CANCER PROGRESS REPORT STEERING COMMITTEE
José Baselga, MD, PhD
AACR President 2015–2016
Memorial Sloan Kettering Cancer Center
New York, New York
Nina Bhardwaj, MD, PhD
Director of Immunotherapy
Mount Sinai Medical Center
Center for Science and Medicine
New York, New York
Lewis C. Cantley, PhD
Sandra and Edward Meyer Cancer Center
Weill Cornell Medical College
New York, New York
Ronald DeMatteo, MD, FACS
Vice Chair, Department of Surgery
Head, Division of General Surgical Oncology
Memorial Sloan Kettering Cancer Center
New York, New York
Raymond N. DuBois, MD, PhD
The Biodesign Institute at
Arizona State University
Margaret Foti, PhD, MD (hc)
Chief Executive Officer
American Association for Cancer Research
Susan M. Gapstur, PhD, MPH
Epidemiology Research Program
American Cancer Society
William C. Hahn, MD
Chief, Division of Molecular and Cellular Oncology
Dana-Farber Cancer Institute
Lee J. Helman, MD*
Scientific Director for Clinical Research
National Cancer Institute
Roy A. Jensen, MD
University of Kansas Cancer Center
Kansas City, Kansas
Electra D. Paskett, PhD
Associate Director, Population Sciences Department
Ohio State University Comprehensive Cancer Center
Theodore S. Lawrence, MD, PhD
Director of the University of Michigan Cancer Center
Professor & Chair, Department of Radiation Oncology
University of Michigan
Ann Arbor, Michigan
Stuart G. Lutzker, MD
Vice President, BioOncology Exploratory
South San Francisco, California
Eva Szabo, MD*
Chief, Lung & Upper Aerodigestive
Cancer Research Group
National Cancer Institute
*These authors contributed to the devlopment and review of this manuscript but are unable to endorse the request for NIH funding.
Shawn M. Sweeney, PhD
Associate Director, Translational Research
Karen Honey, PhD
Lead Science Writer
Senior Managing Editor, Science Communications
Assistant Art Director
Special Publications Designer
Director, Marketing and Creative Services
Director, Brand Strategy Communications
Rasika Kalamegham, PhD
Senior Science Policy Analyst
Senior Graphic Designer
Nicolle Rager Fuller
Jon G. Retzlaff, MBA, MPA
Managing Director, Science Policy and Government Affairs
Mary Lee Watts, MPH, RD
Director, Government Relations
Carl Wonders, PhD
Senior Manager, Science Policy Communications
A MESSAGE FROM THE AACR
On Sept. 20, 2011, the American Association for Cancer Research (AACR) released its inaugural AACR Cancer Progress Report to commemorate the advances in biomedical research that transformed cancer care in the 40 years following the signing of the National Cancer Act of 1971. During this period, biomedical research dramatically increased our understanding of the collection of diseases we call cancer, including the discovery that most cancers are caused by genetic mutations. This laid the foundation for the era of precision medicine, and by Jan. 1, 2011, 20 therapeutics targeting specific molecules involved in cancer had been approved by the U.S. Food and Drug Administration (FDA). Among these therapeutics are some that target cancer-specific molecules, some that target the blood vessel growth that supports tumor development, and some that stimulate a patient's immune system to eliminate their cancer.
As highlighted in the AACR Cancer Progress Report 2015, progress against cancer has continued at a spectacular pace since the start of 2011. In fact, during the five years of publishing the AACR Cancer Progress Report, the number of FDA-approved therapeutics targeting specific molecules involved in cancer more than doubled, reaching 52 therapeutics by July 31, 2015. For some forms of cancer, including melanoma and chronic lymphocytic leukemia, we now have five or more of these new therapeutics, which–as a result of their increased precision–have fewer adverse side effects compared with the traditional treatments that have been the mainstay of cancer care for decades.
This rapid surge in the number of increasingly precise anticancer therapeutics was powered by research, and the cumulative knowledge of the complexities of cancer continues to be the foundation of new advances across the clinical cancer care continuum. Discoveries in the fields of cancer genomics and immunology have been particularly fruitful and have firmly established two new pillars of cancer care: precision therapy and immunotherapy. These exciting fields of research also show immense promise for the future.
Advances in cancer genomics are fueling an expansion in the clinical use of genomic information to make otherwise unexpected treatment decisions for patients with a wide range of cancer types, like the four patients featured in the Transforming Lives One Sequence at a Time section of the AACR Cancer Progress Report 2015 (p. 29). Genomic sequencing of two of these patients' cancers revealed the presence of BRAF gene mutations commonly found in melanoma, and a BRAF-targeted therapeutic approved by the FDA for treating BRAF-mutant melanoma has been transforming the lives of these patients for more than a year.
Precision medicine stories like these are becoming more common because the explosion in our understanding of the biology of cancer is making it increasingly possible to identify the most appropriate therapy for a patient. Our increased knowledge of cancer is also enabling the more precise use of radiotherapy and traditional chemotherapy, as well as cancer prevention strategies tailored for maximal effectiveness.
The dedicated efforts of researchers working throughout the cycle of biomedical research in the United States and around the world are making possible continual progress against cancer. The AACR is encouraged by the fact that 85 percent of American voters recognize that progress is being made against cancer, according to results from a 2015 national survey conducted on behalf of the organization by Hart Research Associates and Public Opinion Strategies. This progress is powering revolutionary advances in cancer care, and the AACR is grateful to the 13 courageous beneficiaries of some of these advances who shared their personal experiences with cancer in the AACR Cancer Progress Report 2015. These stories, coupled with the advances described in the report, inspire great hope for a future in which cancer no longer threatens the lives of millions.
Unfortunately, our ability to fully capitalize on our ever-growing knowledge of cancer is at risk. This is because federal investments in the National Institutes of Health (NIH) and its largest component institute, the National Cancer Institute (NCI), which spur much of the progress made against cancer, have stagnated. Since 2004, the budgets for the NIH and NCI have not kept pace with inflation, resulting in the NIH losing approximately 25 percent of its ability to fund lifesaving biomedical research. On top of these losses due to inflation, direct budget cuts in 2011 and 2013 slashed federal support of the NIH and NCI.
Investments in the federal agencies that are vital for powering progress against cancer also fuel the economy and help the United States to maintain its important position as the global leader in biomedical research. Therefore, reduced federal investments in the NIH and NCI jeopardize not only future lifesaving biomedical research, but also economic development and U.S. leadership in the field.
The AACR urges Congress and the administration to implement a strategy for providing annual budget increases of at least 7 percent for the NIH, NCI, and FDA beginning in FY 2016 and thereafter. This call to action is in line with the opinion of the majority of American voters, because three out of every four voters favor increasing federal funding for cancer research, according to results from the 2015 AACR survey. Thus, we urge all members of the AACR and, indeed, all Americans to join us in calling on Congress and the administration to prioritize the growth of the NIH, NCI, and FDA budgets through annual funding increases that are robust, sustainable, and predictable. There is no time to waste when, in the United States alone, we are losing one person every minute of every day to the devastating collection of diseases we call cancer.
José Baselga, MD, PhD
AACR President (2015–2016)
Margaret Foti, PhD, MD (hc)
Chief Executive Officer
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 35,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in 101 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 25 conferences and educational workshops, the largest of which is the AACR Annual Meeting with nearly 19,300 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit www.AACR.org.
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 some of these diseases.
Much of the research that powers progress against cancer is funded by the U.S. federal government through the National Institutes of Health (NIH), in particular its largest component institute, the National Cancer Institute (NCI). Additionally, federal funding of the U.S. Food and Drug Administration (FDA) helps speed the delivery of safe and effective treatments, such as anticancer therapeutics, to the patients who need them.
As the oldest 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. These investments will contribute markedly to the goal of saving more lives from cancer.
The annual AACR Cancer Progress Report to Congress and the American public is a cornerstone of the AACR's educational and advocacy efforts. This fifth edition of the report chronicles how research continues to transform lives, like the lives of the 13 courageous individuals featured in the report who have shared their experiences with cancer. It also contains a special section showcasing the advances made against cancer in the five years of publishing the report. The progress against cancer highlighted in the report underscores how unwavering, bipartisan support from Congress and the administration, in the form of sustained increases in funding for the NIH, NCI, and FDA, are vital if we are to continue to make progress for the benefit of families everywhere.
Cancer in 2015
Research is the foundation of new and better approaches to cancer prevention, detection, diagnosis, and treatment, which are driving down overall U.S. cancer death rates and increasing the number of people who are living longer, higher-quality lives after a cancer diagnosis.
