AACR Cancer Progress Report 2013

• Charles L. Sawyers, M.D.

• Chairperson, 2013

• Chair, Human Oncology and Pathogenesis Program

• Memorial Sloan-Kettering Cancer Center

• New York, NY

• Cory Abate-Shen, Ph.D.

• Professor of Urology and Pathology & Cell Biology

• Columbia University Medical Center

• New York, NY

• Kenneth C. Anderson, M.D.

• Director, Jerome Lipper Multiple Myeloma Center

• Dana-Farber Cancer Institute

• Boston, MA

• Anna D. Barker, Ph.D.

• Professor and Director, Transformative Healthcare Networks

• Arizona State University

• Tempe, AZ

• José Baselga, M.D., Ph.D.

• Physician-in-Chief

• Memorial Sloan-Kettering Cancer Center

• New York, NY

• Nathan A. Berger, M.D.

• Director, Center for Science, Health & Society

• Case Western Reserve University School of Medicine

• Cleveland, OH

• Margaret Foti, Ph.D., M.D. (h.c.)

• Chief Executive Officer

• American Association for Cancer Research

• Philadelphia, PA

• Ahmedin Jemal, D.V.M., Ph.D.

• Program Director

• American Cancer Society

• Atlanta, GA

• Theodore S. Lawrence, M.D., Ph.D.

• Professor and Chair, Department of Radiation Oncology

• University of Michigan

• Ann Arbor, MI

• Christopher I. Li, M.D., Ph.D.

• Head, Translational Research Program

• Fred Hutchinson Cancer Research Center

• Seattle, WA

• Elaine R. Mardis, Ph.D.

• Co-Director, The Genome Institute

• Washington University School of Medicine

• St. Louis, MO

• Peter J. Neumann, D.Sc.

• Director, Center for the Evaluation of Value and Risk in Health

• Tufts Medical Center

• Boston, MA

• Drew M. Pardoll, M.D., Ph.D.

• Professor, Department of Oncology

• Johns Hopkins Kimmel Comprehensive Cancer Center

• Baltimore, MD

• George C. Prendergast, Ph.D.

• Professor, President and CEO

• Lankenau Institute for Medical Research

• Wynnewood, PA

• John C. Reed, M.D., Ph.D.

• Head of Pharma Research and Early Development (pRED)

• F. Hoffmann-La Roche Ltd.

• Basel, Switzerland

• George J. Weiner, M.D.

• Director, Holden Comprehensive Cancer Center

• University of Iowa

• Iowa City, IA

• Shawn M. Sweeney, Ph.D.

• Project Leader

• Senior Program Administrator

• Philadelphia, PA

• Karen Honey, Ph.D.

• Lead Science Writer

• Senior Managing Editor, Science Communications

• Philadelphia, PA

• Paul Driscoll

• Director, Marketing and Creative Services

• Philadelphia, PA

• Mark Fleury, Ph.D.

• Associate Director, Science Policy

• Washington, DC

• Jennifer Hobin, Ph.D.

• Director, Science Policy

• Washington, DC

• James Ingram

• Senior Manager, Legislative Affairs

• Washington, DC

• Rasika Kalamegham, Ph.D.

• Senior Science Policy Analyst

• Washington, DC

• Srivani Ravoori, Ph.D.

• Senior Science Writer

• Philadelphia, PA

• Jon G. Retzlaff, M.B.A., M.P.A.

• Managing Director, Science Policy and Government Affairs

• Washington, DC

• Mary Lee Watts, M.P.H., R.D.

• Director, Government Relations

• Washington, DC

• Nicolle Rager Fuller

• Illustrator

• Sayo-Art, LLC.

• Bellingham, WA

On April 8, 2013, in an unprecedented effort to highlight the critical importance of biomedical research, the American Association for Cancer Research (AACR) joined with more than 200 organizations representing a broad spectrum of research interests and diseases to “Rally for Medical Research” in our nation's capital. This historic event, which united research advocates across the country and attracted more than 10,000 supporters to Washington, D.C., served as a call to action to raise awareness about the need to increase investments in the National Institutes of Health (NIH) to spur more progress, inspire more hope, and save more lives. The AACR Cancer Progress Report 2013 echoes this rally cry by outlining why funding for the NIH and the National Cancer Institute (NCI) must be a national priority.

The report details how scientific discoveries propelled by federal investments in basic, translational, and clinical research are transforming cancer care and bringing hope to patients and their loved ones everywhere. These discoveries have led to decreases in the incidence of many of the more than 200 types of cancer, cures for a number of these diseases, and higher quality and longer lives for many individuals whose cancers cannot yet be prevented or cured.

Herein, this report focuses on the remarkable progress that has been made against cancer, and highlights how advances in one field can have a profound effect on others. For example, promising new therapies that harness the power of a patient's immune system to treat their cancer would not have been realized without basic research in immunology. These types of therapies are described within a special feature in this report. Cancer research also impacts other diseases. Indeed, drugs originally developed for cancer patients have led to treatments for macular degeneration, atherosclerosis, psoriasis, rheumatoid arthritis, and hepatitis among others. The synergistic relationships among different research fields — and the relationships between certain diseases — underscore why it is so important for scientists, patients, and advocates across the spectrums of research and disease to join together in advocating for sustainable research funding.

This report and the ongoing community-wide effort to rally support for biomedical research could not come at a more important time. Cancer research and biomedical science are facing the most serious funding crisis in decades. Since 2003, the budgets for the NIH and the NCI have been steadily shrinking because the amount of funding provided to them by Congress each year has been significantly less than what is needed to just keep pace with biomedical inflation. As a result, there has been an effective 20 percent reduction in the ability of these agencies to support lifesaving research. In addition to the gradual erosion of funding due to inflation, the NIH was forced to absorb $1.6 billion in direct budget cuts in March 2013, under what is known as sequestration. The NCI suffered a commensurate budget cut of $293 million. As a result, the NIH is now funding the lowest number of research projects since 2001, and unless Congress takes action, sequestration will result in an overall reduction to the NIH budget of $19 billion by 2021.

The current course is simply unacceptable, and Congress must intervene, because the eroding support for cancer research has far-reaching negative implications. For example, shrinking budgets will adversely impact the ability of scientists to carry out ongoing research projects; reduce the number of promising new grant proposals that the NCI can support; diminish the funding available to cancer centers where critical “bench-to-bedside” research and care take place; and slow the progress of clinical trials, which will have a devastating effect on patients who will be forced to endure a delay in the development of new and improved treatments for their diseases.

What is worse is the fact that diminished federal investments in cancer research come at a time when the American people most need new research advances. Cancer is the second most common cause of disease-related death in the United States, exceeded only by heart disease, and it will become the number one killer in the very near future unless we are able to avert this projected increase in cancer cases through research. Cancer currently accounts for nearly one of every four disease-related deaths in the United States, and is expected to claim the lives of 580,350 Americans this year. In addition, it is estimated that 1.6 million Americans will be diagnosed with cancer this year. Globally, cancer incidence is also on the rise, and it is anticipated to claim the lives of approximately 13 million people by 2030.

Despite this sobering reality, federal policymakers can put biomedical research back on course. To do so, however, they must designate the NIH and NCI as national priorities and provide these vitally important institutions with sustained funding increases that are at least comparable to the biomedical inflation rate. In addition, Congress must take action to protect the agencies from sequestration, and to reinstate the $1.6 billion in funding that the NIH lost in March 2013. The AACR also calls upon its members, and indeed all Americans — the beneficiaries of this lifesaving research — to make their voices heard by contacting their representatives and senators in Congress and urging them to vigorously support budget increases for the NIH and NCI. If policymakers fail to act, our ability to transform cancer care for the benefit of current and future cancer patients will be seriously compromised, and the crucial investments we have already made in biomedical research will be jeopardized.

