Progress in Cancer Research
Cancer Progress Report 2011: Contents
Progress in Understanding Cancer
The Genetic Basis of Cancer
One of the greatest advances in cancer research was the discovery that changes, or mutations, in genes can cause cancer. The “genetic code” carried in deoxyribonucleic acid (DNA) units, called bases, is packaged into chromosomes that are passed from parents to offspring. The entirety of a person’s DNA is called a genome. The genetic code within our genome is decoded to produce the various proteins that our cells use to function. In cancer, these chromosomes sometimes break and re-combine; this causes large-scale changes within the genome that can result in the production of abnormal proteins which fuel excessive cell growth, or in the loss of other proteins which usually maintain normal cellular functions. Cancer cells have large numbers of these types of changes.
DNA can also be altered by single mutations in the units that make up DNA. Over the years, researchers have identified two key classes of these abnormal cancer genes: oncogenes and tumor suppressor genes. By directing genes to produce aberrant proteins that permit cancer cells to ignore normal growth regulatory signals, oncogenes can drive the initiation and progression of cancer. Tumor suppressor genes encode proteins that normally stop the emergence of cancer by repairing damaged DNA and regulating the multiplication of cells. Mutations in tumor suppressor genes block DNA repair and allow cancer cells to ignore the signals that control normal cell growth and proliferation. Accumulating DNA mutations enables the cancer cells to continually adapt and evade treatment.
To date, over 290 cancer genes have been discovered, and the list continues to grow as advanced technologies facilitate the generation of complete sequences of DNA from cancer cells. A significant number of these mutations code for abnormal proteins, called kinases, which are key components of the numerous signaling networks in cells that drive a large number of cellular functions. Kinases turn signaling networks on and off; however, within cancer cells, they have become mutated in ways that often keep the networks permanently “on,” thus permitting the cancer cells to grow uncontrollably.
The correlation of genetic mutations with changes in cell behavior, especially in cancer, was the impetus for the Human Genome Project, the international effort spearheaded by the NIH to sequence the three billion bases in the human genome. Completed in 2003, the Human Genome Project provided researchers with the complete normal sequence of DNA in the human body, which could then be used as a reference to identify genetic changes in cancer and other diseases. Capitalizing on the important information provided in this reference genome, the NCI and the National Human Genome Research Institute launched The Cancer Genome Atlas (TCGA) in 2006. The goal of TCGA is to identify all of the relevant genomic changes in most types of cancer by comparing the DNA in a patient’s normal tissue with that of the DNA in the tumor.
Beyond our knowledge of the changes in chromosomes and specific mutations in DNA, through research we have learned that DNA can be further altered by the addition of specific chemical entities to it, or in the way it is “packaged” into chromosomes, known as epigenetics. Research is demonstrating that epigenetic changes, which can occur in the absence of specific DNA mutations, are critically important to understanding how cancer originates and evolves. Like the Human Genome Project, the International Human Epigenome Consortium is currently working to define the normal reference epigenome.
Decades of research to understand how changes in the genome cause cancer have produced unparalleled opportunities for future progress in diagnosing, treating, and preventing this complex disease. Continued progress in cancer genomics and epigenomics will stand as powerful strategies to drive molecularly based cancer science and medicine in the future and speed the delivery of its benefits to patients.
Beyond Genetics: The Cancer Cell’s Environment
In the decades since the passage of the National Cancer Act, cancer researchers have continued to accumulate knowledge that is enabling our understanding of cancer at all levels. We now recognize that the altered genomes of cancer cells can have a profound effect on the development and spread of cancer by changing the environment that surrounds the cancer cells, known as the tumor microenvironment.
Examples of factors that make up the tumor microenvironment are: the type, quantity, and modification of the proteins outside the cell that provide structure and function, known as the extracellular matrix; the ability to create new blood and lymphatic vessels (angiogenesis and lymphangiogenesis, respectively); hormones; nutrients; and the immune system. Because of progress in cancer research, we have discovered that the tumor microenvironment profoundly affects the ability of cancers to grow and spread, or metastasize, to other parts of the body.
Tumor-directed angiogenesis and lymphangiogenesis enable cancers to grow uncontrollably and provide a mechanism for tumor cells to escape into the circulation and potentially infiltrate other organs. Adding to the complexity of metastasis, the extracellular matrix can also be modified by cancer cells to specifically alter these processes.
