AACR Cancer Progress Report 2016

• Nancy E. Davidson, MD

• Chairperson

• AACR President 2016–2017

• Director

• University of Pittsburgh Cancer Institute

• Pittsburgh, Pennsylvania

• Scott A. Armstrong, MD, PhD

• Chair

• Department of Pediatric Oncology

• Dana-Farber Cancer Institute

• Boston, Massachusetts

• Lisa M. Coussens, PhD

• Associate Director for Basic Research

• OHSU Knight Cancer Institute

• Portland, Oregon

• Marcia R. Cruz-Correa, MD, PhD

• Associate Professor of Medicine, Biochemistry, and Surgery

• University of Puerto Rico Comprehensive Cancer Center

• San Juan, Puerto Rico

• Ralph J. DeBerardinis, MD, PhD

• Chief

• Division of Pediatric Genetics and Metabolism

• UT Southwestern Medical Center

• Dallas, Texas

• James H. Doroshow, MD*

• Director

• Division of Cancer Treatment and Diagnosis

• National Cancer Institute

• Bethesda, Maryland

• Margaret Foti, PhD, MD (hc)

• Chief Executive Officer

• American Association for Cancer Research

• Philadelphia, Pennsylvania

• Patrick Hwu, MD

• Chair

• Department of Melanoma Medical Oncology

• The University of Texas MD Anderson Cancer Center

• Houston, Texas

• Thomas W. Kensler, PhD

• Professor

• Department of Pharmacology and Chemical Biology

• University of Pittsburgh

• Pittsburgh, Pennsylvania

• Monica Morrow, MD

• Chief

• Breast Service, Department of Surgery

• Memorial Sloan Kettering Cancer Center

• New York, New York

• Charles G. Mulligan, MSc, MD

• Co-Leader

• Hematological Malignancies Program

• St. Jude Children's Research Hospital

• Memphis, Tennessee

• William Pao, MD, PhD

• Global Head

• Oncology Discovery and Translational Area

• Roche Pharma Research and Early Development

• Basel, Switzerland

• Elizabeth A. Platz, MPH, ScD

• Deputy Director

• Department of Epidemiology

• Johns Hopkins Bloomberg School of Public Health

• Baltimore, Maryland

• Thomas J. Smith, MD

• Harry J. Duffey Family Professor of Palliative Medicine

• Johns Hopkins Medicine

• Baltimore, Maryland

• Cheryl L. Willman, MD

• Director & CEO

• University of New Mexico Comprehensive Cancer Center

• Albuquerque, New Mexico

*This author contributed to the development and review of this manuscript but is unable to endorse the request for NIH funding.

• Shawn M. Sweeney, PhD

• Project Lead

• Associate Director, Translational Research

• Philadelphia, Pennsylvania

• Karen Honey, PhD

• Lead Science Writer

• Project Co-lead

• Senior Managing Editor, Science Communications

• Philadelphia, Pennsylvania

• Brenna L. Adams

• Lead Designer

• Special Publications Designer

• Philadelphia, Pennsylvania

• Paul J. Driscoll, Jr.