The inspiring personal stories of the cancer survivors in this report are a testament to the value and importance of the biomedical research that is supported by the NIH and NCI. The AACR is deeply grateful to these courageous survivors for both their participation and willingness to share their stories. We stand with them and with patients and their loved ones everywhere in calling upon our policymakers to make every possible effort to help eradicate cancer. We ask you to join us in this quest to conquer cancer.

• Charles L. Sawyers, M.D.

• AACR President

• Margaret Foti, Ph.D., M.D. (h.c.)

• Chief Executive Officer

Amazing progress has been made against cancer because of the dedicated work of researchers throughout the biomedical research enterprise. Their efforts have spurred, and continue to spur, the translation of scientific discoveries into new and better ways to prevent, detect, diagnose, and treat cancer. These remarkable advances are contributing to the rise in the number of people who are surviving longer and living life to the fullest after their cancer diagnosis. In fact, the number of cancer survivors living today in the United States is estimated to be more than 13.7 million.

The improvements in health care that have significantly reduced the burden of cancer were made possible by the scientific foundation provided through the many decades of investments in basic, translational, and clinical research. These investments come from the federal government, philanthropic individuals and organizations, and the private sector. The federal investments in biomedical research, made primarily through the National Institutes of Health (NIH) and the National Cancer Institute (NCI), have been particularly instrumental in building our current scientific foundation.

Although extraordinary advances in cancer research have deepened our understanding of how cancer develops, grows, and threatens the lives of millions, it is projected that 580,350 Americans will die from one of the more than 200 types of cancer in 2013. Moreover, because more than 75 percent of cancer diagnoses occur in those aged 55 and older and this segment of the population is increasing in size, we face a future where the number of cancer-related deaths will increase dramatically. As a result, cancer is predicted to soon become the number one disease-related killer of Americans. This trend is being mirrored globally, and it is estimated that in 2030, more than 13 million people worldwide will lose their lives to cancer.

As the number of cancer deaths increases, the economic burden of cancer will mushroom. Given that the global economic toll of cancer already is 20 percent higher than that from any other major disease, it is imperative that all sectors of the biomedical research enterprise work together to deliver future breakthroughs to help reduce the incidence of cancer.

Fortunately, we have never been better positioned to capitalize on our hard-won understanding of cancer — what causes it, what drives it. We now know that changes in an individual's genes alter certain protein components of the cell, driving cancer initiation, development, and spread (metastasis). We also know that therapies that specifically target these defects are often beneficial to patients while being less toxic than older therapies.

However, continued progress is in jeopardy. This is because investments in the NIH by the federal government have been steadily declining for the past decade. On top of this, on March 1, 2013, sequestration slashed the NIH budget by $1.6 billion, or 5.1 percent.

This third AACR Cancer Progress Report to Congress and the American public seeks again to serve as a comprehensive educational tool that illustrates the astounding return on investment in cancer research and biomedical science, while also celebrating the many ways that we have continued to make research count for patients in the past year. Scientific momentum has brought the arrival of a new era in which we will be able to develop even more effective interventions and save more lives from cancer, but to do so will require an unwavering, bipartisan commitment from Congress and the administration to invest in our country's remarkably productive biomedical research enterprise.

Many of the greatest reductions in the morbidity and mortality of cancer have resulted from advances in cancer prevention and early detection.

Yet, more than 50 percent of the 580,350 cancer deaths expected to occur in the United States in 2013 will be related to preventable causes. Most notable among these causes are tobacco use, obesity, poor diet, lack of physical activity, exposure to ultraviolet radiation either through the use of tanning devices or direct sun exposure, and failure to use or comply with interventions that treat or prevent infectious causes of cancer. Modifying personal behaviors to adopt a healthier lifestyle that eliminates or reduces these risks, where possible, could therefore, have a remarkable impact on our nation's burden of cancer. However, a great deal more research and resources are needed to understand how to best help individuals to change their lifestyle.

Finding a cancer early makes it more likely that it can be treated successfully. Thus, population-based screening programs have been implemented to detect a variety of cancers. Such programs have been credited with dramatically increasing the five-year survival rates for the cancers they detect; however, there is growing concern that this heightened surveillance leads to the overdiagnosis and overtreatment of some forms of cancer, and that it can do more harm than good.

One way to reduce overdiagnosis and overtreatment is to target screening programs to those individuals at highest risk for developing the cancers being detected. Therefore, continued research is needed to develop more concrete ways to identify the most at-risk patients, and more and better ways to intervene earlier in the progression of cancer.

Decades of cancer research have deepened our understanding of cancer biology. Exploiting this knowledge to make research count for patients is a continual pursuit that fuels the extraordinary medical and technical advances that are not only helping save millions of lives in the United States and worldwide, but are also improving the quality of lives.

From Sept. 1, 2012, to July 31, 2013, the translation of scientific discoveries into a new drug, device, or technique approved by the U.S. Food and Drug Administration (FDA) was completed for 11 new anticancer drugs, three new uses for previously approved anticancer drugs, and three new imaging technologies that are helping clinicians to better detect, diagnose, and treat many forms of cancer.

There are also many cancer therapeutics showing great potential in clinical trials. One group of cancer therapeutics likely to revolutionize the treatment of certain cancers in the very near future are immunotherapies. These therapeutics, which train a patient's immune system to destroy their cancer, are yielding both remarkable and long-lasting responses. Moreover, not all immunotherapies work in the same way, and early studies indicate that combining immunotherapies that operate differently or combining immunotherapies with either radiation therapy or other drugs can enhance the benefits of these incredibly powerful anticancer therapeutics.

As a result of cancer genomics research, two of the new anticancer drugs approved by the FDA in 2013 were approved together with companion diagnostics to ensure that only patients who are likely to benefit from the drug receive it. This is an example of how large-scale genomic analysis of patients' tumors is beginning to guide cancer diagnosis and treatment. Further innovation is needed, however, if genetic/genomic analysis is to become part of standard clinical practice, and if most cancer treatment and prevention strategies are to be based on both a person's genetic makeup and the genetic makeup of their specific cancer.

Bipartisan support from Congress and the administration for the NIH and NCI has enabled extraordinary progress against cancer. In doing so, it has saved countless lives, both in the United States and throughout the world, while catalyzing the development of the biotechnology industry and promoting economic growth in America. However, there are many challenges to overcome if we are to realize our goal of conquering cancer.

First and foremost, if we are to accelerate progress toward our goal, we must continue to pursue a comprehensive understanding of the biology of cancer. This will only be possible if we make funding for cancer research and biomedical science a national priority. This includes investing in the talent, tools, and infrastructure that drive innovation, as well as advancing policies that enable researchers to more completely understand the complexities of cancer and to translate that knowledge for the benefit of patients.

Innovative efforts to develop new tools, new analytics, new ways of thinking, and new ways of working together will help researchers and their partners in the biomedical research enterprise forge ahead to the finish line — to the day when cancer is removed as a major threat to our nation's citizens and to future generations. Realizing this bright future requires that Congress, the administration, and the general public stand firm in their commitment to the conquest of cancer.

To fulfill the extraordinary scientific and medical promise of cancer research and biomedical science, the AACR respectfully urges Congress to:

• Designate the NIH and NCI as national priorities by providing annual budget increases at least comparable to the biomedical inflation rate.

• Protect the NIH and NCI from another year of the insidious budget cuts from sequestration, and reinstate the $1.6 billion in funding that the NIH lost in March 2013.

Therefore, the AACR calls on all Members of Congress to ensure that funding for cancer research and biomedical science is strongly supported. The AACR also urges all Americans — the beneficiaries of this lifesaving research — to make their voices heard by encouraging their policymakers to provide sustainable increases for the NIH.