Cancer metastasis continues to take the lives of too many patients. Increasing our understanding of this process and our ability to control it are major challenges in cancer research today. Many questions remain about how metastatic tumors differ from the primary tumor and about what biological processes are required for metastasis to occur. Cancer metastasis is an area of intense investigation and will be for the foreseeable future (see
The Impact of Metastasis Sidebar).
Finally, progress in our understanding of the immune system and how it contributes to the development and evolution of cancer is producing new therapies. We are just now beginning to understand that inflammation, resulting from a variety of causes, plays a central role in tumor formation and progression. Further, it has recently been discovered that tumors block their own destruction by the immune system through the inactivation of immune cells. This important finding has opened the pathway for the development of novel therapeutics and therapeutic strategies.
In short, the Nation’s investments in cancer research over the last 40 years have produced remarkable progress in understanding the causes of cancer initiation and progression at the molecular, cellular, and tissue levels. This new knowledge is a result of an ever-accelerating pace of discovery, fueled in large part by the availability of exciting new technologies. As a result, we now know that the complexity of cancer exists at every level: from populations, to individuals, to specific cancers, and to the very genes that drive these cancers.
Uncovering the mysteries of cancer requires the collaboration of researchers from a wide range of disciplines and the convergence of new advanced technologies and computing with the molecular sciences. Clearly the promise of future cancer cures and prevention will be fulfilled in this unprecedented era of molecularly based medicine.
Setting the Standard of Care
Our more complete understanding of the biology of cancer is moving cancer research in exciting new directions. Continued research is now yielding an unprecedented insights into the biology of cancer at the molecular level, and this new knowledge is beginning to transform the current standard of care from a one-size-fits-all approach to personalized cancer care (see,
A Future of Personalized Cancer Medicine). However, before discussing the advances that will revolutionize the standard of care in the near future, it is important to cite the many discoveries that have established our current standard of care. We would not be on our current path were it not for the extraordinary medical, scientific, and technological advances that have given us the tools we now use to prevent, detect, diagnose, and treat cancer. Collectively, these advances have helped and continue to define the current standard of care and have saved millions of lives in the U.S. and throughout the world.
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Advances in Cancer Prevention
An important area of cancer research includes understanding the causes of cancer and developing the means to detect it and intervene earlier in its progression; or to prevent the onset of cancer altogether. Tremendous progress in cancer prevention has been made through the integration of various research disciplines and technologies, including biochemistry, cell biology, imaging, molecular biology, toxicology, biostatistics, and epidemiology. Some of the greatest reductions in cancer mortality have resulted from the implementation of public health measures and improvements in screening practices that are based on our knowledge of the causes of cancer.
When a family member or friend develops cancer, many people often ponder why. All too often, there is no easy answer because the variables are too numerous and complex. Researchers are beginning to understand some of the risk factors and root causes for certain types of cancer. For example, tobacco use, radiation exposure, hormones, environmental and occupational carcinogens, and infectious agents play a major role in causing cancer. Although they are incompletely understood at this time, factors such as diet, lifestyle, and other medical conditions can modify a person’s cancer risk (see
Behavioral Research Sidebar).
Tobacco Use and Cancer
The causal relationship between cigarette smoking and lung cancer was first brought to the public’s attention in 1964 by the U.S. Surgeon General’s Report on Smoking and Health. The Report marked the beginning of major U.S. policy changes, media campaigns, and other measures to combat cigarette smoking, all of which have helped to reduce the percentage of Americans who smoke to about 20% of the population, down from 42% in 1965.
Since that landmark Report, research has shown that tobacco use is a cause of 18 different cancers, including lung, head and neck, stomach, pancreas, and cervical cancers, among others, and accounts for 30% of all cancer deaths in the U.S. A substantial evidence base also proves that exposure to secondhand smoke, or environmental tobacco smoke, also causes cancer, a finding that has led to important policies restricting smoking in public places. In recent decades, there has been a steady decline in lung cancer death rates among men, which is directly attributable to the decrease in smoking prevalence. This success is representative of how scientific progress can inform public policy and educational efforts to measurably reduce cancer rates.
The Surgeon General’s 31st report on tobacco, released in 2010, concludes that there is no safe level of exposure to tobacco smoke. Yet, every day 4,000 American youths smoke their first cigarette, and 1,000 join the 71 million Americans, aged 12 and older, who regularly use tobacco. Clearly, countless lives can be saved in the future through continued research to develop and implement effective tobacco control strategies.