Even though extraordinary advances have been made, cancer continues to exert an enormous global toll. In 2015 alone, it is estimated that about 8.9 million people worldwide will die from some form of cancer, 589,430 of whom are individuals living in the United States. Moreover, these numbers are projected to increase dramatically in the coming decades if new and better ways to prevent, detect, diagnose, and treat cancer are not developed.
Fueling the anticipated increase in cancer deaths will be a rise in the number of cancer diagnoses, which will, in turn, drive up the costs of cancer. In the United States alone, it is estimated that the direct medical costs of cancer care 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 2015, which is just $5 billion, it is clear that research that spurs lifesaving progress against cancer is a wise national investment.
Special Feature on Five Years of Progress Against Cancer
To celebrate the fifth edition of the AACR Cancer Progress Report, a special feature is included that highlights the incredible advances that have been made against cancer in the five years of publishing the report. Discoveries in the fields of cancer genomics and immunology have spurred particular progress, including the rapid expansion of two new pillars of cancer care: precision therapy and immunotherapy.
Information generated by the field of cancer genomics is the foundation of precision therapy, which is revolutionizing the standard of cancer care from a one-size-fits-all approach to one in which the best therapeutic strategy for a patient is determined by an increasingly deep understanding of the patient and his or her tumor. This information is being used not only to expand the repertoire of precision therapeutics, but also to identify additional patients who could benefit from the precision therapeutics that we already have–like the four patients in the Transforming Lives One Sequence at a Time highlight (see p. 29)–and to increase the precision with which traditional chemotherapy and immunotherapy are utilized.
An increased understanding of the role of genetic alterations in developing cancer is also the foundation on which changes are being made in the way that many cancer clinical trials are conducted and regulated. These changes are essential if we are to continue to move precision medicine forward more rapidly than ever before.
Preventing Cancer From Developing
Many cases of cancer could be prevented by eliminating or reducing exposure to factors that increase a person's risk of developing cancer.
Past U.S. public education and policy initiatives have been successful in reducing cancer morbidity and mortality through prevention. However, given that an estimated 50 percent of the 589,430 U.S. cancer deaths expected to occur in 2015 are attributable to preventable causes, it is clear more needs to be done.
Most prominent 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).
Unfortunately, some individuals continue to expose themselves to preventable causes of cancer despite public education and policy initiatives. Moreover, not all cancer risk factors are avoidable. As a result, cancer screening strategies that can identify a precancer or cancer early in development, when it can be more easily and successfully intercepted, are an important part of health care. However, given that each person has his or her own unique risks for developing each type of cancer, everyone should consult with his or her health care practitioners to develop a personalized cancer screening plan.
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 interception.
Transforming Lives Through Precision Medicine
The dedicated efforts of researchers working throughout the cycle of biomedical research fuel advances across the clinical cancer care continuum that are transforming lives in the United States and worldwide.
As a result of research advances, the FDA approved nine new anticancer therapeutics, one new cancer prevention vaccine, and one new cancer screening test in the 12 months leading up to July 31, 2015. During this time, the FDA also approved new uses for six previously approved anticancer therapeutics and one imaging agent.
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 transforming the lives of patients like Patty Klein, Janet Klein, and Lori Cuffari (p. 72, 76, and 80, respectively).
Four of the new anticancer therapeutics approved by the FDA are immunotherapeutics that are yielding remarkable and durable patient responses, as illustrated in the report by the experiences of Donna Fernandez, Elizabeth Buell-Fleming, and Sergio Ramirez (p. 86, 90, and 92, respectively). This is the largest number of immunotherapeutics approved in a 12-month period since the first AACR Cancer Progress Report was published in 2011, highlighting how this powerful form of cancer treatment has emerged as a key pillar of cancer care.
Even though significant progress has been made in precision therapy and immunotherapy for the treatment of cancer, surgery, radiotherapy, and traditional chemotherapy continue to form the foundation of treatment for almost all patients, as they did for Congresswoman Rosa DeLauro and Congressman Tom Marino (p. 66 and 68, respectively). However, the more we learn about the molecular makeup of individual patients and their tumors, the more precisely we will be able to use these treatment strategies so that each patient's treatment is only as aggressive as is necessary for it to be effective.
What Progress Does the Future Hold?
Cancer genomics research is central to the precision medicine revolution that has been improving the lives of an increasing number of patients with cancer, particularly during the past five years. However, many researchers, including AACR President José Baselga, MD, PhD (p. 102), think that the best is yet to come, and that as we look to the future, the pace of progress in precision medicine will continue to accelerate.
Increased deployment of cancer genomics research promises not only to increase the number of potential targets for the development of novel precision anticancer therapeutics, but also to identify markers of response and resistance to all forms of treatment. The power of this information to transform patient care could be dramatically enhanced by pairing knowledge of genetic markers of response and resistance with emerging technologies, often referred to as liquid biopsies.
Building Blocks to Further Precision Medicine
Federal investments in the NIH, NCI, and FDA have powered extraordinary progress against cancer by catalyzing scientific discovery and enabling the translation of discoveries into advances across the continuum of clinical cancer care. Progress in the area of precision medicine has been particularly striking, although there are many challenges to overcome if we are to realize our goal of expanding precision medicine to all forms of cancer prevention, detection, diagnosis, and treatment.
First and foremost, 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 prioritize and increase federal funding for biomedical research, cancer research, and the FDA. 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.
Following more than a decade of budget stagnation and outright funding cuts, the administration and a bipartisan majority of members of Congress have demonstrated, thus far in 2015, a strong commitment to increasing the budgets for the NIH, NCI, and FDA.
During this time of unprecedented promise in biomedical and cancer research, robust, sustained, and predictable investments in the NIH and NCI, are urgently needed. This is a sentiment shared by the majority of American voters, as a 2015 national survey conducted on behalf of the AACR by Hart Research Associates and Public Opinion Strategies found that three out of every four voters favor increasing federal funding of cancer research.
Therefore, the AACR respectfully urges Congress and the administration to:
Implement a strategy for robust, sustained, and predictable growth in funding for the NIH and NCI by providing annual budget increases of at least 7 percent. This level of funding would represent strong growth in excess of the biomedical inflation rate, resulting in fiscal year (FY) 2020 funding levels for the NIH and NCI of $42.5 billion and $7 billion, respectively.
Increase the FDA budget in FY 2016 by $200 million above its FY 2015 level (a 7 percent increase from $2.6 billion to $2.8 billion) and ensure that the agency receives comparable annual percentage increases thereafter.
Achieving these goals will require Congress to work in a bipartisan fashion to enact a broad-based budget deal that raises the discretionary funding caps for FY 2016 and beyond. This would allow our nation's policymakers to invest in priority areas, such as biomedical research, cancer research, and regulatory science, which will speed innovation and accelerate the pace of development of products that are safe, effective, and ultimately advance public health.
By committing to provide the NIH, NCI, and FDA with annual funding increases that are robust, sustained, and predictable, we will transform cancer care, spur innovation and economic growth, maintain our position as the global leader in science and biomedical research, and, most importantly, bring hope to cancer patients and their loved ones.
A YEAR IN PROGRESS
CANCER IN 2015
IN THIS SECTION YOU WILL LEARN:
IN THE UNITED STATES, OVERALL CANCER DEATH RATES ARE DECREASING AND THE NUMBER OF SURVIVORS IS INCREASING.
IT IS PROJECTED THAT MORE THAN 1.65 MILLION PEOPLE IN THE UNITED STATES WILL RECEIVE A CANCER DIAGNOSIS, AND MORE THAN 589,000 WILL DIE FROM THE DISEASE IN 2015.
IT IS PREDICTED THAT ALMOST 2.4 MILLION NEW CASES OF CANCER WILL BE DIAGNOSED IN THE UNITED STATES, AND 24 MILLION WILL BE DIAGNOSED GLOBALLY IN 2035.
NOT ALL SEGMENTS OF THE U.S. POPULATION BENEFIT EQUALLY FROM ADVANCES AGAINST CANCER.
THE COST OF CANCER IS IMMENSE, BOTH IN THE UNITED STATES AND GLOBALLY.
Progress Against Cancer: Powered by Research
Research improves survival and quality of life for millions of individuals around the world by catalyzing the development and implementation of new and better ways to prevent, detect, diagnose, treat, and cure some of the diseases that we call cancer.
It takes many years of hard work by individuals from all segments of the biomedical research community to bring a new medical product from initial research discovery through approval by regulatory agencies and into the clinic (see sidebar on The Biomedical Research Community, p. 9). Among the new medical products approved by the U.S. Food and Drug Administration (FDA) between Aug. 1, 2014, and July 31, 2015, were nine new anticancer therapeutics, one new cancer prevention vaccine, and one new cancer screening test (see Table 1 , p. 10). During this period, the FDA also approved new uses for six previously approved anticancer therapeutics and one imaging agent.