If we are to ultimately transform scientific discoveries into therapies that improve and save the lives of cancer patients, it is going to require an unwavering commitment of Congress and the administration to invest in our country's remarkably productive biomedical research enterprise led by the NIH and NCI.

Significant progress has been and continues to be made against cancer. This progress is the result of dedicated efforts across all sectors of the biomedical research enterprise to increasingly translate basic scientific discoveries about cancer into new and better ways to prevent, detect, diagnose, and treat this disease (see Figure 1, p. 3). Indeed, in just 11 of the 12 months since the AACR Cancer Progress Report 2012 (Sept. 1, 2012, to July 31, 2013), the U.S. Food and Drug Administration (FDA) approved 11 new drugs for treating cancers, three new uses for previously approved anticancer drugs, and three new imaging technologies (see Table 1, p. 4).

Due in part to advances like these, more people survive their cancers today than in the past (see Figure 2, p. 5). The National Cancer Institute (NCI) estimates that approximately 13.7 million Americans with a history of cancer were alive on Jan. 1, 2012 (1). This is almost 2 million more than its previous estimate of nearly 12 million in 2008 (2), and more than 10 million more than in 1971, the year the U.S. Congress passed the National Cancer Act (3).

The progress has been spurred by many decades of investments in basic, translational, and clinical research by the federal government, philanthropic individuals and organizations, and the private sector. Of particular importance are the investments in basic research supported by public funds through the National Institutes of Health (NIH) and NCI. Together, investments in biomedical research from all sectors have led to decreases in incidence for many of the more than 200 diseases we call cancer; cures for some of these diseases; and higher quality and longer lives for many individuals whose cancers cannot yet be prevented or cured.

Unfortunately, advances have not been uniform for all types of cancer (see Table 2, p. 6). The five-year survival rates for some cancers, such as the most aggressive form of brain cancer (glioblastoma multiforme), and pancreatic, liver, and lung cancers, have not improved significantly over the past four-plus decades and remain very low, at 4 percent, 6 percent, 14 percent, and 16 percent, respectively (1, 4). In contrast, the five-year survival rates for women diagnosed with invasive breast cancer and for children diagnosed with acute lymphocytic leukemia have increased from 75 percent and 58 percent, respectively, to 90 percent or more since the mid-1970s (1). Moreover, advances have not been identical for all patients with a certain type of cancer, nor is the burden of cancer distributed evenly across the population, due to numerous interrelated factors.

Despite significant improvements in survival from many cancers, it is estimated that 580,350 Americans will die from some form of cancer in 2013 (1). Cancer will account for nearly one in every four deaths, making it the second most common cause of disease-related death in the United States. Unless more effective preventive interventions, early detection tools, and treatments can be developed, it will not be long before cancer is the leading cause of death for all Americans, as it already is among the U.S. Hispanic population (5).

It is projected that more than 1.6 million Americans will be diagnosed with cancer in 2013 (1). This number will dramatically increase in the next two decades, largely because cancer is primarily a disease of aging (1). Most cancer diagnoses occur in those aged 65 and older (1, 4), and this portion of the population is rapidly growing (6, 7) (see Figure 3, p. 7). Compounding the problem is the increasing prevalence of obesity and the continued use of tobacco products by nearly 20 percent of the U.S. population, both of which are linked to an elevated risk for several cancers (8, 9). Given these compelling statistics, cancer prevention represents an area of particular promise because it is estimated that more than half of the cancer deaths that occur in the United States are preventable through lifestyle modifications (10).

Cancer is not unique to America; it is a global problem. Cancer incidence worldwide is predicted to increase from 12.8 million new cases in 2008 to 22.2 million in 2030 (11). Without the development of more effective preventive interventions and treatments, this will translate to more than 13 million lives claimed by cancer in 2030 (12).

Of all major causes of disease worldwide, cancer has the greatest economic burden from premature death and disability. The global economic toll is 20 percent higher than that from any other major disease, at $895 billion in 2008 (13). This figure does not include the direct costs of treating cancer. In the United States, the latest estimates from the NIH indicate that the overall economic costs of cancer in 2008 were $201.5 billion: $77.4 billion for direct medical costs and $124.0 billion for lost productivity due to premature death (1).

Given that cancer is the most costly disease to our nation, and it is poised to become the number one killer of Americans, it is urgent that we increase our investments in the scientific research needed to develop more effective interventions. This report highlights many of the remarkable recent advances that are the direct result of the dedicated work of thousands of researchers funded through the federal government and other sectors of the biomedical research enterprise. There is little doubt that the ability of these researchers to continue making lifesaving progress is in significant jeopardy given that NIH and NCI budgets are decreasing (see Funding Cancer Research and Biomedical Science Drives Progress, p. 69).

At its simplest, cancer can be considered a disease in which normal cells start “behaving badly”, multiplying uncontrollably, ignoring signals to stop, and accumulating to form a mass that is generally termed a tumor (see Developing Cancer, p. 17).

Unfortunately, research has taught us that cancer is anything but simple.

First and foremost, there are perhaps as many as 200 different types of cancer, each named for the organ or type of cell from which it originates. Moreover, cancer is complex at every level, from populations, to individuals, to specific cancers, to the molecular and genetic defects that drive these cancers.

Despite cancer's complexity, we are beginning to exploit our growing knowledge of the molecular changes that generally drive cancer initiation and development for the benefit of patients, providing new ways to reduce the burden of cancer (see sidebar on The Virtuous Cycle of Biomedical Research, p. 9).

An in-depth understanding of what happens when normal cells become cancerous is essential if we are to answer the question: What is cancer?

We know that to keep our bodies healthy, most cells multiply or divide in a tightly controlled process to replace old and damaged cells. Sometimes, this well-regulated process goes awry, and cells do not die when they should or new cells form when they should not. These extra cells can accumulate, forming a tumor. What upsets this delicately balanced system and causes cancer?

Changes, or mutations, in the genetic material of normal cells can disrupt the balance of factors governing cell survival and division, and lead to cancer. This discovery, which was primarily enabled through NIH funding, was one of the greatest research advances in the modern era.

The genetic material of a cell is made of deoxyribonucleic acid (DNA) strands, which are composed of four units called bases. These bases are organized into genes, and the order, or sequence, of these bases provides the code for producing the various proteins a cell uses to function. The organization of DNA is similar to the way in which letters of the alphabet are carefully ordered to form words and sentences (see Figure 4, p. 10).

The entirety of a person's DNA is called a genome. Almost every cell in the body contains a copy of the genome, which is packaged together with proteins called histones into thread-like structures called chromosomes. In the analogy of the written word, the genome and chromosomes are similar to a story and the chapters that make up that story, respectively (see Figure 4, p. 10).

Since a cell deciphers the DNA code to produce the proteins it needs to function, mutations in the code can result in altered protein amounts or functions, ultimately leading to cancer (see Figure 5).

There are many different types of mutations that can cause cancer. These range in size from a single base change (a letter is out of order or missing) to extra copies of a gene (a paragraph is repeated many times) to the deletion of a large segment of a chromosome (part of a chapter is missing) (see Figure 6, p. 12). Further, chromosomes can break and recombine, resulting in the production of entirely new proteins, like the one that causes most cases of chronic myelogenous leukemia (CML) and the one that leads to about 5 percent of non-small cell lung carcinomas.

Over the years, researchers have determined that cancer-associated genetic mutations are most often found in one of two classes of genes: proto-oncogenes and tumor suppressor genes. These genes normally regulate the natural processes of cell growth and death to keep our tissues and organs healthy.

Mutations in proto-oncogenes change them into oncogenes that result in altered proteins that can drive the initiation and progression of cancer. These altered proteins usually work by over activating the normal networks that drive cell division and survival; some can be directly targeted by precision medicines.