Exposure to Radiation and Environmental and Occupational Toxins and Cancer
Epidemiological research has determined that even low levels of radiation exposure increase cancer risk, and that efforts to limit diagnostic X-ray exposure should be made. Likewise, excessive exposure to ultraviolet light (UV), a form of radiation, is a risk factor for skin cancer, particularly the most lethal form, melanoma. New standards for sunscreen, increased sun protection, and decreased UV exposure, including avoiding the use of tanning beds, should greatly reduce melanoma and other skin cancers.
Exposure to the naturally occurring radioactive gas,radon, causes between 15,000 and 22,000 lung cancer deaths a year, making it the second leading cause of lung cancer after smoking. This discovery has led to policies for reducing exposure through home and business inspections, and the containment or elimination of the source when possible. Increased awareness along with these mitigation strategies should greatly reduce the incidence of lung cancer caused by these exposures.
The role of environmental and workplace exposures in cancer and other health outcomes has been an important area of epidemiologic and toxicologic research. Agents such as asbestos and the related volcanic rock, erionite, cause an aggressive form of cancer, called mesothelioma, that is difficult to treat. Chemicals like arsenic, aflatoxin, and pesticides, particularly dichlorodiphenyltrichloroethane (DDT), are also associated with an increased risk of a variety of cancers. Our knowledge of their roles in causing cancer has paved the way for important preventive interventions and public policy. Our understanding of how overall exposure, length of exposure, and exposures to multiple toxins contributes to the formation of cancer is still incomplete and requires further study.
Hormones in Cancer
Hormones are associated with modified risk of breast and ovarian cancers. It is now established that postmenopausal hormone replacement therapy, which includes progesterone, increases breast cancer in women who have a uterus, while oral contraceptive use and tubal ligation decrease the risk of ovarian cancer in premenopausal women. Fetal exposure to diethylstilbestrol, a synthetic estrogen, increases the risk of vaginal/clear cell adenocarcinoma in adulthood. The association of hormones with an increase in cancer, particularly of the breast, has led to the approval by the U.S. Food and Drug Administration (FDA) of anti-estrogen therapies to prevent breast cancers in high-risk women (see
Molecularly Based Prevention). However, the role of hormones in cancer causation is even more complex. Plant-based, weak estrogens, such as those derived from soy products, may be beneficial, but only when consumed over a lifetime. Further, new research is probing the influence of hormone-like substances in the environment, like those found in some plastic containers, on cancer causation. This emerging topic illustrates the power of contributing our knowledge of the biology and epidemiology of carcinogenesis to the evaluation of potential harm from modern-day products.
Infectious Agents and Cancer
The discovery that a number of infections, such as human papillomavirus (HPV), hepatitis B and C viruses (HBV and HCV, respectively), potentially cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and Helicobacter pylori bacteria, cause a variety of cancers was an advance of major significance in prevention. This new knowledge has informed the identification of high-risk individuals, as well as the development of new methods of prevention and treatment (see
Conquering Cancer by Eliminating Infectious Agents Sidebar).
For example, screening and vaccination for HBV have greatly reduced the incidence of hepatocellular carcinoma in endemic regions. Researchers are actively investigating potential connections between CMV infections and some cases of glioblastoma. Likewise, the treatment and/or elimination of EBV may reduce the minority of stomach cancers not caused by H. pylori, Hodgkin’s and non-Hodgkin’s lymphomas, and nasopharyngeal cancers. The establishment of a link between HPV and cervical cancer in 1974 led to the development and recent FDA approval of two HPV vaccines for the prevention of cervical cancer. Further, an HPV vaccine was recently approved for prevention of anal cancer, and its indications may soon be expanded to head and neck cancers. The effectiveness of the HPV vaccine in preventing cervical cancer is approaching 100%. The extraordinary impact of cancer vaccines has set a high standard for the promise of cancer prevention, and has revolutionized our thinking regarding its potential for saving lives from cancer.