Advances such as those listed in Table 1 (p. 10) help ensure that, year after year, overall U.S. cancer death rates continue to decrease (2) and that the number of people who survive their cancer continues to rise. In fact, in the United States alone, the percentage of the population living with, through, or beyond a cancer diagnosis has more than tripled since 1971 (3-5).
The significant progress that has been and continues to be made against cancer is the result of investments from governments, philanthropic individuals and organizations, and the private sector the world over. In the United States, federal investments in biomedical research, cancer research, and the FDA are of particular importance. The majority of U.S. federal investments in biomedical research are administered through the 27 component institutes and centers of the National Institutes of Health (NIH), the largest of which is the National Cancer Institute (NCI) (see sidebar on The National Institutes of Health by the Numbers, p. 11). Continued progress against cancer requires robust, sustained, and predictable growth in funding of lifesaving biomedical research from all sources.
Cancer: An Ongoing Challenge
We have made tremendous progress against cancer—for example, the U.S. five-year relative survival rate for all cancers combined increased from 49 percent in the mid-1970s to 68 percent in 2010 (6). In spite of this progress, this collection of diseases continues to exert a devastating toll on the global population. In fact, it is predicted that about 8.9 million people worldwide will die from some form of cancer in 2015 (7), 589,430 of these individuals in the United States (6) (see Table 2 , p. 12).
One of the reasons that cancer continues to be an enormous public health challenge is that advances have not been uniform for all types of cancer (see Table 3 , p. 14). For example, although death rates for most types of cancer have been declining in the United States since the early 1990s, those for adults diagnosed with liver or pancreatic cancer rose 2.5 percent and 0.3 percent per year, respectively, from 2007 to 2011 (6). Overall five-year relative survival rates for U.S. adults with these two types of cancer are also very low, at 17 percent for liver cancer and 7 percent for pancreatic cancer, in stark contrast to the overall five-year relative survival rates for women with invasive breast cancer and men with prostate cancer, which are 89 percent and almost 100 percent, respectively (6).
Another reason that cancer continues to be a challenge is that advances have not been uniform for all patients with a given type of cancer. Five-year relative survival rates vary not only with stage at diagnosis, but also among different segments of the population (see sidebar on Cancer Health Disparities in the United States, p. 15).
The reality is that cancer will continue to pose challenges for researchers, clinicians, and patients in the coming decades unless more effective strategies for cancer prevention, early detection, and treatment are developed. Given that cancer is primarily a disease of aging (12), and that the portion of the U.S. population age 65 and older is expected to double in size by 2060 (13), it is anticipated that the number of new cancer cases diagnosed each year in the United States will increase dramatically (7). In fact, it is estimated that in 2035, there will be almost 2.4 million new cases of cancer diagnosed in the United States. Also contributing to the projected increase are the continued use of cigarettes by 18 percent of U.S. adults (14) and high rates of obesity and physical inactivity, both of which are linked to an increased risk for several types of cancer (15, 16).
A rise in the number of U.S. cancer cases will lead directly to an increase in the number of cancer deaths, and in the near future cancer is expected to overtake heart disease as the country's leading cause of death (17).
These challenges are not unique to the United States; they are also global problems (see sidebar on Cancer: A Global Challenge). Thus, it is imperative that the global biomedical research community collaborates to address cancer incidence and mortality, and spur continued advances against cancer.
Cancer: A Costly Disease. Research: A Vital Investment
Cancer exerts an immense global toll not only through the number of lives it affects each year, but also as a result of its substantial economic impact. It is estimated that the 13.3 million cases of cancer diagnosed worldwide in 2010 cost $290 billion in that year alone (18) (see Figure 1 ). With the number of cancer cases projected to rise dramatically in the next few decades, so too will the costs. In fact, it is estimated that the 21.5 million new cases of cancer projected to be diagnosed in 2030 will cost $458 billion (18).
In the United States alone, it is estimated that the direct medical costs of cancer care in 2010 were nearly $125 billion, and that these costs will likely rise to $156 billion in 2020 (19). These costs stand in stark contrast to the NIH budget for fiscal year (FY) 2015, which is $30.3 billion.
Given the increasing economic and personal burden of cancer, it is clear that more research is required if we are to continue to make new advances against cancer. In the United States, most biomedical research, as well as the federal regulatory agency that assures the safety and efficacy of advances—the FDA—is supported by funds from the federal government. Therefore, it is imperative that Congress and the administration increase investments in the federal agencies that are vital for fueling progress against cancer, in particular the NIH, NCI, and FDA.
IN THIS SECTION YOU WILL LEARN:
CANCER IS NOT ONE DISEASE; IT IS A COLLECTION OF MANY DISEASES CHARACTERIZED BY THE UNCONTROLLED GROWTH OF CELLS.
CHANGES IN THE GENETIC MATERIAL IN A NORMAL CELL UNDERPIN CANCER INITIATION AND DEVELOPMENT IN MOST CASES.
A CANCER CELL'S SURROUNDINGS INFLUENCE THE DEVELOPMENT AND PROGRESSION OF DISEASE.
THE MOST ADVANCED STAGE OF CANCER, METASTATIC DISEASE, ACCOUNTS FOR MORE THAN 90 PERCENT OF CANCER DEATHS.
THE MORE WE KNOW ABOUT THE BIOLOGY OF CANCER, THE MORE PRECISELY WE CAN PREVENT, DETECT, DIAGNOSE, AND TREAT IT.
Cancer is not one disease; it is a collection of many diseases that arise when the processes that control the multiplication and life span of normal cells go awry.
As humans develop, we grow, through extensive cell multiplication, from a single cell to an estimated 37.2 trillion cells in an adult body (20). When a person matures, the pace of cell multiplication slows. In adults, normal cells primarily multiply only to replace cells that die either due to exposure to a variety of external factors or naturally as a result of normal cellular wear and tear, which is related to the number of times the cell has multiplied.
When 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, these cancerous cells form a tumor mass, and in the blood or bone marrow, they crowd out the normal cells.
Without medical intervention, over time, some cancerous cells gain the ability to invade local tissues, and some spread, or metastasize, to distant sites. The progression of a cancer to metastatic disease is the cause of most cancer-related deaths.
Changes, or mutations, in the genetic material of cells are the primary cause of cancer initiation and development. Not all mutations contribute to cancer development, but the greater the chance that a cell will acquire a mutation, the greater the chance that the cell will acquire a mutation that will cause cancer. The identity, order, and speed at which a cell acquires genetic mutations determine the length of time it takes for a cancer to develop and are influenced by numerous interrelated factors (see sidebar on Why Me? Why This Cancer? p. 19).
Cancer Development: Influences Inside the Cell
Cancer develops largely as a result of the accumulation of mutations in the genetic material inside a cell (see sidebar on Genetic and Epigenetic Control of Cell Function). A 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 sequence of DNA bases determines what proteins are produced by a cell and how much of each protein is produced, thereby defining cellular function. Many different types of mutation can lead to cancer, largely by altering the amount or function of certain proteins (see sidebar on Genetic Mutations, p. 21), although it is important to note that not all mutations result in cancer.
Most cancer cells have not only numerous genetic mutations, but also profound abnormalities in their epigenomes when compared with normal cells of the same tissue. In many cases, epigenetic alterations and genetic mutations work in conjunction to promote cancer development. Of immense therapeutic interest is the discovery that although genetic mutations are permanent, some epigenetic abnormalities may be reversible. In fact, the FDA has already approved six therapeutics that cause changes in the epigenome (see Targeting the Epigenome, p. 82).
Cancer Development: Influences Outside the Cell
Genetic mutations underpin cancer initiation and development in most cases. However, interactions between cancer cells and their environment—known as the tumor microenvironment—as well as interactions with systemic factors, also play an important role in cancer development (see sidebar on Cancer Growth: Local and Global Influences, p. 22). Therefore, developing a more comprehensive, whole-patient understanding of cancer has the potential to provide novel approaches to cancer prevention and treatment.
Cancer Development: Exploiting Our Expanding Knowledge to Improve Health Care
Research has significantly increased our knowledge of the processes by which cancer starts, progresses, and results in disease. It also has expanded our ability to exploit this knowledge to develop new and better approaches to cancer prevention, detection, diagnosis, and treatment. Most of the new treatments are more precise than traditional therapies, providing patients with not just longer, but also higher-quality lives, and researchers are beginning to use the same precision strategy to develop new cancer prevention and interception interventions (see Special Feature on Five Years of Progress Against Cancer, p. 23).
In the United States, the research that fuels advances against cancer is largely supported by the NIH and NCI. Given that continued progress will be made only through additional research, it is vital that the administration and Congress increase investments in the NIH and NCI, as well as the FDA, which assures the safety and efficacy of advances.