Tumor suppressor genes code for proteins that normally stop the emergence of cancer by repairing damaged DNA or by restraining signals that promote cell survival and division. Mutations in these genes typically inactivate them and can result in the production of dysfunctional proteins that do not stop the accumulation of harmful mutations or that allow overactive cells to survive, causing cancer to develop.

The understanding that cancer can be caused by genetic changes that lead to altered proteins and disruption of normal cell behaviors has spurred the development of cancer drugs that target these proteins. This approach, treating cancer patients based on the genetic and molecular profile of their cancer, is referred to as personalized cancer medicine, molecularly based medicine, precision medicine, or tailored therapy. Although it is a relatively new concept, it is already transforming the prevention, detection, diagnosis, and treatment of cancer.

It is clear that mutations in the genome of a normal cell can lead to cancer. However, recent research has shown that changes in the regions of the genome available for use by a cell also influence the development of cancer. To return to the analogy of a book, these changes in genome accessibility alter how the book is read; for example, creasing a page to hide one or more sentences. Understanding how these changes arise and how they affect cellular functions is part of the field of research called epigenetics.

Each cell in an individual contains the same 25,000 genes. Natural differences in genome accessibility, which generate different patterns of gene usage, lead to the diverse array of cell types in our bodies. Special chemical marks on DNA and histones together determine genome accessibility, and thus gene usage, in a given cell type. The sum of these chemical marks, called epigenetic marks, is referred to as the epigenome.

Most cancer cells have profound abnormalities in their epigenomes when compared with normal cells of the same tissue. In many cases, these epigenetic defects work in conjunction with permanent changes in the genetic material of the cell to promote cancerous behaviors.

One of the most exciting discoveries is that some epigenetic abnormalities are reversible. As a result, researchers are exploring whether therapies that work by reversing specific epigenetic defects can be used to treat cancer. The potential of this concept is highlighted by the fact that there are already four FDA-approved epigenetic drugs, which are used to successfully treat some patients with lymphoma or preleukemia who are nonresponsive to traditional chemotherapy. With efforts underway to map the epigenetic changes in all major types of cancer, it seems likely that more epigenetic drugs are destined to benefit many more patients in the near future and for years to come.

It is clear that cancer develops as a result of alterations to the genetic material of a cell that cause malfunctions in its behavior. Research has revealed, however, that cancer cannot be understood simply by characterizing the abnormalities within cancer cells. Interactions between cancer cells and their environment, known as the tumor microenvironment, as well as interactions with the person as a whole, profoundly affect and can actively promote cancer development (see Figure 7, p. 14). This means that cancer is much more complex than an isolated mass of proliferating cancer cells, which adds immense complexity to the answer to the question: What is cancer?

Key components of the tumor microenvironment include the matrix of proteins that surrounds the cancer cells, blood and lymphatic vessels, nutrients, hormones, and the immune system. Some of these cancer-influencing factors are normal parts of the tissue in which the cancer is growing, for example, the protein matrix surrounding the cancer cells. Others, such as hormones and nutrients, percolate and act throughout the body, including the tumor microenvironment. Yet others are actively recruited or formed as a result of signals emanating from the cancer cells; for example, many cancer cells release molecules that trigger the growth of new blood and lymphatic vessels. Whether passive participants or active recruits, the various components of the microenvironment are often used by cancers to advance their growth and survival.

The immune system and the blood and lymphatic vasculature are not only important elements of the tumor microenvironment that shape the course of cancer, but are also global factors that affect the whole body. Therefore, if we are to advance our mission to prevent and cure all cancers, we must develop a more comprehensive, whole-patient picture of cancer.

The immune system can be considered an integrated network of organs, tissues, cells, and cell products that protects our bodies from disease-causing pathogens. For example, it is responsible for clearing the viruses that cause the common cold and the bacteria that lead to some forms of meningitis.

Only about 2 percent of immune cells are circulating in the blood at any given time; the rest are percolating through our tissues, including any tumors that are present, constantly on patrol. As it does with pathogens, the immune system can identify and eliminate cancer cells. Clearly, this function of the immune system sometimes fails, and some cancer cells evade the immune system, forming tumors. As researchers have learned more about the components of the immune system and how they interact with cancer cells, they have been able to design therapies that modify a patient's immune system to make it capable of destroying the patient's cancer cells. Progress in this critical area of cancer treatment is highlighted in this report in the Special Feature on Immunotherapy (see p. 38).

While some immune responses have anticancer effects that can be exploited for cancer treatment, research has established that other immune responses can, instead, promote cancer development and progression in some situations (14). For example, persistent inflammation, which occurs as a result of constant stimulation of the immune system, creates an environment that enables cancer formation, growth, and survival. Infection with pathogens such as hepatitis B or C viruses, as well as continual exposure to toxins like alcohol or asbestos, can cause this destructive persistent inflammation.

Since the immune system has both tumor-promoting and antitumor functions, we need to learn more about its intricacies if we are to fully exploit it for patient benefit. This will only be achieved through more research into this promising area of science.

Like normal cells, cancer cells require nutrients and oxygen to rapidly grow and survive. They must also get rid of the toxic substances they generate through their use of these fuels. To achieve these goals, many cancer cells promote the growth of new blood and lymphatic vessels, processes called angiogenesis and lymphangiogenesis, respectively.

Among the many molecules cancer cells use to induce angiogenesis and lymphangiogenesis is a family of growth factors called VEGFs. These molecules attach to proteins on the surface of the cells that form blood and lymphatic vessel walls, stimulating vessel growth.

Some cancers are more dependent than others on the growth of new blood and lymphatic vessels to thrive. These cancers, such as the most common type of kidney cancer in adults (renal cell carcinoma), are particularly susceptible to a group of drugs that target the VEGFs or the proteins to which VEGFs bind, the VEGF receptors, impeding blood and lymphatic vessel growth (see Table 3).

In addition to nourishing tumors, the new network of blood and lymphatic vessels provides a route by which cancer cells can escape their primary location. Once cancer cells enter the vessels, they have the potential to move to and grow in other areas of the body where they can establish new tumors; this is called metastasis. Metastasis is responsible for more than 90 percent of the morbidity and mortality associated with cancer.

Many cancers, particularly those that arise in tissues other than the blood, are progressive in nature (see Figure 8). They begin with one or more changes to the genetic material of normal cells. These mutations continue to accumulate over time, first turning normal cells into precancerous cells, which multiply to form precancerous lesions. As more mutations arise within a precancerous lesion, some cells evolve into cancer cells, further dividing to form a tumor. Further mutations can cause some cancer cells to become capable of metastasizing, leading to the emergence of metastatic cancer.

Metastatic disease is a dire occurrence that almost inevitably leads to death. A fundamental understanding of this process is essential to conquering cancer. Research over the past few decades has just begun to teach us why metastatic disease is so difficult to treat. To begin, metastasis is a complex, multistep process, and virtually every step can be achieved through multiple different pathways. Thus, obstructing only one pathway therapeutically is generally insufficient to stop the entire process. Compounding this problem is the fact that cancer cells can travel to other parts of the body before the initial tumor is found, and then lie dormant in this location, becoming active years later to form a metastatic tumor. Currently, we do not know enough about cancer cell dormancy to either efficiently locate and eliminate these cells or design therapies that could prevent them from reawakening, facts that underscore the critical need for further research in these areas.

Improvements in our understanding of the development of cancer have allowed us to detect some precancerous lesions and intercept them before they become life-threatening. For example, in the cervix, precancerous lesions are called cervical intraepithelial neoplasia. These can be detected using the Papanicolaou (Pap) test and can be removed or destroyed by several procedures including cryocautery, electrocautery, and laser cautery.

It is clearly advantageous to detect and stop cancer as early as possible in the course of its development, particularly prior to metastasis. Currently, we successfully do this for some cancers. Only through more research will we be able to apply this approach more generally to cancers that kill. We obviously must support the research needed to fully understand the metastatic process if we are to ultimately cure and control all cancers.