• Senior Director, Marketing and Creative Services

• Philadelphia, Pennsylvania

• Joshua F. Goldstein

• Director, Brand Strategy Communications

• Philadelphia, Pennsylvania

• James A. Ingram II

• Assistant Director, Government Relations and Advocacy

• Washington, DC

• Mary Anne Mennite

• Executive Editor and Senior Liaison to the CEO

• Philadelphia, Pennsylvania

• Jon G. Retzlaff, MBA, MPA

• Managing Director, Science Policy and Government Affairs

• Washington, DC

• Anna B. Sadusky, PhD

• Associate Director, Regulatory Science and Policy

• Washington, DC

• Shimere Williams Sherwood, PhD

• Associate Director, Health Policy

• Washington, DC

• Mary Lee Watts, MPH, RD

• Director, Government Relations and Advocacy

• Washington, DC

• Nicolle Rager Fuller

• Illustrator

• Sayo-Art, LLC

• Bellingham, Washington

It is a tremendously exciting time for the cancer community. Thanks to research, we are making significant progress against the many diseases we call cancer. More people than ever before are living longer and fuller lives after a cancer diagnosis. In fact, the number of children and adults living in the United States with a history of cancer rose by 1 million from 2014 to 2016, reaching a record 15.5 million. Moreover, there has been a renewed, bipartisan commitment from Congress and the Administration to prioritize biomedical science and cancer research. In December 2015, members of the U.S. House and Senate came together to agree to a $2 billion increase in the National Institutes of Health (NIH) budget for fiscal year 2016. Then, in January 2016, President Obama announced that Vice President Biden would lead a “National Cancer Moonshot Initiative.” These actions have touched off an unprecedented national and international dialogue about cancer and re-enforced the importance of research for improving health and saving lives from cancer.

The AACR Cancer Progress Report 2016 adds important perspective to the dialogue by highlighting how research, much of which is supported by federal investments in the NIH and National Cancer Institute (NCI), powers the development of new and better ways to prevent, detect, diagnose, treat, and cure some types of cancer. This progress is improving lives around the world—for example, the lives of the 15 courageous men, women, and children who shared their personal experiences with cancer in this report. The AACR is extremely grateful to these inspiring individuals because their stories, coupled with the advances described herein, provide enormous hope for a much brighter future for cancer patients and their loved ones.

Seven of the anticancer therapeutics highlighted in the report harness the power of a patient's immune system to treat his or her cancer (p. 81). These revolutionary treatments are improving survival and quality of life for patients with an increasing number of types of cancer. For example, in January 2015, immunotherapeutics that release certain brakes on the immune system had been approved by the U.S. Food and Drug Administration (FDA) for treating just one type of cancer—melanoma. As of July 31, 2016, they have been approved for treating five types of cancer—bladder cancer, Hodgkin lymphoma, kidney cancer, lung cancer, and melanoma—and more approvals are anticipated in the near future.

The development of immunotherapeutics was made possible by dedicated researchers integrating scientific discoveries in the fields of immunology and cancer biology. Historically, researchers working in these two fields tended to work independently, but by coming together, they spurred the development of powerful new approaches to cancer treatment. As we increase the diversity of scientific disciplines represented in the cancer research effort—for example, by including those working in nonbiological disciplines such as physical, chemical, engineering and mathematical sciences, as well as computational biology and bioinformatics—we will be in a position to make even more breakthroughs in cancer research.

Discoveries in the field of cancer genomics wrought by collaborative teams of researchers in the fields of cancer genomics, computational biology, and bioinformatics have already led to numerous anticancer therapeutics that more precisely target cancer than the treatments that have been the mainstay of cancer care for decades, such as cytotoxic chemotherapy and radiotherapy. Further collaboration from additional specialties will further enhance our ability to exploit the enormous amounts of genomic information available for the benefit of cancer patients around the world.

Collaboration has been a mainstay of biomedical research, and new and innovative methods of collaborating are currently being explored. Among the new initiatives that aim to harness the power of collaboration is AACR Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE). AACR Project GENIE is an international cancer registry built by sharing clinical cancer sequencing data from eight international institutions that are global leaders in genomic sequencing for clinical utility. By collecting, cataloging, and linking tumor genetic data with data on patient outcomes from all participating institutions and then making the data publicly available, AACR Project GENIE will facilitate clinical decision making and catalyze new clinical and translational cancer research.

Vice President Biden, who oversees the National Cancer Moonshot Initiative, has said that he sees increased data sharing and collaboration as keys to achieving the goal of the National Cancer Moonshot Initiative, which is to bring about a decade's worth of advances in cancer prevention, early detection, and treatment in 5 years.