SPECIAL FEATURE ON FIVE YEARS OF PROGRESS AGAINST CANCER
IN THIS SECTION YOU WILL LEARN:
ONCOLOGY IS LEADING PRECISION MEDICINE EFFORTS AND TRANSFORMING LIVES.
GENOMICS IS THE FOUNDATION ON WHICH PRECISION MEDICINE IN ONCOLOGY IS BUILT.
IN THE PAST FIVE YEARS, MOLECULARLY TARGETED THERAPEUTICS AND IMMUNOTHERAPEUTICS HAVE BECOME PART OF ROUTINE CARE FOR PATIENTS WITH SEVERAL TYPES OF CANCER.
BIG DATA SHOW PROMISE FOR INCREASING THE NUMBER OF PRECISION THERAPEUTICS IN OUR TOOLKIT.
GENOMICALLY INFORMED CLINICAL TRIAL DESIGNS ARE ESSENTIAL FOR MOVING PRECISION MEDICINE FORWARD AS QUICKLY AS POSSIBLE.
To celebrate the fifth edition of the AACR Cancer Progress Report, included here is a special feature in which we highlight advances that have been made against cancer in the five years of publishing the report.
The year 2011 marked the 40th anniversary of the signing of the National Cancer Act of 1971, which focused the nation's efforts and attention on the fight against cancer. Much changed between 1971 and 2011, and the AACR commemorated the amazing advances in cancer research made during that time with the publication of its inaugural AACR Cancer Progress Report.
In the four decades after 1971, we went from the concept that cancer is a single disease caused by viruses to the understanding that cancer is a vast collection of diseases, some of which are indeed caused by chronic infection with certain viruses, united by overgrowth of cells (see Prevent Infection With Cancer-causing Pathogens, p. 46). More important, however, was the discovery that cancer arises from a myriad of genetic changes within cells that accumulate with time (see Developing Cancer, p. 18).
That discovery, coupled with advances in biology, chemistry, physics, and technology, set the stage for the new era of precision medicine. In fact, by Jan. 1, 2011, 20 therapeutics targeting specific molecules involved in the development and progression of cancer had been discovered and approved for patient benefit. Included in this list are not only therapeutics that target cancer-specific molecules, but also those that target the blood vessel growth that supports tumor development and some immunotherapeutics.
As described in this Special Feature on Five Years of Progress Against Cancer, much has changed since Jan. 1, 2011.
Powered by fundamental research, our understanding of the inner workings of cancer has continued to explode. As we have learned more about the biology of cancer and both the normal and pathologic responses of the patient to cancer, we have been able to develop increasingly precise therapies that reduce the adverse effects of treatment while simultaneously enhancing their ability to eliminate certain forms of cancer, including some drug-resistant cancers.
Moreover, the pace at which this is being accomplished continues to accelerate year after year, providing a glimpse of an even brighter future. For example, from Jan. 1, 2011, through July 31, 2015, 32 additional therapeutics targeting molecules involved in the development and progression of cancer were discovered and approved for patient benefit, which is more than in the entire four prior decades.
Treating Cancer More Precisely
In 2001, the FDA approved imatinib (Gleevec) for the treatment of Philadelphia chromosome–positive chronic myelogenous leukemia (CML).
This was a watershed moment.
Imatinib changed the standard of care for CML and transformed the lives of many patients with this previously fatal disease by increasing the five-year relative survival rate from 17 percent in the mid-1970s to 63 percent in 2007 (23). It also went on to become an effective treatment for gastrointestinal stromal tumors (GIST), as well as several other forms of leukemia and myeloproliferative disorders. Equally important, imatinib helped to usher in the age of precision medicine by becoming the first chemical agent to target a cancer-specific protein, BCR-ABL.
What, then, is precision medicine?
Precision medicine, also known as personalized medicine, molecular medicine, or tailored therapy, is broadly defined as treating a patient based on characteristics that distinguish that individual from other patients with the same disease. Factors such as a person's genome, his or her cancer genome, disease presentation, gender, exposures, lifestyle, microbiome, and other yet-to-be-discovered features are considered in precision medicine (24) (see Figure 2 ). Currently, genomics is the predominant factor influencing precision medicine in oncology.
In essence, what precision medicine aims to do is identify the factors most unique to the disease state and use them for the purposes of preventing cancer, diagnosing disease, predicting patient outcomes, and directing therapy. Further, in the research and development setting, these characteristics are used to develop an ever-expanding toolkit of increasingly more precise anticancer therapeutics (see Appendix Table 1, p. 122). In other words, by understanding more about a particular disease, one should be able to develop “magic bullets” specific for that disease that would leave healthy tissue unharmed, a concept pioneered over 100 years ago by Paul Ehrlich, the father of chemotherapy for disease (25).
Over the course of more than 60 years, we have gone from a limited understanding of the specific factors that influence cancer development to a greater appreciation of the particular genetic mutations that can fuel a cancer (see Figure 3 , p. 25, and (Re)Setting the Standard of Care, p. 26). With this more precise knowledge of cancer development, the tools used to prevent, detect, diagnose, and treat cancer have also become more precise.
Although precision medicine is not unique to the practice of oncology, oncology is leading such efforts largely because of our immense knowledge of the role of genetic mutations in the development and progression of cancer (see Developing Cancer, p. 18). When this fact is coupled with our increasing ability to read all parts of a person's genome faster than ever before, it becomes clear that genomics is and will continue to be a key driver of precision medicine. It should be noted, however, that genetics is but one of the many factors relevant to precision medicine (see Figure 2 ). As our ability to analyze all aspects of these other characteristics rapidly catches up with our current genomic prowess, we can expect faster and broader implementation of precision medicine, not only in oncology, but also in the treatment of other diseases.
(Re)Setting the Standard of Care
Numerous advances over the past five years have greatly benefited patients. Chief among these has been a change in the standard of care for many types of cancer, as well as the addition of entirely new therapeutic modalities. Together with those that have been the mainstay of cancer treatment for many years, these new therapies give patients and their physicians many more options to treat, manage, and hopefully overcome their cancers.
In the not-so-distant past, there were three “pillars” of cancer treatment to effectively treat disease—radiotherapy, surgery, and traditional chemotherapy (see Figure 4 ).
With the advent of molecular biology, we began to understand various cancers at the molecular level and to develop new therapeutics that targeted those molecules that were closely associated with the root cause of the disease. Some of the earliest examples of such “molecularly targeted” therapeutics, which became the first generation of precision therapeutics, include rituximab (Rituxan) for the treatment of B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin) for the treatment of HER-2–positive breast cancer; and imatinib for the treatment of CML.
This first generation of precision therapeutics added a fourth pillar of cancer treatments, and provided new, less-toxic options for physicians treating patients with these cancers (see Figure 4 ). Unfortunately, at the time, for patients for whom these therapeutics were ineffective, or for those who developed resistance, there were no other precision medicine treatment options. Fortunately, today this is different for patients with many, but not all, types of cancer.
Melanoma is the deadliest form of skin cancer, with only 16 percent of patients with metastatic disease surviving five or more years after diagnosis (6). The first new treatment option for melanoma in 30 years was approved by the FDA in 2011. Prior to that, the standard of care for patients with metastatic melanoma was dacarbazine, a traditional chemotherapeutic, and high-dose aldesleukin (Proleukin), an immune stimulant; however, neither agent had demonstrated a significant effect on overall survival in randomized trials (27).
Since Jan. 1, 2011, the FDA has approved six systemic therapeutics for treating patients with metastatic melanoma, three of which more precisely target the cancer than any other agents previously used to treat patients with this deadly disease (see Figure 5 ). Two of these novel agents, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), are so precise that they are effective only against the approximately 50 percent of melanomas that harbor mutant forms of BRAF. These therapeutics have transformed the lives of many patients with metastatic melanoma and show the power of this approach to cancer treatment.
In addition, there are now six precision therapeutics for the treatment of CML, including an agent that targets the common T35I mutation (see Ref. 28 for more details). Similarly, chronic lymphocytic leukemia (CLL) patients have an equally extensive selection of precision therapeutics to treat their disease, including two new agents that were approved in 2014 (see Ref. 1 for more details). Importantly, patients with melanoma, CLL, or CML are not the only individuals with numerous precision therapeutic options, as this is rapidly becoming the rule rather than the exception.
Undoubtedly, as we continue to learn more about the biology of those types of cancer for which no, or relatively few, precision therapeutic options currently exist, we will be able to develop equally impressive and deep toolkits of therapeutic options for patients with these diseases.