Many of the greatest reductions in the morbidity and mortality of cancer have come from advances in cancer prevention and early detection. These remarkable effects were achieved by translating advances in our understanding of the causes and progressive nature of cancer into effective new clinical practices, and public education and policy initiatives.

Changes in the clinic include improved screening practices (e.g., colonoscopy to detect and remove precancerous adenomatous polyps) and the introduction of targeted interventions (e.g., administering vaccines to prevent infection with pathogens associated with cancer risk, such as hepatitis B virus or human papilloma viruses). Likewise, public education regarding common factors that increase cancer risk (such as physical inactivity and unhealthy diets) have also played a role, as has the implementation of policies aimed at promoting healthier lifestyles and minimizing exposure to cancer-causing agents (such as tobacco smoke and asbestos).

Decades of research have led to the identification of numerous factors that affect a person's risk of developing cancer (see Figure 9, p. 19). Through this work, scientists have come to the conclusion that more than 50 percent of the 580,350 cancer deaths expected to occur in the United States in 2013 will be related to preventable causes such as tobacco use, obesity, poor diet, and lack of physical activity (10). Modifying personal behaviors (see Figure 10, p. 20) to eliminate or reduce these risks, where possible, could, have a tremendous impact on our nation's burden of cancer. However, a great deal more research and resources are needed to understand how to best help individuals to change their lifestyle.

Everyone could dramatically reduce their risk of certain cancers by making two changes to the ways they live: cutting out tobacco products and avoiding excessive exposure to ultraviolet (UV) light, a form of damaging radiation emitted by the sun, sunlamps, and tanning beds. Making these changes not only reduces the chances of developing certain cancers, but can also reduce cancer recurrence or improve outcomes following a cancer diagnosis.

The scientifically established causal relationship between cigarette smoking and lung cancer was first brought to the public's attention in 1964, when the “U.S. Surgeon General's Report on Smoking and Health” was published (15). This report set in motion major policy changes, media campaigns, and other measures to combat cigarette smoking in the United States (see Table 4, p. 21). As a result of these efforts, the prevalence of smoking decreased from 42 percent of Americans in 1965 to 18 percent in 2012 (16). This decrease has been credited with saving millions of lives that would otherwise have been lost not only to lung cancer, but also to 17 other types of cancer directly related to tobacco use (9) (see Figure 11, p. 22).

Even armed with this information, 70 million Americans, including some who have been diagnosed with and/or are actively being treated for cancer, regularly use tobacco products. Further, every day in 2010, 6,500 Americans aged 12 years and older smoked their first cigarette and approximately 40 percent of this group, or 2,600 individuals per day, became regular smokers (17). This is why tobacco use will be responsible for an estimated 30 percent of all cancer deaths that occur in the United States in 2013 (1).

It is not only the lives of those who use tobacco products that are at risk; scientific evidence has shown that exposure to secondhand tobacco smoke also causes cancer. This prompted the surgeon general to declare that there is no safe level of exposure to tobacco smoke (19). Although this has led to some important public health policies restricting smoking in public places (see Table 4, p. 21), smoking remains a huge threat to the public's health (20, 21). Countless lives could be saved through continued development and implementation of effective tobacco prevention, cessation, and control strategies.

Exposure to UV light is the predominant cause of all three of the main types of skin cancer — basal cell carcinoma, squamous cell carcinoma, and melanoma. In fact, the International Agency for Research on Cancer (IARC), an affiliate of the World Health Organization, includes UV tanning devices and UV radiation from the sun in its highest cancer-risk category, “carcinogenic to humans” (22), alongside agents such as plutonium and cigarettes. Adopting sun-safe habits and avoiding the use of indoor UV tanning devices would dramatically decrease the incidence of skin cancer; for example, daily sunscreen use can cut the incidence of melanoma in half (23).

Despite the overwhelming scientific evidence that tanning bed use increases an individual's risk for developing cancer, particularly at a younger age (24, 25), tens of millions of Americans visit tanning salons each year (25). According to a 2011 report from the Centers for Disease Control and Prevention (CDC), this number includes more than 13 percent of all high school students and 21 percent of high school girls (27, 28). Responding to the clear cancer risk posed by tanning beds, the FDA has proposed reclassifying tanning beds into a more stringent category of medical products that would require warning labels to advertise their role in increasing skin cancer risk.

Preventing skin cancer by protecting skin from UV light exposure would not only limit the morbidity and mortality caused by these conditions, but would also save enormous amounts of money. It has been estimated that the total direct cost associated with the treatment of melanoma in 2010 was $2.36 billion in the United States (28). Given that melanoma incidence rates continue to increase (1), patients, researchers, and politicians seeking to balance their budgets need to come together to develop and implement more effective policy changes and public education campaigns to help reduce the health and economic burdens of skin cancer.

Persistent infection with one of several pathogens is an important cause of about 20 percent of cancers worldwide (29, 30) (see Table 5). This knowledge has enabled the development of new cancer prevention strategies that use medicines and vaccines to eliminate or prevent infection with these agents. One of the best examples of this relates to human papillomavirus (HPV), which is estimated to have been responsible for almost 39,000 new cases of cancer in the United States in 2010 and more than 9,500 deaths (31).

Several decades of research have established that persistent infection with certain strains of HPV causes most, it not all, cervical cancers, a majority of anogenital cancers, and many cancers arising in the upper part of the neck (32). This information enabled the development of a clinical test for detecting the cancer-causing types of HPV. This test, when combined with a standard Pap test for cervical cancer, more effectively identifies women at high risk for cervical cancer than a standard Pap test alone. As a result, this test safely extends cervical cancer screening intervals (33), providing a less-burdensome cervical cancer screening option and potentially reducing health care costs.

Determining which strains of HPV can cause cervical cancer also led to the development of two vaccines that the FDA has approved for the prevention of cervical cancer (31, 34). In addition, the FDA approved one of the vaccines, Gardasil, for the prevention of vulvar and vaginal precancerous lesions as well as for the prevention of HPV-associated anal cancer. Future studies will determine whether the vaccines also reduce the risk for head and neck cancers caused by HPV. Early signs are promising, as a recent study found that vaccination dramatically reduced oral infection with HPV (34).

Even though two highly effective vaccines are available, the CDC estimates that in 2012 only 33 percent of girls in the United States aged 13 to 17 years had received the recommended three doses of HPV vaccine (35) (see sidebar on HPV Vaccine Usage, p. 23). Moreover, coverage has been reported to be significantly lower among the uninsured and in several states in which cervical cancer rates are highest and recent Pap testing prevalence is the lowest (33). However, recent data indicate that despite the low vaccine uptake, there has been a dramatic reduction in cervical infection with HPV among girls aged 14 to 19 years since the introduction of the vaccines (36). Thus, research has provided the tools for dramatic reductions in the burden of HPV-related cancers, but their use must be fully implemented if they are to have maximum impact.

“Energy balance” refers to the difference between the number of calories consumed and the number burned. Tipping of this balance so that a person accumulates excess energy reserves plays a crucial role in promoting the diseases responsible for the majority of deaths in the United States: heart disease and cancer.

While calories are consumed only through eating and drinking, they are burned in many ways. Simply existing, breathing, digesting food, and pumping blood around the body use some calories. Added to these expenditures are the calories burned through a person's daily routine; the more physical activity in a routine, the more calories are burned.

Although this may seem straightforward, research has shown that energy balance is, in fact, a complex dynamic (see Figure 12). It is not only influenced by calorie consumption and physical activity, but also by numerous other factors including genetics, diet composition, body weight, or body composition, and sleep (see sidebar on Sleep Disturbances and Cancer, p. 24).