We have never been better poised to realize this goal than we are now. We have the scientific knowledge and capability to deliver advances across the continuum of cancer care and a commitment from the U.S. government to remove barriers to progress and to forge the partnerships necessary to make this a reality.

However, the revitalized commitment from the U.S. government to making research a national priority comes after the biomedical research community has faced more than a decade of stagnant federal investments in the NIH and NCI. Thus, the AACR urges Congress and the Administration to ensure that the NIH, NCI, and U.S. Food and Drug Administration (FDA) receive robust, sustained, and predictable budget increases each year and that the National Cancer Moonshot Initiative is strongly supported with the new funds required to ensure its success. In addition, elected leaders must readjust the current discretionary budget caps upward to allow for healthy and lasting growth in the annual funding levels for the NIH, NCI, and FDA.

The AACR calls upon all its members and indeed all Americans to join us in our goal to make cancer research a long-term national priority. By all of us working together we can seize these unprecedented scientific opportunities and make strides to eradicate cancer worldwide.

• Nancy E. Davidson, MD

• AACR President

• Margaret Foti, PhD, MD (hc)

• AACR Chief Executive Officer

Research powers progress against cancer by increasing our understanding of the collection of diseases we call cancer and by allowing us to translate this knowledge into new and increasingly precise ways to prevent, detect, diagnose, treat, and cure a number of these diseases.

Much of the research is made possible by investments from the U.S. federal government administered through the National Institutes of Health (NIH), in particular its largest institute, the National Cancer Institute (NCI). Federal funding of the U.S. Food and Drug Administration (FDA) is also important because it helps speed the approval of safe and effective treatments, such as anticancer therapeutics.

As the first and largest cancer organization in the world dedicated to advancing every aspect of cancer research, from basic science to translational research to clinical research and population science, the American Association for Cancer Research (AACR) is committed to increasing public understanding of cancer and the importance of cancer research to public health, as well as to advocating for increased federal funding for the NIH, NCI, and FDA.

The annual AACR Cancer Progress Report to Congress and the American public is a cornerstone of the AACR's educational and advocacy efforts. This sixth edition of the report highlights how research continues to improve lives, like the lives of the 15 courageous individuals featured in this report who have shared their experiences with cancer. It also underscores how unwavering, bipartisan support from Congress and the Administration, in the form of robust and sustained increases in funding for the NIH, NCI, and FDA, is vital if we are to accelerate the pace of progress against cancer for the benefit of patients and their loved ones everywhere.

Research is our best defense against cancer. It powers the development of new and better ways to prevent, detect, diagnose, treat, and cure a number of the many diseases we call cancer. These advances are driving down overall U.S. cancer incidence and death rates and increasing the number of children and adults who are living longer, higher quality lives after a cancer diagnosis.

Although we are making extraordinary advances, cancer continues to be an enormous public health challenge globally. In fact, this collection of diseases accounts for one in every seven deaths worldwide and one in every four deaths in the United States. Moreover, as a result of an increase in the number of individuals over the age of 65, among other factors, the number of cancer deaths is expected to rise dramatically in the coming decades if new and better ways to prevent, detect, diagnose, and treat cancer are not developed. In the United States alone, the number of cancer deaths is predicted to rise from 595,690 in 2016 to 946,833 in 2030.

Fueling the projected increase in the number of cancer deaths will be a rise in the number of cancer diagnoses, which will, in turn, drive up the costs of cancer. In fact, it is estimated that the direct medical costs of cancer care in the United States will rise to $156 billion in 2020, from nearly $125 billion in 2010. When these costs are compared to the total NCI budget for fiscal year 2016, which is just $5.21 billion, it is clear that the research powering progress against cancer is a vital national investment.

Decades of research have led to the identification of numerous factors that increase a person's risk of developing cancer. Given that exposure to many of these factors can be eliminated or reduced, it is clear that many cases of cancer could be prevented. In fact, it is estimated that about half of cancer cases worldwide are attributable to preventable causes.

