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The Basic Science
of Oncology
Fifth Edition
Editors
Ian F. Tannock, Robert G. Bristow,
MD, PhD, DSc MD, PhD
Staff Physician and Senior Scientist Staff Physician and Senior Scientist
Princess Margaret Cancer Centre Ontario Cancer Institute and Campbell
University Health Network Family Institute for Cancer Research
Professor of Medicine and Medical Biophysics Princess Margaret Cancer Centre
University of Toronto University Health Network
Toronto, Ontario Professor of Radiation Oncology
and Medical Biophysics
University of Toronto
Richard P. Hill, PhD Toronto, Ontario
Senior Scientist, Ontario Cancer Institute and
Campbell Family Institute for Cancer Research
Princess Margaret Cancer Centre Lea Harrington, PhD
University Health Network IRIC-Institut de Recherché en Immunologie
Professor of Medical Biophysics and et en Cancérologie
Radiation Oncology Professor, Faculty of Medicine
University of Toronto Université de Montréal
Toronto, Ontario Montréal, Québec
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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Contents
Contributors vii
Preface xi
1. Introduction to Cancer Biology 1 13. Heterogeneity in Cancer:
Lea Harrington, Robert G. Bristow, The “Cancer Stem Cell” Hypothesis 295
Richard P. Hill, and Ian F. Tannock Craig Gedye
2. Methods of Molecular Analysis 5 14. Imaging in Oncology 317
Anthony M. Joshua, Paul C. Boutros, David A. Jaffray
and Thomas Kislinger
15. Molecular and Cellular Basis
3. Cancer Epidemiology 51 of Radiotherapy 333
Gord Fehringer, Rayjean J. Hung, Shane M. Harding, Richard P. Hill,
and Geoffrey Liu and Robert G. Bristow
4. Chemical Carcinogenesis 73 16. Tumor and Normal Tissue Response
Denis M. Grant to Radiotherapy 357
Richard P. Hill and Robert G. Bristow
5. Genomic Stability and DNA Repair 89
Shane M. Harding, Robert G. Bristow, 17. Discovery and Evaluation
and Lea Harrington of Anticancer Drugs 393
Aaron D. Schimmer and Ian F. Tannock
6. Oncogenic Viruses and Tumor Viruses 117
Fei-Fei Liu and Christopher D. Richardson 18. Pharmacology of Anticancer Drugs 419
Eric X. Chen
7. Oncogenes and Tumor-Suppressor
Genes 147 19. Drug Resistance 443
Previn Dutt and Vuk Stambolic Susan P.C. Cole and Ian F. Tannock
8. Cellular Signaling Pathways 173 20. Hormones and Cancer 469
Michael Reedijk and C. Jane McGlade Paul S. Rennie, Eric Leblanc,
and Leigh C. Murphy
9. Cell Proliferation and Death 193
Paul Jorgensen and Razqallah Hakem 21. The Immune System and
10. Tumor Progression and Metastasis 219 Immunotherapy 501
Linh T. Nguyen, Evan F. Lind,
Yang W. Shao, Rama Khokha, and Richard P. Hill
and Pamela S. Ohashi
11. Angiogenesis 243
Janusz Rak
22. Guide to Clinical Studies 529
Eitan Amir and Ian F. Tannock
12. Tumor Growth, Microenvironment,
and Metabolism 271 Index 553
Rob A. Cairns, Ian F. Tannock,
and Bradly Wouters
v
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Contributors
Eitan Amir, MB ChB, PhD Susan P.C. Cole, PhD, FRSC, FCAHS
Staff Physician and Clinician Scientist Canada Research Chair and Bracken Chair in
Ontario Cancer Institute and Princess Margaret Genetics and Molecular Medicine
Cancer Centre Professor of Pathology and Molecular Medicine
University Health Network Queen’s University
Assistant Professor of Medicine Kingston, Ontario
University of Toronto Previn Dutt, PhD
Toronto, Ontario Postdoctoral Fellow
Paul C. Boutros, PhD Ontario Cancer Institute and Princess Margaret
Principal Investigator, Informatics and Biocomputing Cancer Centre
Assistant Professor of Medical Biophysics University Health Network
Assistant Professor of Pharmacology and Toxicology Toronto, Ontario
University of Toronto Gord Fehringer, PhD
Toronto, Ontario Scientific Associate