Obesity increases risk for a growing number of cancers, most prominently the adenocarcinoma subtype of esophageal cancer, and colorectal, endometrial, kidney, pancreatic, and postmenopausal breast cancers (8). It also negatively impacts tumor recurrence, metastasis, and patient survival for several types of cancers (51, 53, 54).

How, then, does obesity promote and adversely affect survival for certain cancers? Several recent scientific discoveries have identified just some of the interrelated factors through which obesity influences cancer (46, 51, 52) (see Figure 12). Among these factors are hormones such as estrogen and insulin, which directly influence cell survival and division, and chemicals released by the fat itself, which influence the function of many organs of the body. In addition, obesity leads to inflammation, which is clearly linked to cancer development and progression (14, 55) (see The Immune System, p. 15).

Importantly, identifying some of the factors that link obesity and cancer is providing potential targets for treating obesity-related cancers. For example, the knowledge that several of the factors discovered act directly on cancer cells to drive their survival and division via a signaling network called the PI3K/AKT/mTOR (46, 51, 52), suggests that drugs targeting this pathway might be effective in this context.

Any new therapeutic approaches developed in the future will need to be used together with approaches to balancing energy intake and output. For many people, modifying behaviors to reduce calorie consumption and increase physical activity may be sufficient, but other people may require surgical or therapeutic interventions to help them lose weight. The urgent need for an effective and comprehensive strategy is highlighted by the fact that the number of Americans classified as obese is at an all-time high. Currently, more than 35 percent of adults and 17 percent of children and adolescents are obese (56).

Type 2 diabetes mellitus is a complex medical condition caused by a combination of factors, including obesity. Independent of obesity, type 2 diabetes increases an individual's risk of developing cancer (57, 58). Those with type 2 diabetes are most at risk for developing liver, pancreatic, and endometrial cancers, but also have an increased risk for developing biliary tract, bladder, breast, colorectal, esophageal, and kidney cancers, as well as certain forms of lymphoma (58, 59).

Type 2 diabetes not only increases cancer risk, but also reduces short- and long-term cancer survival rates through both direct and indirect mechanisms (58). For example, type 2 diabetes has been reported to have a direct negative effect on tumor recurrence and survival in patients with colon cancer (60). In general, survival for cancer patients with type 2 diabetes is worse than for their nondiabetic counterparts because of indirect factors associated with diabetes. For example, they are more likely to suffer from other potentially fatal diseases, like heart disease, and to be poor candidates for surgery and the highest doses of chemotherapy (58).

Despite the fact that type 2 diabetes affects about 7.5 percent of the U.S. population (61), it is not well established how type 2 diabetes increases cancer risk. Research suggests that it likely influences cancer development in several ways, many of which are similar to the ways in which obesity affects cancer (58, 59). For example, similar to obesity, type 2 diabetes increases levels of insulin and causes persistent inflammation.

Importantly, recent evidence suggests that treatments directed at reducing the hallmark of type 2 diabetes may influence cancer risk. Metformin, which is one of the most commonly used drugs for treating patients with type 2 diabetes, appears to reduce a type 2 diabetic's risk of developing colon and pancreatic cancers (62, 63). In contrast, sulfonylureas, a different class of drugs commonly used to treat type 2 diabetes, may increase risk of cancer development (58). However, further studies are needed to clarify these issues (58). Given what we have learned about the anticancer effects of metformin in patients with type 2 diabetes, numerous clinical studies are underway to assess whether it has the potential to benefit nondiabetic patients with cancer (64).

In light of the large number of Americans living with type 2 diabetes (61), it is critical for physicians managing these patients to be keenly aware of their patients' increased cancer risks if we are to reduce the burden of cancer in this portion of the population. Moreover, it is vital that we undertake more research so that we better understand the biological pathways linking the disease to cancer. Armed with this knowledge, we can investigate potential new therapeutic approaches. However, our best approach to reducing individuals' risks for type 2 diabetes and for certain forms of cancer, as well as improving outcomes, is to combine any new therapeutic approaches with behavior modifications, like eating a healthier diet, increasing physical activity, and reducing calorie consumption.

A lack of regular physical activity (see sidebar on Physical Activity Guidelines, p. 27) is strongly associated with an increased risk for colon, endometrial, and postmenopausal breast cancers, independent of weight (8). Mounting evidence suggests that it may also be associated with lung, pancreatic, and premenopausal breast cancers (8).

In addition, several recent studies indicate that sedentary behavior may increase risk for developing certain cancers and for mortality in cancer survivors independent of physical activity and weight.

For example, one study showed that individuals who spent 10 or more years in sedentary work had almost twice the risk of cancers arising in their rectum or in a specific part of their colon compared with individuals who did not spend any time in sedentary work (67). In a second study, patients with colorectal cancer who spent six or more hours a day sitting after their diagnosis had a dramatically increased risk of death from their cancer compared with patients who spent fewer than three hours a day sitting (68). Likewise, a large-scale study also showed that the more time a person spent sitting, the greater their risk of death from any cause, regardless of their level of physical activity (69).

Conversely, research has shown that for patients with certain forms of cancer, including breast, colorectal, and prostate cancers, physical activity improves outcomes by reducing recurrence and increasing survival (8, 70–73).

Clear guidelines for physical activity for cancer survivors have been published (8, 65, 66). However, it appears that these have mostly been applied in clinical settings and research interventions, and that they have not yet become general standards of practice in the United States.

There are many barriers to increasing physical activity among cancer survivors and the general public. More research and resources at all levels are needed if this lifestyle modification is to be widely adopted.

We know that most cancers arise from genetic mutations that have accumulated during the patient's lifetime (see Developing Cancer; p. 17). Our knowledge of the causes, timing, sequence, and frequency of these pivotal changes is increasing, as is our insight into the specific implications of the changes. This knowledge provides us with unique opportunities for developing the means to prevent cancer onset or to detect it and intervene earlier in its progression.

Unfortunately, we have also learned that it is not always easy to identify at-risk patients or those with early-stage disease. However, researchers and clinicians are looking to pair our molecular understanding of cancer development with indicators of cancer risk to create personalized prevention and early-stage intervention programs. For example, some patients may be able to reduce their risk by simply modifying their behaviors. Others might need to increase their participation in screening or early detection programs or even consider taking a preventive medicine or having precautionary surgery (see Tables 6 and 7, pp. 28 and 30, respectively).

About 5 percent of all new cases of cancer diagnosed in the United States each year are caused by an inherited mutation (1) (see sidebar on How do I Know if I am at High Risk for Developing an Inherited Cancer?). In most of these cases the inherited mutation is unknown. However, research has identified 17 mutations that put people, like Congresswoman Wasserman Schultz, at very high risk of developing cancer (see Table 8, p. 31). If a patient's cancer is suspected to be caused by one of these mutations, genetic testing can be performed to verify this and identify relatives who carry the familial mutation. These family members can then consider taking risk-reducing measures, while those without the mutation can avoid unnecessary and costly medical procedures.

Beyond inherited cancers, a number of medical conditions place an even smaller group of individuals at high risk for developing certain types of cancer. Among these medical conditions are ulcerative colitis and Crohn's disease, which are chronic inflammatory diseases of the intestines that increase an individual's risk for colorectal cancer sixfold (74). Moreover, medical conditions and interventions that suppress the normal function of the immune system, such as HIV/AIDS and the treatment of solid organ transplantation with immunosuppressive drugs, also increase risk for certain types of cancer (75).

However, high-risk individuals are the minority, so what is to be done for the broader population? One approach to identifying at-risk patients, as well as those with early-stage disease, is to test generally healthy individuals for potential disease through population-based screening programs (see sidebar on USPSTF Cancer Screening Guidelines). These programs largely function by using age and gender to grade, or stratify, a person's risk, with those identified as most at risk being those who are most likely to benefit from the screening.