The Role of Diet, Lifestyle, and Other Medical Conditions in Cancer Risk and Recurrence
Numerous studies have shown that diet, physical activity, and body weight or body composition, collectively known as energy balance, play a major role in both cancer risk and recurrence. Medical conditions like obesity and immunosuppression also increase the risk of different cancers (see
Energy Balance Sidebar). Also, excessive intake of alcohol has been shown to increase the risk of mouth, throat, esophageal, liver, and colon cancers, particularly in men, and of breast cancer in women. Finally, research into the various components of “healthy” foods that may prevent cancer must go deeper and identify the primary component and mechanism of action in order for these compounds to become effective preventive measures (see
Health Behaviors Sidebar).
Together, this means that, conservatively, at least 50% of cancers that occur in the U.S. could be preventable. Measurable changes in cancer incidence and mortality can be accomplished by investing in evidence-based behavior modification research and educational campaigns and programs that promote the benefits of a healthy diet, regular exercise, weight loss, smoking cessation, the use of prophylactic vaccines, and the reduction of risky behaviors (see
Behavior Research Sidebar). It is imperative that we continue to build upon our knowledge of the causes of cancer and increase the number of cancers that we can prevent through behavior modification.
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Advances in Cancer Detection and Screening
Finding a tumor early, before it has spread to other parts of the body, makes it more likely that cancer can be treated successfully with fewer side effects and a better chance of survival.
Many cancers, particularly those that arise in tissues other than the blood, are progressive in nature. These cancers begin with a series of genetic and cellular changes that cause normal cells to develop into pre-cancerous lesions, called intraepithelial neoplasia (IEN), and end in metastatic disease. These processes typically take place over a period of years, and improvements in our ability to identify these changes have allowed us to detect some pre-cancers and intercept them before they become advanced disease. It is believed that continued research into how to intercept the progression from pre-cancer to cancer could make virtually all cancers preventable.
Population-based screening programs, which test generally healthy individuals for potential disease, provide opportunities to intervene in the cancer process as early as possible. Studies have shown that the widespread screening programs implemented in the U.S. have been both beneficial and cost effective.
Screening is routinely done for the early detection of cervical cancer using the Papanicolaou (Pap) tests, for breast cancer with mammography, for prostate cancer using prostate specific antigen (PSA) tests, for colon cancer using colonoscopy, and, most recently, for lung cancer in current and former heavy smokers using spiral computed tomography (CT). To be successful, early detection must lead to reduced cancer mortality.
Some tests, such as the Pap test, directly examine cellular shape, or histological analysis, to look for abnormal cells. The Pap test has contributed significantly to the 99% reduction in deaths from cervical cancer in the U.S. by identifying the pre-cancerous cells to allow for their removal, thus preventing the progression to cancer. The PSA screening for prostate cancer has resulted in earlier detection and intervention. This approach leads to fewer severe side effects from treatment and a better quality of life.
Imaging technologies have also improved our ability to detect and screen for cancer. Routine mammography screening, although the results have been variable, has been shown to reduce breast cancer deaths by as much as 29% for women in their 40s. Likewise, colonoscopy detects pre-cancerous polyps so that they can be removed before they develop into advanced disease. This early intervention is estimated to have reduced colorectal cancer deaths by 50%.
Finally, earlier this year, researchers reported that, among current and former heavy smokers, spiral CT screening reduced lung cancer mortality by 20% by identifying small tumors; however, this is an early result and more work needs to be done before it is applied population wide.
New imaging technology will make identifying premalignant lesions and early disease more effective, thus providing opportunities for chemoprevention strategies, more effective treatments for early disease, and the reduction of cancer mortality. The challenges are to identify the population that will most benefit from these strategies and to determine the optimal frequency of screening. Cost containment so as to make this approach affordable will be essential to its success.
Clearly, screening to detect cancers early can greatly reduce their incidence. Although not all cancers are amenable to screening, cancer research promises to develop molecular biomarkers and other technologies that can serve as indicators of disease and serve as new screening tools to find cancers that currently elude us, like pancreatic and ovarian cancer.
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Advances in Cancer Treatment
Over the past four decades we have seen important advances in the primary triad of cancer patient care—chemotherapy, surgery, and radiation—as well as in the provision of supportive or palliative care.
Advances in Chemotherapy
During the past four decades, new types and combinations of cytotoxic chemotherapy drugs, which largely work by stopping rapidly dividing cells, have been widely used in cancer treatment. Despite their side effects, these drugs have led to major increases in the survival of patients with childhood acute lymphoblastic leukemia, Hodgkin’s disease, aggressive lymphomas, and testicular cancers, to the point of cures or near cures. In addition, significant reductions in death rates have been achieved in breast and cervical cancers in women; prostate and lung cancers in men; and colorectal, oral cavity and pharynx, and stomach cancers in both genders.