Robert G. Bristow, MD, PhD Prosserman Centre for Health Research
Staff Physician and Senior Scientist Samuel Lunenfeld Research Institute of Mount
Ontario Cancer Institute and Campbell Family Sinai Hospital
Institute for Cancer Research Toronto, Ontario
Princess Margaret Cancer Centre Craig Gedye, MBChB, FRACP, PhD
University Health Network Postdoctoral and Medical Oncology Fellow
Professor of Radiation Oncology and Ontario Cancer Institute and Princess Margaret
Medical Biophysics Cancer Centre
University of Toronto University Health Network
Toronto, Ontario University of Toronto
Toronto, Ontario
Rob A. Cairns, PhD
Associate Scientist Denis M. Grant, PhD
Campbell Family Institute for Cancer Research Professor
Ontario Cancer Institute and Princess Margaret Department of Pharmacology and Toxicology
Cancer Centre Faculty of Medicine and Department
University Health Network of Pharmaceutical Sciences
Toronto, Ontario Leslie Dan Faculty of Pharmacy
University of Toronto
Eric X. Chen, MD, PhD Toronto, Ontario
Staff Physician
Ontario Cancer Institute and Princess Margaret Razqallah Hakem, PhD
Cancer Centre Senior Scientist
University Health Network Ontario Cancer Institute and Princess Margaret
Assistant Professor of Medicine Cancer Centre
University of Toronto University Health Network
Toronto, Ontario Professor of Medical Biophysics and Immunology
University of Toronto
Toronto, Ontario
vii
viii CONTRIBUTORS
Shane M. Harding, PhD Rama Khokha, PhD
Post-Doctoral Fellow Senior Scientist
Department of Cancer Biology Ontario Cancer Institute and Campbell Family Institute
University of Pennsylvania School of Medicine for Cancer Research
Philadelphia, Pennsylvania Princess Margaret Cancer Centre
Lea Harrington, PhD University Health Network
IRIC-Institut de Recherché en Immunologie Professor of Medical Biophysics
et en Cancérologie University of Toronto
Professor, Faculty of Medicine Toronto, Ontario
Université de Montréal Thomas Kislinger, PhD
Montréal, Québec Senior Scientist
Richard P. Hill, PhD Ontario Cancer Institute and Princess Margaret
Senior Scientist Cancer Centre
Ontario Cancer Institute and Campbell Family Institute University Health Network
for Cancer Research Professor of Medical Biophysics
Princess Margaret Cancer Centre University of Toronto
University Health Network Toronto, Ontario
Professor of Medical Biophysics and Radiation Oncology Eric Leblanc, PhD
University of Toronto Research Associate
Toronto, Ontario Urologic Sciences
Rayjean J. Hung, PhD, MS The Vancouver Prostate Centre
Principal Investigator, Samuel Lunenfeld Research University of British Columbia
Institute of Mount Sinai Hospital Vancouver, British Columbia
Cancer Care Ontario Research Chair in Evan F. Lind, PhD
Population Studies Postdoctoral Fellow
Division of Epidemiology The Campbell Family Institute for Breast
Dalla Lana School of Public Health Cancer Research
University of Toronto Ontario Cancer Institute and Princess Margaret
Toronto, Ontario Cancer Centre
David A. Jaffray, PhD, ABMP University Health Network
Head Toronto, Ontario
Radiation Physics, Radiation Medicine Program Fei-Fei Liu, MD, FRCPC
Princess Margaret Cancer Centre Chief
Director, Techna Institute Radiation Medicine Program
Senior Scientist Princess Margaret Cancer Centre
Ontario Cancer Institute University Health Network
University Health Network Professor of Radiation Oncology
Professor of Radiation Oncology, Medical Biophysics, University of Toronto
and IBBME Toronto, Ontario
University of Toronto
Toronto, Ontario Geoffrey Liu, MD, FRCPC
Alan B. Brown Chair in Molecular Genomics and
Paul Jorgensen, PhD Senior Scientist
Senior Research Associate Ontario Cancer Institute and Princess Margaret
Terrence Donnelly Centre for Cellular and Cancer Centre