This approach to risk stratification has been extremely successful for cervical cancer screening, as the program has greatly reduced the incidence and mortality of cervical cancer in the United States (76, 77). Further inroads against cervical cancer incidence are likely given the dramatic reduction in cervical infection with the cervical cancer–causing infectious agent HPV among girls aged 14 to 19 years since the introduction of the HPV vaccines (36).

Stratifying risk based on age has also worked for colonoscopy, which has contributed significantly to dramatic declines in colorectal cancer incidence and mortality (38). However, only about 59 percent of all Americans aged 50 years and older, the group for whom colorectal cancer screening is currently recommended, get screened (78). Among the more than one-third of Americans who do not follow colorectal cancer screening guidelines is a disproportionately high number of African-Americans (78, 80), a group that shoulders an overly high colorectal cancer burden (see sidebar on Cancer Health Disparities in America). Evidently, innovative ways to increase the number of individuals, in particular racial and ethnic minorities, following colorectal cancer screening guidelines are needed.

Since 2003, a spectacularly successful initiative at eliminating colorectal cancer disparities has been running in Delaware (81). The cancer control program, as it is known, increased colorectal cancer screening among all Delawareans age 50 or older from 57 percent in 2002 to 74 percent in 2009. Moreover, screening rates for African-Americans rose from 48 percent to 74 percent, matching the screening rate among non-Hispanic whites for the same period of time. Perhaps most importantly, disparities in colorectal cancer incidence and mortality rates between non-Hispanic whites and African-Americans were also equalized as a result of the equivalent screening rates between the two groups. The researchers who conducted this study predict that if similar programs could be implemented in all states, racial disparities in colorectal cancer incidence and mortality could be greatly reduced (81).

Screening programs have successfully reduced the incidence and mortality for cervical and colorectal cancers because they identify the diseases at an early-stage before they become life threatening, thereby providing opportunities for early intervention. However, not all population-based screening programs have been equally effective.

For example, while the prostate-specific antigen (PSA) test is very good at detecting early-stage prostate cancer lesions, it does not distinguish between lesions that will progress to advanced disease and those that will not (88). As a result, many patients undergo unnecessary treatment. Concerns about overdiagnosis and overtreatment have led to the current recommendation by a number of organizations to discontinue routine PSA screening (89) and highlight the need for better ways to stratify PSA-positive patients.

Early detection of breast cancer through regular mammography screening of women older than 40 has been credited with reducing the mortality rate for breast cancer (1). However, there is growing concern that it can detect breast tumors that will never cause symptoms or threaten a woman's life. Thus, mammography screening, like PSA screening, can potentially lead to overdiagnosis of the disease and subsequent overtreatment, which carries its own risks. In fact, one study estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31 percent of all breast cancers diagnosed (90).

One approach to more precisely identify at-risk patients is to use their history. In a study investigating the usefulness of low-dose computed tomography (CT) screening for early detection of lung cancer, current and former heavy smokers aged 55 to 74 years were classified as having the highest risk for developing disease (91, 92). The researchers found that in this population, low-dose CT screening reduced lung cancer mortality by 20 percent because it identified small and early-stage tumors (91, 92). There are an estimated 94 million current and former smokers in the United States; however, the majority of them are unlikely to benefit from screening because they are or were not heavy smokers (93).

More work is needed to ensure that Americans understand that cancer screening approaches, including low-dose CT screening for early detection of lung cancer, are most clinically effective when targeted at those at highest risk of developing the disease for which they are being screened (94). Targeting those most at risk also has the benefit of decreasing the complications and cost of unnecessary health care interventions for those at low risk of disease. Research to develop new, accurate, and reliable ways to discern an individual's cancer risk is vital to ensure that the public has confidence in current screening guidelines and any future changes to these guidelines.

As for prevention and early detection of primary tumors, our increasing knowledge of the risk factors for cancer occurrence and progression is enabling us to identify those cancer survivors with the highest risk for tumor recurrence (see sidebar on Cancer Survivorship). This is allowing us to direct risk-reducing medical interventions to only those who will benefit, reducing health care costs associated with treating those who will not benefit and may even be harmed.

Currently, there are few established ways to identify cancer survivors at high risk for disease recurrence. One group known to be at high risk is women who have successfully completed treatment for invasive breast cancer. A subset of patients in this group has breast cancer powered by the hormone estrogen. For these women, drugs that block the effects or production of estrogen have proven very successful at reducing tumor recurrence if taken for five years (96–98) (see Table 6, p. 28). Moreover, recent data from long-term clinical trials indicate that 10 years of therapy with one of these drugs, tamoxifen (Nolvadex), is even more effective at reducing tumor recurrence (99, 100). As all anti-estrogen drugs have serious side effects, our knowledge that these drugs are ineffective for women whose breast cancers are not fueled by estrogen spares these patients from unnecessary and potentially harmful treatments.

Recent research has identified a potential new way to target treatment that reduces tumor recurrence to only those cancer survivors likely to benefit (101). Prior research had indicated that regular aspirin use could lower risk of both primary and recurrent colorectal cancer (102, 103). However, widespread aspirin use was not recommended because of concerns over side effects such as gastrointestinal bleeding. Fortunately, researchers have been able to narrow down the population of colorectal cancer survivors who will benefit from aspirin (101). They found that regular aspirin use by colorectal cancer survivors with tumors harboring mutations in the PIK3CA gene reduced their risk of colorectal cancer death by about 80 percent, but that aspirin showed no benefit for survivors who lacked this mutation in their tumors.

This knowledge promises to reduce colorectal cancer morbidity and mortality for certain colorectal cancer survivors and to eliminate the needless treatment of those who will not benefit. However, additional, large-scale studies are needed before aspirin use can become a standard treatment for patients with PIK3CA-mutated colorectal tumors.

Despite these successes, the use of medical interventions to reduce primary and recurrent tumor risk is not widespread. Therefore, continued research is needed to develop more concrete evidence to identify the most at-risk patients, better screening approaches, and more and better ways to intervene earlier in the progression of cancer.

Decades of cancer research have fueled extraordinary medical, scientific, and technical advances that gave us the tools that we now use for the prevention, detection, diagnosis, and treatment of cancer. Together, these advances have helped save millions of lives in the United States and worldwide. As highlighted in the Special Feature on Immunotherapy, p 38, one area that is beginning to revolutionize the treatment of certain cancers, and that holds incredible promise for the future, is immunotherapy.

It takes many years of dedicated work by thousands of individuals across the research community to bring a new drug, device, or technique from a concept to FDA approval. From Sept. 1, 2012, to July 31, 2013, this Holy Grail was achieved for 11 new drugs, three existing drugs with new uses, and three new imaging technologies, thereby accelerating the pace of progress in both cancer treatment and detection (see Table 1, p. 4). Two of these drugs were approved with companion diagnostics to ensure that only patients who are likely to benefit from the drugs, receive them.

It is important to note that most patients, like Mary Jackson Scroggins and Congressman Fitzpatrick, are not treated with drugs alone but usually with some combination of surgery, radiotherapy, and chemotherapy (see Appendix Tables 1 and 2, p. 81). One new radiotherapeutic, radium-223 dichloride (Xofigo), was approved by the FDA for the treatment of prostate cancer that has spread to the bones in May 2013. This low-energy radioactive drug is the first of its kind to be approved by the FDA. It specifically delivers radiation to tumors in the bones, limiting damage to the surrounding tissues (104) (see Table 1, p. 4).

The following discussion focuses on recent FDA approvals as well as advances against cancer that are showing near-term promise.

An important milestone for cancer research was the discovery that the immune system can identify and eliminate cancer cells the way it does disease-causing pathogens.