Most notable among the preventable causes of cancer are tobacco use, obesity, lack of physical activity, exposure to ultraviolet light from the sun or tanning devices, and failure to use or comply with interventions that treat or prevent infection with cancer-associated pathogens, such as cancer-causing strains of human papillomavirus (HPV).

Although the development and implementation of public education and policy initiatives designed to eliminate or reduce exposure to preventable causes of cancer have reduced cancer morbidity and mortality in the United States, some individuals continue to expose themselves to these risk factors. Thus, a great deal more research and more resources are needed to understand how best to help these individuals eliminate or reduce their risk of some cancers.

Not all cases of cancer are attributable to preventable causes. As a result, cancer screening tests that can identify a precancer or cancer early in development, when it can be more easily and successfully treated, are an important part of health care.

Determining whether broad implementation of a cancer screening test across the population can decrease deaths from the screened cancer and provide benefits that outweigh the potential risks of undergoing the test requires extensive research and careful analysis of the data generated. Independent groups of experts rigorously evaluate data indicating whether cancer screening tests meet these two criteria before putting forth recommendations about the use of the tests. Not all groups of experts give the same weighting to all the benefits and potential risks, which can result in differences in recommendations from distinct groups. These differences highlight the areas in which more research is needed.

Evidence-based cancer screening recommendations are only one consideration when a person makes decisions about which cancers he or she should be screened for and when. A person's own unique risks for developing each type of cancer, his or her tolerance of the potential risks of a screening test, and whether the test is covered by his or her health insurance are also important considerations. Therefore, every individual should consult with his or her health care practitioners to develop a cancer prevention and early detection plan tailored to his or her situation.

As we develop and implement new strategies that pair increased molecular understanding of cancer development with knowledge of an individual's unique cancer risk profile, we will move closer to a new era of precision cancer prevention and early detection.

The hard work of individuals throughout the biomedical research cycle constantly powers the translation of discoveries to advances across the clinical cancer care continuum. These advances are improving survival and quality of life for people around the world.

As a result of research advances, the FDA approved 13 new therapeutics for treating certain types of cancer, one new cancer screening test, one new diagnostic test, two new diagnostic imaging agents, and a new medical device in the 12 months leading up to July 31, 2016. During this time, the FDA also approved new uses for 11 previously approved anticancer therapeutics.

Four of the new anticancer therapeutics approved by the FDA target specific molecules involved in cancer and are referred to as molecularly targeted therapeutics. They are part of the precision medicine revolution in cancer care that is improving the lives of patients like Ginger Tam (p. 72).

Another four of the new anticancer therapeutics are immunotherapeutics that are yielding remarkable and durable patient responses, as highlighted in the report by the experiences of Dave Maddison and Bob Ribbans (p. 88 and 94, respectively). Importantly, immunotherapeutics have been shown to benefit patients with an increasingly diverse array of types of cancer. For example, one immunotherapeutic, nivolumab (Opdivo), was approved by the FDA for use as a treatment for three different types of cancer in just 6 months.

Research-fueled advances in cancer detection, diagnosis, and treatment are helping more and more people to survive longer and lead fuller lives after a cancer diagnosis. Despite this progress, cancer survivors often face serious and persistent adverse outcomes, including physical, emotional, psychosocial, and financial challenges as a result of their disease and treatment. Palliative care, given alongside cancer treatment and through the balance of life, is one approach that can improve quality of life for patients and survivors. Much more research is needed, however, to identify new and better ways to help cancer survivors meet the numerous challenges that they face.

Research is the foundation on which progress against cancer is made. As we look to the future, researchers throughout the cycle of biomedical research, including AACR President Nancy E. Davidson, MD (p. 102), are striving to accelerate the pace of lifesaving progress.

Cancer genomics research, which has been central to the precision medicine revolution, is one area in which the pace of progress is expected to accelerate in the future. This type of research promises to dramatically increase the number of potential targets for the development of novel molecularly targeted anticancer therapeutics and to identify markers that determine which patients are most likely to respond to a particular treatment.