A New Pillar
During the past five years, another major advancement in cancer treatment was the addition of a fifth pillar of cancer treatment: immunotherapy (see Figure 4 , p. 26). The concept of using a patient's own immune system to eliminate his or her cancer is not new, but in the past five years we have finally been able to effectively translate knowledge about the immune system into revolutionary advances in patient care (see Treatment With Immunotherapeutics, p. 82).
There are numerous types of immunotherapeutics (see sidebar on How Immunotherapeutics Work, p. 83). The first immune-checkpoint inhibitor, ipilimumab (Yervoy), was FDA approved in 2011, with two others approved by the FDA in 2014, and many more in various stages of clinical development and regulatory review (see Releasing the Brakes on the Immune System, p. 84). The first therapeutic vaccine for the treatment of cancer, sipuleucel-T (Provenge), was also FDA-approved in 2011 for the treatment of metastatic prostate cancer. Now, some groups are using genomics to develop precision therapeutic vaccines (see Retooling).
The past few years have also brought forth the concept of engineering a patient's immune cells to specifically attack his or her cancer. This promising technique has resulted in chimeric antigen receptor (CAR) T–cell therapy, which has been shown in early clinical trials to successfully treat both pediatric and adult patients with several types of blood cancer (see Boosting the Killing Power of the Immune System, p. 85). Two CAR T–cell therapies recently received FDA breakthrough designations for the treatment of acute lymphoblastic leukemia (ALL), which will help this new form of immunotherapy reach patients as quickly as possible (see Precision Regulation, p. 30).
Our understanding of this powerful class of therapeutics and the newest addition to the pillars of cancer treatment is just beginning. We will undoubtedly uncover even more effective and precise ways of using these tools in the near future (see What Progress Does the Future Hold? p. 100).
As discussed above (see Developing Cancer, p. 18), cancer is characterized by alterations of the genome. We are now able to use these alterations to more precisely diagnose disease, predict patient outcomes, develop therapies, and direct treatment. Although the causes of cancer are far more complex than a collection of genetic mutations (see sidebar on Cancer Growth: Local and Global Influences, p. 22), genetic sequencing is one of our most effective tools for analyzing cancer. Consequently, many researchers have begun to investigate the possibility of using genetic sequencing to increase the relative precision of some non–genetic-based anticancer therapeutics.
As discussed in What Progress Does the Future Hold? (p. 100), several groups are actively using genomic sequencing to determine which patients are most likely to respond to various types of immunotherapeutics. Others are investigating whether genomics can be used to identify ways to develop more precise anticancer vaccines (29).
The earliest traditional chemotherapeutic was based on nitrogen mustard gas and was found to cause damage to DNA, leading to early death of rapidly dividing cells, such as cancer cells. The success of this and compounds like it led to the development of dozens of traditional chemotherapeutics that function to damage DNA (see Appendix Table 1, p. 122). Although these drugs are relatively imprecise, some groups have been using genomics to identify patients who have cancers that, due to certain genetic mutations, cannot efficiently repair damage to their DNA and stand to benefit the most from DNA-damaging agents (see Ways to Use Radiotherapy and Traditional Chemotherapy More Precisely, p. 62). In this manner, physicians can use genomics to more precisely deliver a class of otherwise relatively imprecise anticancer therapeutics.
Another way to increase the precision of a traditional chemotherapeutic is to link it to an antibody that recognizes and attaches to a specific protein on the surface of a certain type of cancer cell. Because this new therapeutic, called an antibody–drug conjugate, more precisely delivers the traditional chemotherapeutic to the cancer cells compared with conventional systemic infusion of the traditional chemotherapeutic, it is less toxic and causes fewer side effects. There are two FDA-approved anticancer antibody–drug conjugates, ado-trastuzumab emtansine (Kadcyla) and brentuximab vedotin (Adcetris), but many more of this emerging category of anticancer therapeutics are currently being tested in clinical trials.
These are but a few examples of how we are learning to use genomics and other molecularly based tools not only to enhance our knowledge of cancer, but also to increase the precision with which we use our existing tools and therapies.
There are many uses for genomics. Two uses have the potential to convert small successes into benefit for much larger groups of patients (see sidebar on Transforming Lives One Sequence at a Time, p. 29). These are the use of genomics to assign a patient to a therapeutic not previously FDA approved for his or her cancer type, known as drug repositioning, and the use of genomics to determine why a few patients' cancers either responded, known as rare-responders, or failed to respond to a particular therapy.
The AACR Cancer Progress Report 2014 featured one such drug-repositioning story (1). At just 5 years of age, Zach Witt was diagnosed with anaplastic large cell lymphoma (see sidebar on Transforming Lives One Sequence at a Time, p. 29). His team of physicians at Children's Hospital of Philadelphia performed genomic sequencing of his tumor and found that it contained a mutation in a gene called ALK. Because the FDA had already approved the ALK-targeted therapeutic crizotinib (Xalkori) for treating patients with non–small cell lung carcinoma (NSCLC) harboring ALK mutations, Zach's physicians had recently initiated a clinical trial testing crizotinib as a treatment for childhood cancers carrying ALK mutations. Zach's parents enrolled him in the trial, and thanks to crizotinib, he has been cancer free for several years. Successes like this have the potential to benefit the 10 to 15 percent of children whose lymphomas harbor the ALK mutation, if they are borne out in large-scale clinical trials.
One rare responder, Warren Ringrose (see sidebar on Transforming Lives One Sequence at a Time, p. 29), is teaching physicians and researchers about how best to use sorafenib (Nexavar), which targets multiple molecules involved in angiogenesis and related signaling pathways that drive cell multiplication and survival. Warren was diagnosed with olfactory neuroblastoma and enrolled in a clinical trial testing sorafenib as a treatment for head and neck cancers. Warren was among the few individuals on the trial who responded to sorafenib, and he continues to respond nearly two years later. In the not-so-distant past, Warren would have simply been considered “lucky,” an interesting medical anecdote. However, over the past five years, physicians and researchers have been increasingly turning to genomics to determine what makes patients like Warren “lucky.” By using genomics to learn about Warren's success, physicians and researchers want to help make others like Warren the rule rather than the exception.
As discussed above, there are numerous characteristics of a person and his or her cancer that need to be considered when implementing precision medicine (see Figure 2 , p. 24). During the past five years, rapid technological progress has allowed us to analyze a person's microbiome, hormones, genome, and epigenome at wholesale scales, a stark contrast from the past, when each would have been analyzed one at a time.
Coupling these advances with recent improvements in our ability to image the body and its contents more quickly, with higher resolution and increasing speed, we have made significant and rapid progress against cancer. This progress, however, brings its own challenges. We are now generating enormous amounts of data per patient, and this will only “balloon” as these types of analyses scale across more patients to entire populations. Implementation of precision medicine for the treatment of cancer is, therefore, a “big data” problem (see Figure 6 , p. 31).
What are “big data”?
Big data are defined as data sets that are so large and complex that they cannot easily be analyzed using traditional methods. For big data to truly benefit patients, researchers must be able to convert this mass of data into meaningful knowledge. As the use of precision medicine, particularly genomics, moves closer to becoming the standard of care for everyone, the need to understand and manipulate big data will become even greater. Thus, researchers from all areas of the biomedical research enterprise need to work together to prepare for the coming tsunami of data.
In the United States and elsewhere, an experimental therapy must be tested in clinical trials and undergo evaluation by the relevant ruling regulatory body to ensure that it is both safe and effective. During the past five years, the pace of progress against cancer has accelerated dramatically. As the research landscape has changed, the regulatory and clinical trial landscapes have adapted to keep pace.
All Trial, No Error
Several changes relating to clinical trials have occurred during the past five years.
The first of these includes a shift in perception about clinical trials. Once viewed as the “last hope” for a given patient, they are now beginning to be considered as a normal part of cancer care. Although there remains room for improvement in attitudes toward and participation in clinical trials (see Building Blocks to Furthering Precision Medicine, p. 104), this change is helping to deliver novel treatments to the right patients as quickly as possible.
A major change to the conduct of clinical trials, particularly in the past five years, has been the use of genomics and adaptive trial designs to identify the patients most likely to benefit from a given therapy (see Biomedical Research, p. 53). These strategies seek to reduce the number of patients required to enroll in a clinical trial to demonstrate that a given therapy is effective.
These trials largely fall into one of two categories: “basket” studies and “umbrella” studies (see Figure 7 , p. 32). Basket studies are those that test a given therapy on a group of patients who all have the same type of genetic mutation, irrespective of the anatomic site of origin of the cancer, whereas umbrella studies aim to identify the best therapy for different types of genetic mutations all within the same anatomic cancer type.