Biomolecular Research University Health Network
University of Toronto Associate Professor of Medicine
Toronto, Ontario Medical Biophysics and Epidemiology
Anthony M. Joshua, MBBS, PhD, FRACP University of Toronto and Dalla Lana School of
Staff Physician and Associate Scientist Public Health
Ontario Cancer Institute and Princess Margaret Toronto, Ontario
Cancer Centre
University Health Network
Assistant Professor of Medicine
University of Toronto
Toronto, Ontario
CONTRIBUTORS ix
C. Jane McGlade, PhD Paul S. Rennie, PhD, FCAHS
Senior Scientist Director
Program in Cell Biology and the Arthur and Sonia Laboratory Research
Labatt Brain Tumour Research Centre The Vancouver Prostate Centre
Hospital for Sick Children Professor, Department of Urologic Sciences
Professor of Medical Biophysics University of British Columbia
University of Toronto Vancouver, British Columbia
Toronto, Ontario
Christopher D. Richardson, PhD
Leigh C. Murphy, PhD Professor and Canada Research Chair
Chair Department of Microbiology and Immunology
Breast Cancer Research Group at the Department of Pediatrics
University of Manitoba Dalhousie University
Senior Scientist, Manitoba Institute for Cell Biology Halifax
Professor of Biochemistry and Medical Genetics Nova Scotia
University of Manitoba
Winnipeg, Manitoba Aaron D. Schimmer, MD, PhD, FRCPC
Staff Physician and Senior Scientist
Linh T. Nguyen, PhD Ontario Cancer Institute and Princess Margaret
Head Cancer Centre
Translational Immunotherapy Laboratory University Health Network
Campbell Family Institute for Breast Cancer Research Associate Professor of Medicine and Medical Biophysics
Ontario Cancer Institute and Princess Margaret University of Toronto
Cancer Centre Toronto, Ontario
University Health Network
Toronto, Ontario Yang W. Shao, BSc
PhD Candidate
Pamela S. Ohashi, PhD Ontario Cancer Institute and Princess Margaret
Director Cancer Centre
Immune Therapy Program University Health Network
Senior Scientist Department of Medical Biophysics
Ontario Cancer Institute and Princess Margaret University of Toronto
Cancer Centre Toronto, Ontario
University Health Network
Professor of Immunology Vuk Stambolic, PhD
University of Toronto Senior Scientist
Toronto, Ontario Ontario Cancer Institute and Princess Margaret
Cancer Centre
Janusz Rak, MD, PhD Associate Professor of Medical Biophysics
Jack Cole Chair in Pediatric Hematology/Oncology University of Toronto
Professor, Department of Pediatrics Toronto, Ontario
McGill University
Montreal Children’s Hospital and The Research Institute Ian F. Tannock, MD, PhD, DSc
of the McGill University Health Centre Staff Physician and Senior Scientist
Montreal, Quebec Princess Margaret Cancer Centre
University Health Network
Michael Reedijk, MD, PhD Professor of Medicine and Medical Biophysics
Surgeon Scientist University of Toronto
Princess Margaret Cancer Centre Toronto, Ontario
University Health Network
Associate Professor of Surgery and Bradly Wouters, PhD
Medical Biophysics Senior Scientist
University of Toronto Ontario Cancer Institute and Princess Margaret
Toronto, Ontario Cancer Centre
University Health Network
Professor of Radiation Oncology and Medical Biophysics
University of Toronto
Toronto, Ontario
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Preface
Since the publication of the fourth edition of The Basic Science biology of cancer. We have maintained a format of using rela-
of Oncology there have been major advances in our knowl- tively short sections that allows the reader to investigate a par-
edge about the molecular basis of cancer, largely as a result of ticular interest selectively, and include references that can be
the rapid development of powerful techniques to study the used as a guide for those seeking information in greater depth.