The study of the structure and function of the immune system is a field of research called immunology (see sidebar on Key Players in the Immune System). Tumor immunology (sometimes called cancer immunology) is the study of interactions between the immune system and cancer cells.

The immune system naturally eliminates some cancers before they become life threatening. Researchers, therefore, thought that it should be possible to develop therapies that would train a patient's immune system to destroy their cancer. Such therapies, referred to as immunotherapies, are now beginning to revolutionize the treatment of some cancers, yielding both remarkable and durable responses. Although getting to this point has proven challenging, the field holds immense promise, as discussed by cancer immunology pioneer Drew Pardoll.

Not all immunotherapies work in the same way. Some boost the natural cancer-fighting ability of the immune system by taking its brakes off, some increase the killing power of the patient's immune cells, and some flag cancer cells for destruction by the immune system.

Researchers studying the intricacies of the immune system are identifying novel immunotherapies and new ways to utilize those that we already have, including the potential for combining immunotherapies that operate in different ways or combining immunotherapies with either radiation therapy or other drugs. For example, it might be possible to design a combination treatment that releases the brakes on the immune system and simultaneously steps on the accelerator to enhance immune cells' killing power.

Immune cells called T cells (see sidebar on Key Players in the Immune System) are naturally capable of destroying cancer cells; however, many tumors develop sophisticated ways to stop these T cells from functioning. One way this happens is that T cells in the tumor microenvironment display on their surface high levels of molecules that act like brakes, making the T cells slow down and stop acting aggressively. This finding led researchers to seek ways to counteract these molecules, which are called immune checkpoint proteins.

The story of immune checkpoint proteins began in 1987, when researchers discovered a gene that they called CTLA4 (105) (see Figure 13). However, it took nearly eight years before the immune checkpoint function of CTLA4 was uncovered, and another 16 years of basic and clinical research before this knowledge was translated into a clinically effective therapy: a therapeutic antibody that targets CTLA4, ipilimumab (Yervoy). Upon attaching to CTLA4 on the surface of patients' T cells, ipilimumab releases the T cells' brakes, spurring them into action. This significantly prolongs survival for patients with metastatic melanoma (106). Ipilimumab was the first treatment in history to improve survival for patients with metastatic melanoma, and the FDA approved it for this use in March 2011.

In some patients, ipilimumab's effects on the immune system generate durable responses. In fact, about one in every five patients treated with only four doses of ipilimumab are still gaining benefit from it more than four years after completing therapy (105, 107). Ongoing clinical studies are investigating whether additional doses of ipilimumab can offer further benefit to patients like Andrew Messinger. Encouraging early results suggest that ipilimumab might also be effective against advanced lung cancer (108) and advanced prostate cancer (109), but these need verification in larger clinical trials.

The amazing success of ipilimumab has motivated researchers to develop similar therapies that target another immune checkpoint protein, called PD1, as well as therapies that target the protein to which PD1 attaches, PDL1 (see Table 9). Early clinical results with these therapies are very promising (110, 111), and large-scale clinical trials are currently ongoing.

One PD1-targeted therapy, nivolumab, has produced several responses persisting more than two years in a number of non-small cell lung cancer patients, advanced melanoma patients, and renal cell carcinoma patients (110, 112, 113). As a result of these encouraging data, the FDA granted nivolumab fast track designation for these cancers (see sidebar on FDA Designations).

The FDA has also designated lambrolizumab, a second therapeutic antibody that targets PD1, as a breakthrough therapy for advanced melanoma, after it was reported to benefit patients (114).

Despite the dramatic responses seen in some patients treated with ipilimumab, or an agent targeting PD1 or PDL1, these individuals are a small fraction of the total number of people affected by cancer. Perhaps the greatest promise of immunotherapy lies in combining immunotherapies that target different immune checkpoint proteins or immunotherapies that operate differently, as well as combining immunotherapies with other types of anticancer treatments.

To this end, a recent study suggests that combining ipilimumab and nivolumab shows promise, and a large-scale trial has been initiated to verify this hypothesis (115). In addition, an early-stage trial found that combining ipilimumab with sargramostim (Leukine), a synthetic version of an immune-system boosting substance naturally produced in the body significantly increased overall survival for patients with advanced melanoma (116). Thus, the potential of combining an immunotherapy that releases the brakes on the immune system with an immunotherapy that boosts the immune system is immense.

To return to the analogy of driving a car, another approach to immunotherapy is to step on the accelerator, enhancing the ability of the immune system to eliminate cancer cells. This can be done in several ways, including giving a patient a therapeutic vaccine or a form of treatment called adoptive immunotherapy.

A therapeutic vaccine trains a patient's immune system to recognize and destroy their cancer. The only therapeutic cancer vaccine currently approved by the FDA is sipuleucel-T (Provenge). It is a cell-based vaccine that was approved in 2010 for the treatment of advanced prostate cancer (117). Each patient receives a customized treatment that uses immune cells called dendritic cells from their own body to boost their cancer-fighting T cells. Researchers are currently conducting small clinical trials to examine whether the effectiveness of sipuleucel-T can be enhanced by combining it with the antihormone therapy abiraterone (Zytiga) (118).

The development of therapeutic cancer vaccines is an intensively studied area of cancer research. In the United States alone, there are several hundred ongoing clinical trials testing therapeutic cancer vaccines. Some are similar to sipuleucel-T, utilizing the patient's own dendritic cells, and these include one that has shown early promise as a treatment for colorectal cancer (119). Others operate in different ways, including one called PROSTVAC, which is being tested in a large clinical trial after early results indicated that it significantly increased survival for men with advanced prostate cancer (120).

Another therapeutic cancer vaccine clinical trial that has recently reported very encouraging early results is assessing the effectiveness of a combination of two vaccines, GVAX Pancreas and CRS-207, as a treatment for advanced pancreatic cancer (121). The two vaccines work together to boost patients' immune systems in different ways. GVAX Pancreas comprises pancreatic cancer cells that release GM-CSF, which generally enhances immune system function. CRS-207 is a nontoxic bacterial vaccine engineered to carry a protein that will boost the killing power of patients' immune cells. Experiments in mice originally showed that the combination of GVAX Pancreas and CRS-207 heightens the activity of a group of cancer-fighting T cells. The fact that this combination almost doubled overall survival compared with GVAX Pancreas alone in a clinical trial (121), highlights the promise of combining immunotherapies that operate in different ways.

Adoptive immunotherapies are complex medical procedures that are built upon our accumulating knowledge of the biology of the immune system, in particular, T cells. There are no FDA-approved adoptive immunotherapies, but numerous approaches are currently being evaluated for several types of cancer.

Here, we highlight one adoptive immunotherapy that is showing considerable promise in adults with chronic lymphocytic leukemia and in some adults and children with acute lymphoblastic leukemia (122–125). A number of patients, including Maddie Major, have been in complete remission for many months, after their cancers failed to respond to other treatment options or relapsed after initially responding.

In this form of adoptive immunotherapy, T cells are harvested from the patient and genetically modified in the laboratory so that they attach to the surface of leukemia cells and are triggered to attack when they do. The number of genetically modified T cells, sometimes called CAR T cells, is expanded in the laboratory before they are returned to the patient, where they eliminate the leukemia cells.

As basic research continues to increase our understanding of how T cells function and how these functions can be exploited, new adoptive immunotherapies are likely to emerge in the near future.

In order for the immune system to eliminate a cancer cell, it must find it first. Several of the therapeutic antibodies that have been approved by the FDA for the treatment of certain cancers (see Appendix Table 1, p. 81), and many of those in clinical trials, do just that. They operate, at least in part, by attaching to cancer cells expressing their target, flagging them for destruction by immune cells. Research into new and better targets for antibodies, as well as work on modifying the antibodies to help the immune system find them more easily, are creating exciting new experimental immunotherapies.