Whatever these types of studies are called, they are essential for moving precision medicine forward as quickly as possible. The conduct of clinical trials has been revolutionized in a few short years, and undoubtedly we can expect this revolution to continue as precision medicine moves forward at an ever-quickening pace.
As discussed above, the revolution in cancer research can be meaningful for patients only if the regulatory bodies that approve the resultant novel therapies adapt as the research landscape changes. In the United States, the FDA has done just that by developing numerous new strategies to get safe and effective therapies to patients as quickly as possible (see sidebar on FDA's Expedited Review Strategies, p. 60).
In addition to these expedited review strategies, in 2012 the FDA initiated a new path to enhance the pace at which experimental breast cancer therapeutics are approved (Ref. 1 for more details). In 2013, pertuzumab (Perjeta) became the first therapeutic to be approved under this new regulatory path, and the molecularly targeted therapeutic is now benefiting patients with HER-2–positive breast cancer.
These are but a few examples of how the FDA is working to transform patients' lives as safely and quickly as possible.
The past five years have been an amazing period of change in cancer research and medicine, and the examples presented here are surely but a small sampling of what we can expect in the next five years.
PREVENTING CANCER FROM DEVELOPING
IN THIS SECTION YOU WILL LEARN:
MORE THAN HALF OF U.S. CANCER DEATHS ARE A RESULT OF PREVENTABLE CAUSES.
NOT USING TOBACCO IS THE SINGLE BEST WAY A PERSON CAN PREVENT CANCER FROM DEVELOPING.
UP TO ONE-THIRD OF ALL NEW CANCER DIAGNOSES IN THE UNITED STATES ARE RELATED TO BEING OVERWEIGHT OR OBESE, PHYSICAL INACTIVITY, AND/OR POOR DIETARY HABITS.
MANY CASES OF SKIN CANCER COULD BE PREVENTED BY PROTECTING THE SKIN FROM ULTRAVIOLET RADIATION FROM THE SUN AND INDOOR TANNING DEVICES.
INFECTION WITH MANY KNOWN CANCER-CAUSING PATHOGENS CAN BE PREVENTED BY VACCINATION OR MANAGED BY TREATMENT.
DEVELOPING A PERSONALIZED CANCER PREVENTION AND EARLY DETECTION PLAN WITH YOUR HEALTH CARE PRACTITIONERS CAN HELP PREVENT CANCER BEFORE IT STARTS OR INTERCEPT IT EARLY IN ITS DEVELOPMENT, WHEN IT CAN BE MORE EASILY AND SUCCESSFULLY TREATED.
Factors that increase the chance that a cell will acquire a genetic mutation consequently increase the chance that a cell will become cancerous and are referred to as cancer risk factors (see sidebar on Why Me? Why This Cancer?, p. 19). Decades of research have led to the identification of many cancer risk factors (see Figure 8 , p. 34), which, in turn, has taught us that many cases of cancer are preventable (34).
In the United States, many of the greatest reductions in cancer morbidity and mortality have been achieved by translating discoveries of cancer risk factors into effective new public education and policy initiatives. For example, major public education and policy initiatives to combat cigarette smoking have been credited with preventing eight million premature deaths from 1964 to 2014 (35) (see Figure 9 , p. 35), and policy initiatives that minimize exposure to other cancer risk factors, such as asbestos and pollutants, have also played a role.
Policies, whether implemented by schools, workplaces, businesses, or government—local, state, or federal—work by helping to create environments that allow individuals to more easily adopt a lifestyle that promotes cancer prevention. Thus, it is imperative that everyone work together to develop and implement new, more effective public education and policy initiatives to help reduce the burden of cancer further, in particular the burden from those cancers related to preventable causes.
In addition, a great deal more research and more resources are needed to understand why some individuals are refractory to public education and policy initiatives and how best to help these individuals eliminate or reduce their risk of some cancers.
Eliminate Tobacco Use
Tobacco use is responsible for almost 30 percent of cancers diagnosed in the United States each year (34) (see Figure 8 , p. 34). 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 eliminate tobacco use (see sidebar on Reasons to Eliminate Tobacco Use, p. 35).
Since the relationship between tobacco use and 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 (43), the development and implementation of major public education and policy initiatives have more than halved cigarette smoking rates among U.S. adults (36) (see Figure 9 ). As a result of these reductions, an estimated 800,000 deaths from lung cancer were avoided between 1975 and 2000 (36).
Unfortunately, U.S. cigarette smoking rates have begun to plateau in recent years (36), and 831,000 individuals age 12 or older began smoking cigarettes daily in 2013 (44). If we continue on this path, researchers estimate that 5.6 million children currently ages 0 to 17 years will die prematurely of smoking-related illnesses, including cancer (36).
Globally, tobacco use was estimated to be responsible for about six million deaths in 2011, and this number is projected to reach eight million in 2030 if current trends continue (45). Given that there were an estimated 1.6 million lung cancer deaths worldwide in 2012 (6), and that the majority of these deaths are attributable to tobacco use, it is clear that tobacco-related lung cancer is responsible for more than one million deaths around the world each year.
Cigarettes are not the only tobacco products that can cause cancer—smoking cigars, using smokeless tobacco (for example, chewing tobacco and snuff), and smoking tobacco in pipes have all been linked to certain types of cancer (38, 39). Given that in the United States, in 2013, there were an estimated 12.4 million current cigar users age 12 or older, 8.8 million smokeless tobacco users, and 2.3 million pipe tobacco users, in addition to the 55.8 million cigarette smokers (44), it is imperative that researchers, clinicians, advocates, regulators, and policymakers continue to work together to develop new and better approaches to prevent tobacco use initiation and facilitate cessation if we are to eradicate one of the biggest threats to public health.
Electronic cigarettes (e-cigarettes) are frequently marketed as a less harmful alternative to traditional combustible cigarettes and as helpful for those trying to quit cigarette smoking (47). However, e-cigarettes may be harmful if they increase the likelihood that nonsmokers—particularly children—or former smokers will start smoking combustible cigarettes, or if they discourage smokers from quitting. Therefore, more research is needed so that we can fully understand the health consequences of e-cigarette use, their value as tobacco cessation aids, and their effects on the use of combustible tobacco products by smokers and nonsmokers (41) (see sidebar on E-cigarettes: What We Know and What We Need to Know, p. 38). The need for this information is particularly pressing because recent data show that in 2014, e-cigarettes were the most commonly used tobacco product among U.S. middle and high school students, with use of these devices tripling from 2013 to 2014 (48).
Maintain a Healthy Weight, Eat a Healthy Diet, and Stay Active
Researchers estimate that one in every three new cases of cancer diagnosed in the United States is related to being overweight or obese, being inactive, and/or consuming a poor diet (15, 34). Therefore, maintaining a healthy weight, participating in regular physical activity, and eating a balanced diet are effective ways people can lower their risk of developing or dying from cancer (49) (see sidebar on Reduce Your Risk for Cancers Linked to Being Overweight or Obese, Being Inactive, and/or Consuming a Poor Diet, p. 40). In fact, two recent studies that followed 650,000 individuals for more than 10 years showed that healthy lifestyles reduced cancer incidence by 10–15 percent, and cancer mortality by 20–25 percent, in addition to 40–50 percent reductions in cardiovascular-associated mortality and 25–40 percent reductions in all-cause mortality (50, 51).
In addition to the fact that being overweight or obese as an adult has been strongly associated with 10 types of cancer (15, 54-56) (see Figure 10 , p. 41), recent data suggest that increased body weight during childhood and adolescence may increase risk for colorectal cancer later in life (57, 58). Larger studies are needed to confirm this finding and investigate whether early-life excess body weight increases risk of other types of cancer.
Given that being overweight or obese and being inactive have such an immense impact on cancer risk, as well as risk for other diseases, it is extremely concerning that in the United States more than two-thirds of adults are overweight or obese (59), 17 percent of youth are obese (60), and nearly half of all adults do not meet the recommended guidelines for aerobic physical activity (61). Unfortunately, the United States is not alone; the latest estimates show that 20 percent or more of the population age 15 or older of nine other countries designated by the Organization for Economic Cooperation and Development (OECD) is obese (62) (see Figure 11 , p. 42). Moreover, sedentary behaviors, such as prolonged sitting at a computer, may increase risk for certain types of cancer (63), although additional research is needed to more clearly define the contribution of sedentary behavior to risk for cancer.
Thus, concerted efforts by individuals, families, communities, schools, workplaces, institutions, health care professionals, media, industry, government, and multinational bodies are required to develop and implement effective strategies to promote the maintenance of a healthy weight and the participation in regular physical activity. Although such interventions will enhance overall health, more research is required to better understand the effect of weight loss at various stages of life on cancer risk.