As our knowledge of cancer biology grows, it is becoming increasingly clear that we cannot study cancer in isolation. We need to know more about the whole person in which the cancer has developed. This knowledge is particularly vital for powering progress in the emerging area of precision cancer prevention.

Federal investments in the NIH, NCI, and FDA have powered extraordinary progress against cancer by catalyzing scientific discovery and facilitating the translation of these discoveries into advances across the continuum of clinical cancer care. However, there are many challenges to overcome if we are to dramatically accelerate the pace of progress in cancer prevention, detection, diagnosis, and treatment.

First, we must continue to increase our understanding of the biology of cancer and to develop new approaches to translating this knowledge into health care advances that will save lives. To do this, we must ensure that robust, sustained, and predictable federal funding is provided for biomedical research, cancer research, and regulatory science. We must also provide strong support for cross-cutting initiatives like the National Cancer Moonshot Initiative and the Precision Medicine Initiative. Only by investing in research talent, tools, and infrastructure; supporting regulatory science initiatives; and increasing patient involvement in precision medicine initiatives, will we be able to accelerate the pace of progress and realize our goal of preventing and curing cancer.

Research improves survival and quality of life for people around the world because it powers the development of new and better ways to prevent, detect, diagnose, treat, and cure some of the many diseases we call cancer.

Each clinical and legislative advance against cancer is the culmination of many years of hard work by individuals from all segments of the biomedical research community (see sidebar on The Biomedical Research Community: Powering Progress Together, p. 9).

Among the most prominent clinical advances against cancer are the new medical products approved for use by the U.S. Food and Drug Administration (FDA). Bringing a new medical product from initial research discovery through development, approval by regulatory agencies, and then into the clinic is a complex, multifaceted process (see Biomedical Research, p. 48). From Aug. 1, 2015, to July 31, 2016, the FDA approved 18 new medical products for use in oncology—13 new anticancer therapeutics, one new cancer screening test, one new diagnostic test, two new diagnostic imaging agents, and a new medical device (see Table 1 , p. 10). During this period, the FDA also approved new uses for 11 previously approved anticancer therapeutics.

Clinical advances such as those listed in Table 1  (see p. 10) are helping drive down U.S. cancer incidence and death rates and increase the number of children and adults who survive a cancer diagnosis (see Table 2 , p.12, for data on childhood cancer) (2-5). In fact, the age-adjusted U.S. cancer death rate declined by 23 percent from 1991 to 2012, a reduction that translates into 1.7 million cancer deaths avoided (3). In addition, the U.S. 5-year relative survival rate for all cancers combined rose from 49 percent in the mid-1970s to 69 percent in 2011 (3).

The research that powers the significant advances that have been and continue to be made against cancer is made possible by investments from governments, philanthropic individuals and organizations, and the private sector the world over. Of particular importance in the United States are federal investments in biomedical research and government agencies conducting research such as the FDA and the Centers for Disease Control and Prevention (CDC). Most U.S. government investments in biomedical research are administered through the 27 institutes and centers of the National Institutes of Health (NIH). The largest component of the NIH is the National Cancer Institute (NCI), which is the federal government's principal agency for cancer research and training.

Although we have made tremendous progress against cancer, this collection of diseases continues to be an enormous public health challenge worldwide, accounting for one in every seven deaths that occur around the world (6) (see Figure 1 ). In the United States alone, it is predicted that 595,690 people will die from some form of cancer in 2016, making it the second most common cause of death after heart disease (3).