genome and epigenome and to the parallel advances in tech- We believe that the book will be useful as a teaching aid and as
niques to study the levels of gene expression and the proteins a broad introduction for those interested in the study and treat-
that are produced. Concurrent with understanding of the ment of cancer.
molecular pathways that drive the development and progres- We are grateful to many people for their assistance in pro-
sion of cancer, and the heterogeneity of the changes in these ducing this fifth edition. To our authors, particularly the new
pathways in individual cancers, new molecular-targeted agents ones, who have responded to our many requests for altera-
have been developed and are being tested, with variable suc- tions with forbearance. To our publishers who have encour-
cess, in attempts to treat cancers selectively. The 5th edition of aged us and accepted with good grace our failure to meet our
The Basic Science of Oncology places the major advances that initial deadlines and whose artists have redrawn all the figures
have occurred in the context of previous studies that have gen- in keeping with the new color format. To our students and
erated the important background to cancer biology. Many of trainees who have provided us with helpful and constructive
the chapters have new authors and all have been extensively criticism. And to our families who have continued to provide
revised and rewritten to reflect our new knowledge. We have support and encouragement during the several phases of
added new chapters on the emerging areas of the tumor micro- writing, rewriting, and reviewing.
environment and metabolism (Chapter 12) and cancer stem
cells (Chapter 13).
As in previous editions we have attempted to bring together I.F. Tannock
the contributions of experts into a book that, we believe, is suit- R.P. Hill
able for fellows, residents, nurses, medical students, graduate R.G. Bristow
students, and senior undergraduates who are interested in the L. Harrington
xi
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1
C H A P T E R
Introduction to
Cancer Biology
Lea Harrington, Robert G. Bristow,
Richard P. Hill, and Ian F. Tannock
1.1 Perspective and History 1.3 The Future of Oncology and Cancer Treatment
1.2 Recent Advances in Oncology References
1.1 PERSPECTIVE AND HISTORY and relationships between histopathological characteristics
of tumors and their prognosis. Development of methods to
One of the first scientific investigations into the cause of can- culture cells, and establishment of colony forming assays to
cer dates from 1775, when Sir Percival Pott carried out an epi- reflect reproductive survival allowed quantitative studies of
demiological study and suggested that the causative agent of the response of cancer cells to radiation and drugs, and allowed
scrotal cancer in young chimney sweeps in the United King- therapeutic response of tumors to be related to the sensitivity
dom might be chimney soot (now known to be tar). Frequent of individual cells within them. The establishment of inbred
washing and changing of clothing that trapped the soot was (syngeneic) mice allowed tumors to be transplanted between
recommended so as to reduce exposure to the “carcinogen” them, while subsequent development of immune-deprived
(see Chap. 4). Not only did Pott’s study identify a putative car- mice allowed further study of some human tumors, and of cell
cinogenic agent but it also demonstrated that a cancer may lines derived from them, in an in vivo environment. Together
develop years after exposure. One other dramatic example with large-scale cell cultures that allowed screening of drugs in
is mesothelioma, which is a rare lung cancer that develops a semiautomated way, these tools were instrumental in allow-
decades after exposure to asbestos. A third epidemiological ing agents to be evaluated for antitumor effects and led to the
example is the identification of tobacco smoke as a major envi- development of some of the drugs used in cancer therapy.
