 1.2, I haven’t tried to pin down exactly how many cancers are caused by each one.4

Figure 1.2 Some of the causes of DNA damage.

Source: Adapted from Ref. [11–14].

Unavoidable Causes of DNA Damage

The byproducts of chemical reactions.

Unfortunately for us (and for all living things),

our cells’ DNA gets damaged every second of every day

. Scientists think that even without the influence of external factors, each of our cells sustains damage to its DNA roughly 20,000 times each day

[15]

.

Much of this damage is caused by the products of chemical reactions that are essential to keep us alive. For example, many of our cells’ important chemical reactions produce oxygen free radicals5 – high‐energy oxygen atoms that essentially bash into and break DNA [16]. Our cells contain well over 100 different DNA repair proteins to fix this damage [17]. But sometimes they fail to spot all the damage, or they simply can’t keep up.

Cells make mistakes as they multiply

. Tissues that need to renew and replenish their cells often (such as the lining of our bowel, our skin, and those that comprise our immune system) are at the highest risk of cancer

6

[

9

,

18

–

20

]. This is because for a cell to multiply, it has to make a complete copy of all of its DNA – all 3000 million base pairs of it. The enzyme that copies DNA, called DNA polymerase, although spectacularly fast and accurate, does occasionally make mistakes

[18]

. Therefore,

cells that need to multiply often are at a greater risk of becoming cancer cells

than cells that rarely, if ever, multiply.

The actions of APOBEC enzymes

. APOBEC

7

enzymes are a family of proteins that our cells use to help protect them from viruses.

APOBEC enzymes attack viruses

by introducing mutations into their DNA. However, if an uninfected cell accidentally makes APOBEC enzymes, the enzymes will attack the cell’s own DNA and introduce lots of mutations that could cause cancer

[19]

. Also, after a cell has become a cancer cell, APOBEC enzymes continue to add more and more damage to the cell’s genes

[20]

.

Inherited mutations

. Some people are

born with DNA faults

that put them at a higher risk of cancer. Sometimes the fault has been passed down from generation to generation, with many family members affected. For example, actress and film director Angelina Jolie has inherited a fault in one copy of her

BRCA1

gene (we inherit two copies of each gene). Because this fault is shared by many of her relatives, she lost her mother, grandmother, and aunt to cancer

[21]

. Faults in high‐risk genes such as

BRCA

genes are relatively rare, but they can have an enormous impact on a person’s cancer risk. More commonly, subtle variations in many genes will combine to affect our risk.

Faults can also arise in an egg or sperm; if the faulty egg or sperm goes on to create an embryo, this fault will be present in every cell. Or, the fault might occur later, as the growing embryo is developing. For example, faults that occur in an embryo’s white blood cells as its immune system forms can cause infant or childhood leukemia [11].

Potentially Avoidable Causes of DNA Damage

Lifestyle and exposures

. Cells that are exposed to high levels of

carcinogens

(anything that causes cancer is called a carcinogen) are particularly vulnerable to becoming cancer cells. This includes cells that line our lungs, skin, bowel, and stomach. Carcinogens include various constituents of cigarette smoke, alcohol, UV light from the sun or from sunbeds, radiation from X‐rays, some viruses, asbestos, and food toxins

[13]

.

Our cancer risk is also linked to our diet (including our consumption of fruit and vegetables, red and processed meat, salt, and fiber), our level of physical activity, and our weight. This is a huge topic. If you would like to learn more, I suggest looking at the Cancer Research UK [22] and American Cancer Society [23] websites.

The influence of sex hormones

. When discussing the causes of cancer, we shouldn’t ignore the influence of sex hormones such as

estrogen, progesterone, and testosterone

. These tiny, fat‐soluble chemicals encourage cells that contain receptors for them to survive, grow, and multiply (estrogen can also cause DNA damage

[24]

). Cancers that develop from hormone‐sensitive tissues in the breast and prostate often retain their sensitivity to hormones. These cancers often respond to treatments that block the production of hormones in the body or that block the impact of hormones on cancer cells.

The risk of various cancers, including breast, ovarian, and endometrial cancer, is linked to a person’s exposure to sex hormones such as estrogen. Reproductive factors (such as age of menarche8 and menopause, along with the number of pregnancies and length of time they breastfed) and bodyweight affect a person’s lifetime exposure to estrogen and thus also influence their cancer risk [25].

The influence of inflammation

. For many people, their cancer diagnosis was preceded by

years of inflammation, infection, or irritation

[26]

. For example, people with a chronic hepatitis B or hepatitis C virus infection are at high risk of liver cancer, whereas people with inflammatory bowel disease are at an increased risk of bowel cancer [

27

,

28

]. It seems that the presence of white blood cells in a tissue can increase the DNA mutation rate in the tissue’s cells and encourage the cells to multiply, raising the risk of cancer

[28]

.

Cancer treatments. Most chemotherapies and radiotherapy work by causing so much DNA damage

that cancer cells die. However, not every cell is killed. Cells that sustain damage to their DNA and yet survive may later become cancer cells. Because of this, people treated for cancer sometimes develop second cancers months or even many years later [

29

,

30

].

Causes of DNA Mutations – Summary

Our risk of cancer in any particular place in our body is therefore a combination of the following [8–10]:

The natural rate that the cells multiply in that tissue.

The extent to which DNA polymerase, oxygen free radicals, and APOBEC enzymes have caused mutations in the tissue’s cells (the amount of damage will gradually increase as we age).

Our biological sex and our inherited genetic makeup.