One of the challenges we face is that advances have not been uniform for all forms of cancer (see Table 3 , p. 14). For example, while the incidence rates for many of the most commonly diagnosed cancers in the United States—including breast, colorectal, lung, and prostate cancer—have been declining for more than a decade, those for other forms of cancer—most notably kidney, liver, and pancreatic cancer, as well as melanoma and childhood cancer—have been increasing (2). Overall 5-year relative survival rates for U.S. patients also vary widely depending on the form of cancer diagnosed (3). Overall 5-year relative survival rates for women with invasive breast cancer and men with prostate cancer are 89 percent and 99 percent, respectively, while those for U.S. adults with liver or pancreatic cancer are just 17 percent and 7 percent, respectively (3).

Another challenge is that advances have not been uniform for all patients diagnosed with a given form of cancer. Five-year relative survival rates vary with stage at diagnosis and among different segments of the population (see sidebar on What Are Cancer Health Disparities?, p. 15 and the sidebar on U.S. Cancer Health Disparities, p. 16).

Of concern is the fact that the devastating toll of cancer is predicted to increase significantly unless more effective strategies for cancer prevention, early detection, and treatment are developed. This is largely because cancer is primarily a disease of aging (9), and the segment of the world population age 65 and older is expected to almost double by 2035, rising from 616 million in 2015 to 1.157 billion in 2035 (15). During this period, the number of global cancer cases is anticipated to increase dramatically, reaching 24 million in 2035 (8). Also contributing to the projected increase in the number of cancer cases are high rates of tobacco use, obesity, infection, and physical inactivity, which are linked to some common types of cancer (6).

The United States is not immune to the rising burden of cancer (see sidebar on The Growing Public Health Challenge of Cancer in the United States, p. 17). Thus, it is imperative that we work with the global biomedical research community to address cancer incidence and mortality and power more progress against cancer.

Cancer exerts an immense global toll that is felt not only through the number of lives it affects each year, but also through its significant economic impact. With the number of cancer cases projected to increase substantially in the next few decades, it is anticipated that the economic burden will rise, too. One study estimates that the global cost of new cancer cases will increase from $290 billion in 2010 to $458 billion in 2030 (21).

In the United States, the direct medical costs of cancer care are projected to rise from nearly $125 billion in 2010 to $156 billion in 2020. These costs stand in stark contrast to the NIH budget for fiscal year (FY) 2016, which is $32.31 billion, of which $5.21 billion is dedicated to the NCI.

The increasing personal and economic burden of cancer underscores the urgent need for more research so that we can accelerate the pace of progress against cancer. Recent advances, some of which are highlighted in this report, were made as a direct result of the cumulative efforts of researchers from across the spectrum of research disciplines. Much of their work, as well as the federal regulatory agency that ensures the safety and efficacy of medical device and therapeutic advances—the FDA—is supported by funds from the federal government. Although the $2 billion increase to the NIH budget in FY 2016 was a welcome boost, it is imperative that Congress and the Administration provide sustained, robust, and predictable increases in investments in the federal agencies that are vital for fueling progress against cancer, in particular the NIH, NCI, and FDA, in the years ahead.

Research has taught us that cancer is a complex disease. In fact, it is not just one disease but rather a collection of many diseases that arise when the processes that control the multiplication and life span of normal cells go awry.

In adults, cell multiplication is a very tightly controlled process that occurs primarily only to replace cells that die due to exposure to various external factors or as a result of normal wear and tear.

If the processes that control the multiplication and life span of normal cells go awry, the cells start multiplying uncontrollably, fail to die when they should, and begin to accumulate. In body organs and tissues, the accumulating cells form a tumor mass, whereas in the blood or bone marrow, they crowd out the normal cells. Over time, some cancer cells within the tumor mass gain the ability to invade local tissues. Some also gain the ability to spread (or metastasize) to distant sites.

The progressive nature of cancer provides distinct sites for medical intervention to prevent cancer, detect it early, or treat progressive disease. In general, the further a cancer has progressed, the harder it is to stop the chain of events that leads to the emergence of metastatic disease, which is the cause of most deaths from solid tumors.