In addition to preventing the development of some cancers, maintaining a healthy weight, engaging in regular physical activity, and eating a balanced diet may also improve outcomes for individuals diagnosed with certain types of cancer, in particular breast, colorectal, and prostate cancers; reduce risk of disease recurrence and metastasis; and increase the chance of long-term survival (65-68).
Protect Skin From Ultraviolet Exposure
Most cases of the three main types of skin cancer—basal cell carcinoma, squamous cell carcinoma, and melanoma—are caused by exposure to ultraviolet (UV) radiation from the sun, sunlamps, sunbeds, and tanning booths (69). In fact, it has been estimated that UV exposure causes as many as 90 percent of U.S. cases of melanoma, the most deadly type of skin cancer (69). Although the majority of these cases are caused by UV radiation exposure from the sun, about 8 percent are attributable to indoor tanning (70). Thus, one of the most effective ways a person can reduce his or her risk of skin cancer is by protecting themselves from the sun and not using UV indoor tanning devices (see sidebar on Ways to Protect Your Skin, p. 43).
Despite this knowledge, melanoma incidence rates in the United States have been increasing for at least three decades, and the number of new cases of melanoma diagnosed each year is projected to rise from 65,647 in 2011 to 112,000 in 2030 if current trends continue (71). Fueling the rise is the fact that one in three adults in the United States report experiencing at least one sunburn in the past 12 months, and 5 percent report using an indoor UV tanning device at least once (72, 73). Moreover, 13 percent of all high school students and 31 percent of white high school girls report using an indoor UV tanning device in the past year (74).
Given these continued exposures and that fewer than 15 percent of men and 30 percent of women use sunscreen regularly on their face and other exposed skin when outside for more than one hour (75), it is vital that all sectors of the U.S. population work together to develop and implement more effective policy changes and public education campaigns to reduce exposure to UV radiation. In fact, it is estimated that implementation of a comprehensive skin cancer prevention program could prevent about 21,000 melanoma cases each year from 2020 to 2030 (71). Moreover, with nearly 5 million people a year treated for all forms of skin cancer in the United States at an estimated cost of $8.1 billion (69), these efforts are vital if we are to reduce the personal and the economic burden of skin cancer.
Prevent Infection With Cancer-causing Pathogens
Persistent infection with a number of pathogens—bacteria, viruses, and parasites that cause disease—is responsible for an estimated 16 percent of worldwide cancer cases diagnosed each year (76-78) (see Figure 12 , p. 45, and Table 4 , p. 45). Therefore, individuals can significantly lower their risk for certain types of cancer by protecting themselves from infection with cancer-associated pathogens or by obtaining treatment, if available, to eliminate an infection.
In fact, there are strategies available to eliminate, treat, or prevent infection with the four pathogens that account for more than 90 percent of pathogen-associated cancer cases: Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV) (78) (see sidebar on Preventing or Eliminating Infection With the Four Major Cancer-causing Pathogens, p. 46). Thus, it is clear that these strategies are not being used optimally and that the global burden of cancer could be significantly reduced through more effective implementation of these strategies.
In the United States, the development of strategies to increase uptake of the three FDA-approved HPV vaccines could have an immense impact on cancer prevention (see Cancer Prevention, Detection, Interception, and Diagnosis, p. 58). The most recent estimates from the Centers for Disease Control and Prevention (CDC) show that in 2013, only 6 percent of men and 37 percent of women ages 19 to 26 had received one or more dose of HPV vaccine (79). In addition, in 2012, only 33 percent of girls ages 13 to 17 had received the recommended three doses of HPV vaccine (80). This low coverage stands in stark contrast to that in other high-income countries, such as Australia and the United Kingdom, and Rwanda, a low-income country that recently reported HPV vaccination of more than 90 percent of eligible girls following implementation of a national, multisector, collaborative, school-based program (81, 82).
Moreover, it is estimated that in the United States, more than 50,000 cases of cervical cancer and thousands of cases of other HPV-related cancers, including many anal, genital, and oral cancers, could be prevented if 80 percent of those for whom HPV vaccination is recommended—girls and boys at age 11 or 12—were to be vaccinated (82). In addition, research has shown that vaccinating boys as well as girls has the potential not only to save lives from oropharyngeal cancer, but also to save health care costs (83).
Limit Exposure to Other Risk Factors
There are numerous additional cancer risk factors, including reproductive factors, occupational cancer-causing agents, and environmental pollutants (84) (see Figure 8 , p. 34). Given that it can be difficult for people to avoid or reduce their exposure to many of these factors, it is imperative that policies are put in place to ensure that everyone lives in a safe and healthy environment.
In the United States, some policies that help prevent cancer have been in place for several decades. For example, there are numerous policies to help prevent exposure to asbestos, which can cause mesothelioma, an aggressive type of cancer for which there remain few treatment options (85). For other known environmental cancer risk factors, for example, radon gas released from rocks, soil, and building materials, there are existing guidelines for reducing exposure, but compliance with these guidelines is not mandatory. For others, for example, exposure to occupational cancer-causing agents and environmental pollutants, there is a clear need to develop and implement more effective policies.
One environmental pollutant that was recently classified by the International Agency for Research on Cancer (IARC), an affiliate of the World Health Organization, as “carcinogenic to humans,” alongside agents such as plutonium and cigarettes, is outdoor air pollution (87).
Outdoor air pollution is a complex cancer-risk factor because it is a mixture of pollutants, some of which are currently classified as carcinogenic to humans by IARC, that vary over space and time as a result of differences in climate and sources. However, we know the sources of much outdoor air pollution—emissions from motor vehicles, industrial processes, power generation, and the burning of solid fuels for domestic heating and cooking—and it is clear that new policy efforts to reduce the release of pollutants into the atmosphere are sorely needed if we are to reduce the global burden of cancer.
Screening for Early Detection and Interception
We know that most cancers arise as a result of the accumulation of genetic mutations and that the chance that a cell acquires a genetic mutation is influenced by many different factors (see sidebar on Why Me? Why This Cancer? p. 19). Although people can avoid some of these factors, thereby significantly reducing their risk for cancer, not all factors are avoidable—for example, the acquisition of mutations during cell multiplication (21)—and not everyone avoids factors that can be avoided. This is where we have learned to exploit our knowledge of the causes, timing, sequence, and frequency of the genetic, molecular, and cellular changes that drive cancer initiation and development to implement screening strategies that allow us to intercept these events at the earliest possible stage.
Some screening tests can prevent cancer from developing because they detect precancerous changes in a tissue that can be intercepted and removed before they have the chance to develop into cancer. For example, colonoscopy can detect abnormal growths, or polyps, in the colon and rectum that can be removed before they develop into colorectal cancer. In fact, the CDC estimates that between 2003 and 2007, approximately 33,000 cases of colorectal cancer in the United States were prevented by colorectal cancer screening (88).
Other screening tests can detect cancer at a very early stage of development so that it can be intercepted before it has spread to other parts of the body, which makes it more likely that a patient can be treated successfully.
Screening to detect and intercept cancer before an individual shows signs or symptoms of the disease for which he or she is being screened has many benefits, but it can also result in unintended adverse consequences (see sidebar on Cancer Screening, p. 48). Thus, population-level use of a cancer screening test must not only decrease deaths from the screened cancer, but it must also provide benefits that outweigh the potential risks. Determining whether broad implementation of a screening test can achieve these two goals requires extensive research and careful analysis of the data generated.
In the United States, rigorous data analysis by members of the U.S. Preventive Services Task Force (USPSTF)—an independent group of experts convened by the Public Health Service—has led to evidence-based recommendations for the use of screening tests for four types of cancer among the general U.S. population (see sidebar on USPSTF Cancer-screening Recommendations for Average-risk Adults). These recommendations are re-evaluated as new research becomes available and can be revised if deemed necessary.
The USPSTF and other relevant professional societies' 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. This is because everybody has his or her own unique risks for developing each type of cancer, and the established screening guidelines apply to average-risk individuals. A person's overall risks are determined by genetic, molecular, cellular, and tissue makeup, as well as by lifetime exposures to cancer risk factors (see Figure 8 , p. 34). 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 personal cancer risks. Given that risk for different types of cancer can vary over time—for example, risk for most cancers increases with age—it is important that individuals continually evaluate their personal screening plans and update them if necessary.
A New Era of Precision Prevention and Interception
As we develop and implement new strategies that pair our increased molecular understanding of cancer development with knowledge of an individual's unique cancer risk profile, including genetic makeup at birth, exposures to cancer-risk factors, age, and gender, we will usher in a new era of precision prevention and interception (89) (see Figure 13 ).