Through clinical trials, we have also learned how to use these drugs after surgery or radiation in patients with early-stage disease to significantly reduce the risk of recurrence. These advances have been bolstered by the use of new treatment protocols that combine cytotoxic and other drugs before surgery or radiation, which can shrink the tumor and help ensure that the surgery or radiation maximizes the elimination of tumor cells. Similar principles guide the use of these therapies in the treatment of leukemias and lymphomas, for which surgery has a lesser role. Additionally, anti-hormonal therapies form the basis of treatment for many breast and prostate cancers, and are very successful in reducing the risk of recurrence and mortality.
Advances in Surgery and Radiotherapy
During the last four decades, surgical procedures have been refined, resulting in fewer disfiguring surgeries with less damage to normal tissue, faster healing times, and better overall recoveries. This is especially true in breast cancer, where clinical trials have shown that lumpectomy and radiation are as effective as radical mastectomy, and that sentinel node biopsy (which is a way to detect whether the cancer has spread to nearby lymph nodes) is as effective as complete axillary (armpit) node dissection in determining how far a breast tumor has spread and which treatments are needed.
Technological advances have also reshaped surgery. For certain cancers in the abdomen, laparoscopic procedures through which tumors are removed through small incisions have proved to be as effective as open surgery. In addition, computer-assisted robots perform extremely complex surgeries. For example, computer-assisted advanced prostatectomies further reduce damage to the surrounding delicate nerves and blood vessels, translating into a substantial improvement in quality of life for these patients.
Just as surgery has been improved with the addition of computer guidance, so too has radiotherapy. Computer-guided machines, like the cyberknife, have markedly improved the precision of radiation therapy, permitting patients to receive increasingly focused and higher doses that can kill more cancer cells with less damage to the surrounding tissue. Also, intensity modulated radiation therapy (IMRT) makes it possible to deliver very high radiation doses to very precise areas, and is now widely used to treat head and neck, and prostate cancers. Similarly, stereotactic radiosurgery, also known as the gamma knife, has made a critical difference in the treatment of various brain and inoperable lung cancers by more precisely treating the tumor and sparing healthy tissue.
Advances in Imaging
As the technologies have improved, so have the imaging capabilities that permit us to diagnose cancer and to determine whether and to what parts of the body a tumor may have spread. For example, positron emission tomography (PET) scans are now used along with a radiolabeled glucose tracer, called 18fluorodeoxyglucose (FDG), to identify micrometastases that were previously undetectable by standard imaging techniques, which informs subsequent treatment options.
In addition, it is now possible to combine advanced imaging technologies, such as FDG-PET, with CT, or double contrast magnetic resonance imaging (DC-MRI). These combination scans are now being used to simultaneously obtain detailed information about the extent of a patient’s cancer and the precise location of metastases, enabling better surgical removal and/or directed radiation of the tumor.
Advances in Supportive Care
A number of palliative or supportive care approaches and technologies have been developed that make the administration of chemotherapy safer and more tolerable.
Anti-emetics have improved the ability of patients to tolerate chemotherapy by reducing nausea and vomiting. The hematopoietic growth factors, which stimulate the production of red and white blood cells in the bone marrow that have been depleted by chemotherapy, have helped prevent severe infections that were common during cancer treatment, allowing for treatment without interruption. Additionally, the class of drugs, known as bisphosphonates, and a new therapeutic antibody, called denosumab (Xgeva), are now used to reduce bone fractures from metastases of certain cancers to the bone, as well as the metastases themselves.
Finally, our increased understanding of pain management has led to the wider use of analgesics. These drugs have greatly improved the quality of life for patients during and after treatment. This is especially important today as the new therapies and improved management of metastatic disease continue to increase the number of years that patients can survive after initial treatment, thus changing an increasing number of cancers into chronic, manageable conditions rather than a death sentence.
All of these advances have made a real difference in the lives of cancer patients and their families. Because of the molecular revolution, we are now in an era of great promise in our ability to reduce the number of deaths due to cancer and to reduce the suffering caused by this most feared disease.
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Progress Report 2011 Contents