Changes, or mutations, in the genetic material of a normal cell are the primary cause of cancer initiation. Over time, additional mutations are acquired by cells within a growing tumor mass, and this drives cancer progression. The number of cells within a growing tumor that carry a given mutation depends on when the mutation was acquired during tumor growth. Thus, even within the same tumor, different cancer cells may have different genetic changes. In general, the more genetically heterogeneous a tumor is, the harder it is to effectively treat.

Not all mutations acquired by a cell contribute to cancer initiation and development. In fact, the identity, order, and speed at which a cell acquires genetic mutations determine whether a given cancer will develop and, if a cancer does develop, the length of time it takes to happen. Numerous interrelated factors influence mutation acquisition and determine the overall risk that a person will develop a particular type of cancer (see sidebar on Why Did I Get This Cancer? p. 19).

The accumulation of mutations in the genetic material of a cell over time is the predominant cause of cancer initiation and progression (see sidebar on Genetic and Epigenetic Control of Cell Function, p. 20). A genetic mutation is a change in the type or order of the four deoxyribonucleic acid (DNA) units, called bases, that make up the genetic material of a cell. The order, or sequence, of DNA bases is a key determinant of what proteins are produced by a cell and how much of each protein is produced. Many different types of mutation contribute to cancer initiation and development, primarily by altering the amount or function of certain proteins (see sidebar on Genetic Mutations, p. 20).

In addition to genetic mutations, most cancer cells also have profound epigenetic abnormalities, compared with normal cells of the same tissue. In many cases, epigenetic alterations and genetic mutations work together to promote cancer development. Although genetic mutations are permanent, some epigenetic abnormalities appear to be reversible, and harnessing this discovery for therapeutic purposes is an area of intensive investigation.

Genetic mutations that disrupt the orderly processes controlling the multiplication and life span of normal cells are the main cause of cancer initiation and development. However, interactions between cancer cells and their environment—known as the tumor microenvironment—as well as interactions with systemic factors, also have an important role in cancer development (see sidebar on Cancer Growth: Local and Global Influences). In fact, cancer cells often exploit tumor microenvironment components to promote their multiplication and survival.

Research has powered an explosion in our understanding of the individual factors inside and outside a cell that cause cancer initiation, development, and progression. It is also beginning to provide us with a picture of how these factors work together and are influenced by each person's unique biological characteristics. This knowledge is the essence of precision medicine, as well as the more nascent strategy of precision prevention (see Figure 2 ).

Precision prevention and medicine aim to tailor each person's health care to the prevention and/or treatment strategies most likely to be of benefit, sparing each person the cost of and potential harms from those prevention interventions and/or treatments that are unlikely to be of benefit (25, 26). As we develop an even more comprehensive, whole-patient understanding of the way in which cancer starts, progresses, and results in sickness, we can expect to see an acceleration in the pace of progress in precision medicine and prevention for cancer (see Anticipating Future Progress, p. 100).

Factors that increase the chance of developing cancer are referred to as cancer risk factors. These factors directly or indirectly increase the chance that a cell will acquire a genetic mutation and therefore increase the chance that a cell will become cancerous (see sidebar on Why Did I Get This Cancer?, p. 19). Decades of research have led to the identification of numerous cancer risk factors (see Figure 3 , p. 24) (27).

Many of the risk factors that have the biggest impact on cancer incidence are avoidable (see Figure 3 , p. 24). For example, many cases of cancer could be prevented either by individuals modifying their behaviors or through the development and implementation of new public education and policy initiatives that encourage individuals to avoid cancer risk factors or protect people from cancer risk factors in the workplace or environment. In fact, a recent study suggests that between 40 percent and 60 percent of cancer cases among white Americans could be prevented if each person did not smoke, limited alcohol consumption, maintained a healthy weight, and undertook regular physical activity (29). These lifestyle behaviors also increase risk for cancer in other U.S. racial and ethnic groups, but the absolute contributions of these factors to cancer risk in nonwhite populations remain to be determined.