ronmental cause of cancer. Doll and Hill (1950) showed that The 1980s ushered in the modern era of molecular biology
cigarette smoking is causative in lung cancer: heavy smokers that led to the discovery of genes involved in cancer develop-
older than the age of 50 years have a 1 in 2 chance of dying from ment. Notably, dysregulation of endogenous genes encoded
a smoking-related disease such as lung cancer (see Chap. 3). in normal cells, called (proto)oncogenes, and/or loss of func-
On the positive side, individuals who quit smoking exhibit a tion of genes that provided checks on processes such as cell
gradual return to a near-normal risk of lung cancer after a 10- proliferation, called tumor-suppressor genes, were found to
to 15-year smoke-free period. These and other studies under- be associated with cancer induction and progression (see
score the possibility that, with some types of cancer, a degree Chap. 7). These findings helped to explain earlier observa-
of prevention may be achieved via changes in lifestyle. tions that viruses can cause cancer as they had evolved to
Early advances in understanding of the biological proper- carry oncogenes that mimic cellular gene function and sub-
ties of cancer followed the development of the microscope, vert normal cellular processes to promote viral replication,
which allowed Virchow, a 19th-century pathologist, to declare: such as the Rous sarcoma virus that was first discovered to be
“Every cell is born from another cell.” This property is true a causative factor in the development of tumors in chickens
of both normal and cancer cells. Microscopic examination of (v-src). Viruses are now known to be causative in the devel-
tumors and normal tissues established many important prop- opment of some common human cancers, including hepatitis
erties, including the characteristics of the cell cycle; the hier- viruses (B and C) as precursors of hepatocellular carcinoma,
archical organization of cells within normal tissues and to a and human papilloma viruses (HPVs) as a causative agent for
lesser extent in tumors; the requirement for angiogenesis for cervical and oropharyngeal cancer (see Chap. 6). The develop-
tumor growth; heterogeneity among tumor cell populations; ment of vaccines against HPVs (Future II Study Group, 2007)
1
2 CHAPTER 1
and of vaccination programs against hepatitis B virus (HBV) treatment, known as cancer stem cells (CSCs; see Chap. 13).
and hepatitis C virus (HCV) in regions where these viruses Surface markers have been identified, which appear to charac-
are endemic (Luo and Ruan, 2012) holds promise for marked terize CSCs, but the stability of these markers, and of the CSC
reduction in the incidence of these cancers. phenotype is uncertain and may be heterogeneous within and
Other historically important contributions to the under- between tumors. The plasticity of cancer cells allows them to
standing of cancer include an appreciation that cancer is develop or select for resistance to therapeutic agents, and this
heritable. Studies of geographically or socially isolated popu- property will likely pose a major challenge to treating tumors
lations, such as the Mormons in Utah, and of changes in can- by targeting specific genetic pathways (see Chap. 19).
cer incidence in migrant families, demonstrated that both The past 10 years has yielded a watershed in our molecu-
genetic predisposition and environmental factors are impor- lar understanding of the genetic basis of cancer (see Chap. 2).
tant in cancer causation. Analysis of cancer-prone families The use of genetically modified mice has enabled research-
have assisted in the identification of genetic abnormalities that ers to demonstrate that loss-of-function or gain-of-function
can lead directly to malignancy, such as mutation of tumor- in tumor-suppressor genes and oncogenes are important
suppressor genes, including the retinoblastoma gene (Rb) in changes that occur during the development of cancers. Such
children, the p53 gene in the Li-Fraumeni syndrome, and the animal models, for example those deficient in TP53 or har-
BRCA1 and BRCA2 genes, which are associated with familial boring constitutively active cellular signaling factors (eg,
breast and ovarian cancer (see Chap. 7). Thus cancer has been the guanosine triphosphatase [GTPase] Ras), have provided
established as a genetic disease. key model systems in which to dissect the progression from
normal cell growth to malignant transformation and metas-
tasis. These studies have yielded a working model in which
1.2 RECENT ADVANCES IN ONCOLOGY cancer acquisition and progression is believed to result from
a series of successive mutations that destabilize the genome
The underlying biology of cancer can perhaps be best concep- and permit unregulated cell growth, which, in turn, elicit fur-
tualized as a process of many small changes similar to evolu- ther alterations in the surrounding tissue that permit growth
tion. Genetic changes that affect growth potential provide an and invasion (see Chap. 5). These genetic alterations may arise
environment permissive for further changes that are selected directly or indirectly from inherited gene mutations, chemi-
for (or against) by environmental conditions. Increasing cal- or radiation-induced DNA damage and genetic instability,
knowledge of cellular signal-transduction pathways has incorporation of certain viruses into the cell, or random errors
revealed that many aspects of cellular function, including during DNA synthesis (see Chaps. 3 and 15). The behavior
proliferation and death, are controlled by a balance of positive of cancer cells is also determined by epigenetic modifications
and negative signals received from inside and outside the cell that influence the expression of genes, and which contribute to
(see Chaps. 8 and 9). Thus, a decreased or increased ability more transient changes in properties of cancer cells, including
to respond to a specific signal may allow the cell to prolifer- those that convey resistance to therapy (see Chap. 2).