Precision prevention and interception are not entirely new concepts. For example, we know that some individuals are at increased risk of certain cancers because they inherited a cancer-predisposing genetic mutation (see Table 5 , p. 51). If a person thinks that that he or she are at high risk for developing an inherited cancer (see sidebar on How Do I Know If I Am at High Risk for Developing an Inherited Cancer?, p. 52), he or she should consult a physician and consider genetic testing, and if the person does indeed carry one of these mutations, risk-reducing measures tailored to his or her precise needs can be taken (see sidebar on Direct-to-Consumer Genetic Testing, p. 52). Some people at high risk might be able to reduce their risk of developing cancer by modifying their behaviors, whereas others might need to increase their participation in screening programs or consider taking a preventive medicine or having risk-reducing surgery (see Table 6 , p. 51 and Appendix Table 2, p. 124).
Despite the progress that has been made in cancer prevention, early detection, and interception, not all cancers are currently preventable and not everyone has access to or takes advantage of current prevention and early detection strategies. Moreover, these strategies are not equally effective for all individuals.
Precision prevention and interception have the potential to address these issues and to significantly reduce the personal and financial burdens of cancer. However, achieving this potential will require input from researchers across the spectrum of biomedical research.
TRANSFORMING LIVES THROUGH PRECISION MEDICINE
IN THIS SECTION YOU WILL LEARN:
FROM AUG. 1, 2014, TO JULY 31, 2015, THE FDA APPROVED NINE NEW THERAPEUTICS FOR TREATING CERTAIN TYPES OF CANCER, ONE NEW CANCER PREVENTION VACCINE, AND ONE NEW CANCER SCREENING TEST.
DURING THE SAME PERIOD, THE FDA AUTHORIZED NEW USES FOR SIX PREVIOUSLY APPROVED ANTICANCER THERAPEUTICS AND ONE IMAGING AGENT.
PAIRING THE INCREASED UNDERSTANDING OF CANCER BIOLOGY WITH INFORMATION ABOUT EACH PATIENT'S OWN CANCER IS INCREASING THE PRECISION WITH WHICH RADIOTHERAPY AND TRADITIONAL CHEMOTHERAPY ARE USED.
CLINICAL TRIALS THAT AIM TO MATCH THE RIGHT THERAPEUTICS WITH THE RIGHT PATIENTS EARLIER ARE BASED ON CANCER GENOMICS RESEARCH, AND ARE BECOMING MORE COMMON.
IDENTIFYING WAYS TO HELP CANCER SURVIVORS MEET THE NUMEROUS CHALLENGES THEY FACE AFTER THEIR INITIAL DIAGNOSIS IS AN AREA OF INTENSIVE RESEARCH.
The dedicated efforts of individuals working throughout the cycle of biomedical research (see Figure 14 , p. 54) have led to extraordinary advances across the continuum of clinical care that are transforming and saving lives in the United States and worldwide.
Biomedical research is an iterative cycle, constantly building on prior knowledge, with one discovery influencing the next (see Figure 14 , p. 54). In recent years, the cycle has become increasing efficient as the pace of discoveries has increased, and various sectors within the biomedical research enterprise have become further integrated, leading to one seamless ecosystem (see sidebar on Biomedical Research: What It Is and Who Performs It, p. 55). As a result of these changes, the pace at which patient lives are transformed through precision medicine has accelerated and will continue to do so for the foreseeable future (see What Progress and Promise Does the Future Hold? p. 100).
In short, the biomedical research cycle is set in motion when discoveries with the potential to affect the practice of medicine are made by researchers in numerous disciplines, including laboratory research, population research, clinical research, and clinical practice. Ultimately, the discoveries lead to questions, or hypotheses, that are tested by researchers performing experiments in a wide range of models that mimic healthy and disease conditions (see sidebar on Research Models, p. 56). The results from these experiments can lead to the identification of a potential therapeutic target or preventive intervention, or they can feed backward in the cycle by providing new discoveries that lead to more hypotheses.
After identification of a potential therapeutic target, it takes several years of hard work before a candidate therapeutic is developed and ready for testing in clinical trials (see sidebar on Therapeutic Development, p. 57). During this time, candidate therapeutics are rigorously tested to identify any potential toxicity and to ensure that they have the maximum chance of success in clinical testing.
Clinical trials are a central part of the biomedical research cycle. Before most potential new diagnostic, preventive, or therapeutic products can be approved by the FDA and used as part of patient care, their safety and efficacy must be rigorously tested through clinical trials (see sidebar on What Is the FDA? p. 58). There are several types of cancer clinical trials, including treatment trials, prevention trials, screening trials, and supportive or palliative care trials, each designed to answer different research questions.
Treatment trials evaluating potential new anticancer therapeutics predominantly add an investigational intervention to the current standard of care. These types of clinical trial have traditionally been done in three successive phases, each with an increasing number of patients (see sidebar on Phases of Clinical Trials, p. 59). Recently, the Tufts Center for the Study of Drug Development estimated that it costs pharmaceutical companies more than $2.5 billion to develop and gain approval for a new therapeutic, a process often lasting longer than a decade (90), although others have noted that not all costs associated with the discovery and development of new therapeutics are borne by industry (91). In the past five years, immense efforts have been made to address these issues by identifying new ways of conducting and regulating clinical trials that can eliminate the need for large, long, multiphase clinical trials (see Special Feature on Five Years of Progress, p. 23, and below).
Briefly, many efforts to streamline the development of new anticancer therapeutics are powered by our increasing knowledge of cancer biology, in particular, cancer genomics. This knowledge has led researchers to focus on the production of therapeutics that precisely target the molecules disrupted as a result of cancer-specific genetic mutations. This, in turn, has led to novel clinical trial designs that aim to match the right therapeutics with the right patients earlier, to reduce the number of patients that need to be enrolled in clinical trials before it is determined whether or not the therapeutic being evaluated is safe and effective, and to decrease the length of time it takes for a new anticancer therapeutic to be tested and made available to patients.
One example of these new clinical trials is the phase II/III Lung Master Protocol (Lung-MAP) trial, which was launched in June 2014 (92). In this trial, patients with advanced squamous cell carcinoma of the lung are screened for more than 200 genetic alterations using DNA sequencing technologies and then assigned to the segment of the trial testing an investigational therapeutic that best suits their genomic profile. A second example is the NCI-MATCH (NCI-Molecular Analysis for Therapy Choice) trial, which opened for patient enrollment in August 2015 (93). Tumors from patients enrolled in NCI-MATCH will be analyzed for more than 4,000 different genetic alterations. Patients whose tumors, regardless of origin, harbor mutations that match any of the anticancer therapeutics being evaluated in the trial will go on to be assessed for other trial eligibility criteria.
This new era of clinical trials offers the promise to accelerate the pace at which new anticancer therapeutics are tested in the clinic and reduce the number of patients that need to be enrolled in clinical trials, both of which may drive down costs. Therefore, the outcomes of these trials are eagerly anticipated by investigators and patient advocates throughout the biomedical research community.
Other major efforts to reduce the time needed for a clinical trial to continue before a clear result is achieved have been spearheaded by the FDA. For example, the FDA has developed four evidence-based strategies to expedite the evaluation of therapeutics for life-threatening diseases such as cancer (see sidebar on FDA's Expedited Review Strategies, p. 60). An increasing number of anticancer therapeutics is being approved by the FDA using the most recently introduced of these review strategies, breakthrough therapy designation. A key part of this review strategy is that the FDA engages with those developing the investigational therapeutic early in the clinical trials process and provides continued guidance throughout the review period.
Progress Across the Clinical Cancer Care Continuum
The dedicated efforts of individuals working throughout the biomedical research cycle power the development of the tools that are used routinely to prevent, detect, diagnose, and treat cancer. The number of tools in the physician's armamentarium increases over time, because research is a continuous endeavor that constantly translates scientific discoveries to new FDA-approved medical products.
In the 12 months leading up to July 31, 2015, the FDA approved one new cancer prevention vaccine, one new cancer screening test, and nine new anticancer therapeutics, including four immunotherapeutics (see Table 1 , p. 10). During this period, the FDA also approved new uses for one imaging agent and six previously approved anticancer therapeutics, including the molecularly targeted chemotherapeutic ibrutinib (Imbruvica).
The January 2015 FDA approval of ibrutinib for Waldenström macroglobulinemia was the first-ever FDA approval of a treatment for this rare and incurable type of non-Hodgkin lymphoma. It followed earlier approvals of ibrutinib for chronic lymphocytic leukemia and mantle cell lymphoma, which were highlighted in the AACR Cancer Progress Report 2014 (1). The approval of ibrutinib for Waldenström macroglobulinemia was based on the results of a clinical trial showing that the agent transformed the lives of many patients (94), like Shelley Lehrman (who was featured in the AACR Cancer Progress Report 2014; see Ref. 1).