Many cancer risk factors are also risk factors for other chronic diseases, such as cardiovascular disease, respiratory diseases, and diabetes. Therefore, reducing or eliminating exposure to these factors through behavior modification or public education and policy initiative implementation has the potential to reduce the burden of both cancer and other diseases.

In the United States, many of the greatest reductions in cancer morbidity and mortality have been achieved through the implementation of effective public education and policy initiatives. For example, major public education and policy initiatives to combat cigarette smoking have been credited with preventing almost 800,000 deaths from lung cancer from 1975 to 2000 (31). The researchers concluded, however, that this figure represented just 32 percent of the lung cancer deaths that could have been prevented during that period if tobacco control strategies had completely eliminated cigarette smoking (31).

Clearly, a great deal more research and more resources are needed to understand why some individuals continue to engage in risky behaviors despite current public education and policy initiatives, and how best to help these individuals eliminate or reduce their risk of some cancers. One recent study suggested that the way that public education messages are framed can dramatically influence whether or not an individual modifies his or her behavior because it showed that dieting individuals who saw a message focusing on the negative aspects of unhealthy food actually increased their consumption of unhealthy foods (32).

Smoking tobacco exposes a person to toxicants that can cause genetic mutations, increasing his or her risk of developing not only lung cancer, but also 17 other types of cancer (see Figure 4 , p. 25) (33). It is responsible for one in every three cases of cancer diagnosed in the United States each year (27). Therefore, one of the most effective ways a person can lower his or her risk of developing cancer, as well as other smoking-related conditions such as cardiovascular, metabolic, and lung diseases, is to avoid or eliminate tobacco use.

Since the relationship between tobacco use and cancer was first brought to the public's attention in 1964 (37), the development and implementation of major public education and policy initiatives have driven down cigarette smoking rates among U.S. adults from 42 percent in 1965 to 15 percent in 2015 (20, 34). In addition, the most recent data show declining use of cigarettes among high school students: In 2011, 15.8 percent of high school students were current users of cigarettes, compared with 9.3 percent in 2015 (38).

We have made tremendous progress reducing the public health burden of tobacco use, with researchers estimating that more than 8 million smoking-related deaths were prevented in the United States from 1964 to 2014 as a result of declines in cigarette smoking rates (39). The reductions in cigarette smoking rates have not been evenly distributed among all segments of the population, as defined by race, ethnicity, educational level, socioeconomic status, and place of residence (40). For example, 29.2 percent of non-Hispanic American Indians/Alaska Natives, 18.2 percent of non-Hispanic whites, 17.5 percent of non-Hispanic blacks, 11.2 percent of Hispanics, and 9.8 percent of non-Hispanic Asians are smokers (40).

In addition, U.S. adult use of other tobacco products that can cause certain types of cancer—cigars, smokeless tobacco products (e.g., chewing tobacco and snuff), and pipe tobacco—has not changed over the past decade (41). Moreover, use of emerging tobacco products, such as electronic cigarettes (e-cigarettes) and water pipes, among high school students is increasing rapidly. In 2011, 1.5 percent of high school students were current users of e-cigarettes, and 4.1 percent were current users of hookahs, compared with 16.0 percent and 7.2 percent, respectively, in 2015 (38).

Given that tobacco use and addiction mostly begin during youth and young adulthood, more research into the health consequences of using e-cigarettes and water pipes is urgently needed (43). In particular, we need to fully understand whether e-cigarettes have value as cigarette-smoking cessation aids and how they affect use of other tobacco products by smokers and nonsmokers (see sidebar on E-cigarettes: What We Know and What We Need to Know, p. 27) (44). We also need more research into the health consequences of smoking marijuana; for example, there is concern it could cause cancer because it involves the burning of an organic material, much like tobacco smoking. The need for this research is driven by the growing number of states that have legalized marijuana use for medical and/or recreational purposes (see Figure 5 , p. 26).