ate in the face of other signals that would normally prevent Cancer treatment has evolved to employ a combination of
such proliferation. Interaction of cancer cells with their sur- traditional approaches, such as surgery, chemotherapy, and
rounding tissue (stroma) is also a key factor in cancer initia- radiotherapy, increasingly in conjunction with each other
tion, progression, and metastasis (see Chap. 10). For example, and with drugs that target specific biological networks (see
the development of the vascular networks in tumors (angio- Chaps. 15–20). Some successful targeted biological thera-
genesis) is necessary for tumor growth, and the behavior of pies already in clinical use include the treatment of chronic
cancer cells is influenced by external signals from circulating myelogenous leukemia with a specific, competitive inhibitor
molecules (hormones and growth factors) and from neigh- (imatinib) of the binding site of the Bcr-Abl protein kinase,
boring cells and the extracellular matrix (see Chap. 11). Fur- the protein that is aberrantly expressed as a result of the
thermore, changes to the extracellular environment in tumors Philadelphia chromosome translocation. Another example
(such as poor oxygenation) can cause changes in gene expres- is trastuzumab, a monoclonal antibody that recognizes the
sion that enhance the development of more aggressive tumor HER2/neu receptor expressed on the tumor cells of some
phenotypes (see Chap. 12). These investigations have led to a patients with aggressive breast cancer; treatment with this
better understanding of how and why cancer cells can spread agent has been shown to improve quality and duration of sur-
from the primary tumor to grow at other sites in the body; vival. A third example is vemurafenib, which improves sur-
metastasis is the property of a malignant cancer, which makes vival by inhibiting the BRAF kinase in the approximately 50%
it particularly difficult to treat successfully (see Chap. 10). of human melanomas that have a BRAF mutation. Although
Although cancers may originate from a single cell, they these therapies have improved outcome for patients, tumor
become heterogeneous in their cellular properties and cells cells can become resistant to them; for example, resistance
within different regions of an established tumor may express to imatinib develops as a result of outgrowth of tumor cells
different genes (Gerlinger et al, 2012). One aspect of hetero- bearing a drug-resistant mutation within Bcr-Abl, and resis-
geneity may be retention of a limited number of cells with tance of metastatic disease to other targeted agents develops
high proliferative potential that can regenerate the tumor after invariably after a few months of therapy. Thus, as with more
Introduction to Cancer Biology 3
traditional approaches, a combinatorial approach to cancer modulate immune responses and clinical trials have begun to
treatment is most likely to be successful, although combina- demonstrate an impact in promoting patient survival. Novel
tions of targeted therapies have in some instances proven to immunotherapeutic approaches are starting to take their place
be more toxic. in the cancer treatment armamentarium.
Traditional methods have also undergone substantial There is intense research in large cancer centers into
refinement and improvement. New methods for deliv- “personalized medicine,” where the goal is to provide treat-
ery of radiotherapy, such as image-guided and intensity- ment of an individual’s cancer that will be tailored to the
modulated radiotherapy and stereotactic body radiotherapy, genetic profile of his or her cancer. The cost for sequenc-
have allowed higher doses to be delivered to the tumor with ing an entire genome costs approximately $800 in 2012, and
increased precision and at the same time, lower doses to nor- many genomes from tumor samples have been analyzed;
mal tissue. These techniques have improved local control however, the cancer genome is far more complex than many
of primary tumors, such as those in the prostate and brain, anticipated and still requires high costs for complex bioin-
and new combinations of radiation with surgery and chemo- formatic analysis in order to understand the results of such
therapy are also improving patient survival. One instrument, sequencing. For example, a recent study of the genomes of
called the Cyber-knife, is an example of stereotactic preci- 100 breast cancer patients found that the genetic profiles of
sion radiotherapy, which is already in use in cancer centers their cancers were extremely diverse and did not fit neatly
around the world, and is able to deliver a highly focused into histopathological classifications (Stephens et al, 2012).
beam of irradiation (in 3 dimensions) to tumors in the Furthermore, the tumor microenvironment (eg, hypoxia)
brain. Development of these techniques has paralleled that may further alter gene expression and tumor biology such
of enhanced methods of imaging tumors in the body with that both microenvironmental and genetic heterogeneity
high resolution including CT, MRI, and positron emission may have to be addressed in providing a “true” state of an
tomography (PET) (see Chap. 14). individual’s cancer genome (see Chaps. 10 and 12). Also,
several studies have confirmed that genetic sequencing of
single cells or from small regions of primary cancers shows
1.3 THE FUTURE OF ONCOLOGY substantial heterogeneity. This implies that there is ongo-
AND CANCER TREATMENT ing mutation of cancer cells after tumor induction, and that
multiple targeted agents would be necessary to eradicate all
The recent ability to sequence the DNA and RNA of can- of the cells within a tumor. Anecdotal instances have been
cer and normal tissue genomes has provided insights into reported in which an individual’s tumor has been sequenced
the molecular signals that are associated with various types and the information used to obtain access to an early stage
of cancers. Molecular profiling of key oncogenic factors has clinical drug. Although such patients may have a transient
allowed many types of cancers to be subdivided into subcat- response, the inability to achieve a substantial extension in
egories and is being validated for use in defining better treat- life span or quality of life may reflect the limitations of the
ments for subpopulations of patients to optimize survival early stage drug itself, or that we have much to learn about
(see Chaps. 2 and 22). For example, a breast tumor is now simplistically choosing a single therapy based on a cancer
defined not just by “stage” (size of the primary tumor, and genotype.
whether it has spread to lymph nodes) and grade (the extent A positive aspect arising from the sequencing of cancer
to which it differs from normal breast tissue), but whether genomes is the realization that each cancer may have an
the tumor is estrogen-responsive (eg, estrogen receptor or Achilles heel. In single-celled organisms, such as the bud-
ER-positive or ER-negative) and whether it expresses HER-2 ding yeast Saccharomyces cerevisiae, the concept of synthetic
(see Chap. 20). These data enable the clinician to recommend lethality is well established. This phenomenon is based
treatment with agents that inhibit stimulation of growth by on the observation that a mutation in a gene pathway “A,”
estrogens (tamoxifen or aromatase inhibitors) and by agents although not lethal on its own, becomes incompatible with
such as trastuzumab (which targets the HER-2 receptor). survival when combined with another nonlethal mutation in
More recently, larger scale genomic profiling with Oncotype a separate gene pathway “B.” Because cancer genomes pos-
DX or the “Amsterdam” 70-gene signature are aimed at defin- sess many mutations that differentiate them from surround-
ing patients whose outcome can be significantly improved by ing normal tissue, it should be possible to exploit this unique
adjuvant chemotherapy, or those where it adds only toxicity complexity of the cancer cell. As one example, researchers
and hormonal therapy should be instead used alone. discovered that mutations in BRCA1 and BRCA2 predis-
Another area where the last decade of research has shown pose cancer cells to cell death upon inhibition of members
considerable progress is immunotherapy (see Chap. 21). of the polyadenosine diphosphate (ADP) ribosyl polymerase
Research is leading to an understanding of how to promote (PARP) gene family (Farmer et al, 2005; see Chaps. 5 and 17).
an immune response against cancers as well as developing a Treatment with PARP inhibitors elicits cell death with exqui-
detailed understanding of how the tumor microenvironment site specificity in BRCA-deficient tumor cells, and several
exerts a negative influence. Reagents have been developed that highly potent PARP inhibitors are now in clinical trial for
are directed against many molecules that have the potential to BRCA-mutated ovarian cancers.
4 CHAPTER 1
The notion of personalized medicine also raises several REFERENCES
social and ethical questions. Should insurance companies have
Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary
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