AACR Cancer Progress Report 2012

• Frank McCormick, Ph.D., FRS, D.Sc. (hon.)

• AACR President

• Director

• UCSF Helen Diller Family Comprehensive Cancer Center

• San Francisco, CA

• Kenneth C. Anderson, M.D.

• Director, Jerome Lipper Multiple Myeloma Center

• Dana-Farber Cancer Institute

• Boston, MA

• Anna D. Barker, Ph.D.

• Professor and Director, Transformative Healthcare Networks

• Arizona State University

• Tempe, AZ

• Margaret Foti, Ph.D., M.D. (h.c.)

• Chief Executive Officer

• American Association for Cancer Research

• Philadelphia, PA

• Ernest T. Hawk, M.D., M.P.H.

• Vice President and Division Head

• Division of Cancer Prevention and Population Science

• UT MD Anderson Cancer Center

• Houston, TX

• Peter W. Laird, Ph.D.

• Director, University of Southern California Epigenome Center

• Los Angeles, CA

• David Piwnica-Worms, M.D., Ph.D.

• Director, Washington University School of Medicine

• St. Louis, MO

• Lewis C. Cantley, Ph.D.

• Director,

• Beth Israel Deaconess Medical School

• Harvard Medical School

• Boston, MA

• William S. Dalton, M.D., Ph.D.

• President, Chief Executive Officer and Center Director

• H. Lee Moffitt Cancer Center and Research Institute

• Tampa, FL

• Raymond N. DuBois, M.D., Ph.D.

• Provost and Executive Vice President

• UT MD Anderson Cancer Center

• Houston, TX

• Olivera J. Finn, Ph.D.

• Chair and Distinguished Professor, Department of Immunology

• University of Pittsburgh School of Medicine

• Pittsburgh, PA

• P. Andrew Futreal, Ph.D.

• Professor of Genomic Medicine

• UT MD Anderson Cancer Center

• Houston, TX

• Todd R. Golub, M.D.

• Director, Cancer Program

• Broad Institute of the Massachusetts Institute of Technology and Harvard University

• Cambridge, MA

• William N. Hait, M.D., Ph.D.

• Global Head Janssen Research & Development, L.L.C.

• Raritan, NJ

• Guillermina Lozano, Ph.D.

• Chairman and Professor, Department of Genetics

• UT MD Anderson Cancer Center

• Houston, TX

• John M. Maris, M.D.

• Chief, Division of Oncology

• Children's Hospital of Philadelphia

• Philadelphia, PA

• William G. Nelson, M.D., Ph.D.

• Director

• Johns Hopkins Kimmel Comprehensive Cancer Center

• Baltimore, MD

• Charles L. Sawyers, M.D.

• Chair, Human Oncology and Pathogenesis Program

• Memorial Sloan-Kettering Cancer Center

• New York, NY

• Stuart L. Schreiber, Ph.D.

• Director, Department of Chemical Biology

• Broad Institute of the Massachusetts Institute of Technology and Harvard University

• Cambridge, MA

• Margaret R. Spitz, M.D.

• Professor, Department of Epidemiology

• Baylor College of Medicine

• Houston, TX

• Patricia S. Steeg, Ph.D.

• Chief, The Women's Cancer Section

• Laboratory of Molecular Pharmacology

• National Cancer Institute

• Bethesda, MD

• Mauro Ferrari, Ph.D.

• President and CEO

• Ernest Cockrell, Jr. Distinguished Endowed Chair

• The Methodist Hospital Research Institute

• Houston, TX

• Ahmedin Jamal, D.V.M., Ph.D.

• Vice President, Surveillance Research

• American Cancer Society

• Atlanta, GA

• Bruce S. Kristal, Ph.D.

• Associate Professor

• Department of Neurosurgery

• Brigham & Women's Hospital

• Boston, MA

• Joyce A. O'Shaughnessy, M.D.

• Co-Chair, Breast Cancer Research

• Baylor University Medical Center

• Charles A. Sammons Cancer Center

• Dallas, TX

• Sudhir Srivastava, Ph.D., MPH

• Chief, Cancer Biomarkers Research Group

• Division of Cancer Prevention

• National Cancer Institute

• Rockville, MD

• Francesco Versace, Ph.D.

• Assistant Professor

• The University of Texas MD Anderson Cancer Center

• Houston, TX

• Shawn M. Sweeney, Ph.D.

• Project Leader

• Senior Program Administrator

• Philadelphia, PA

• Karen Honey, Ph.D.

• Science Writer

• Senior Managing Editor, Science Communications

• Philadelphia, PA

• Pamela Bradley, Ph.D.

• Director, Science Policy

• Washington, DC

• Paul Driscoll

• Director, Marketing and Creative Services

• Philadelphia, PA

• Jon Retzlaff, M.B.A., M.P.A.

• Managing Director, Science Policy and Government Affairs

• Washington, DC

• Mary Lee Watts, M.P.H., R.D.

• Director, Government Relations

• Washington, DC

• Mark Fleury, Ph.D.

• Associate Director, Science Policy

• Washington, DC

• James Ingram

• Manager, Legislative Affairs

• Washington, DC

• Nicolle Rager Fuller

• Illustrator

• Sayo-Art, LLC

• Bellingham, WA

At the opening of its Annual Meeting on April 1, 2012, in Chicago, Illinois, leaders from the American Association for Cancer Research (AACR) declared that the ability of cancer researchers to bring the promise of science to improve the outcomes for cancer patients is in peril due to a decade of declining budgets at the National Institutes of Health (NIH) and the National Cancer Institute (NCI). The AACR Board of Directors also announced that it would redouble its efforts to engage with Congress to make cancer research and biomedical science funding a national priority, raise public awareness of the importance of continued investment in cancer research and biomedical science, and call on its 34,000 members and the broader advocacy community constituencies to join together to better explain the value of research to saving lives and to the economic health and well-being of our Nation.

The AACR Cancer Progress Report 2012 is one of the major steps toward achieving the goals outlined five months ago by the AACR Board. In addition to detailing how scientific discoveries are transforming the prevention, detection, diagnosis and treatment of cancer and ushering in a new era of personalized medicine where cancer patients are treated based on the molecular profile of their cancer, this Report is a Call to Action for the general public and for policymakers to intensify their efforts to support research. The AACR is deeply grateful to the cancer survivors and their loved ones who selflessly shared in this Report their personal experiences to further our efforts to communicate the importance of research to each and every individual facing cancer.

For the past decade the NIH budget has remained essentially flat, and when factoring in the rate of biomedical inflation, the agency has effectively lost more than $6 billion or nearly 20% of its ability to support life-saving research. And as a result of a budget mechanism, called sequestration, which was created by the U.S. Congress in the Budget Control Act of 2011 to force the government to address the federal deficit, on January 2, 2013, funding for every federal program, including the NCI and its parent agency, the NIH, may be forced to absorb another budget cut of 8%.

If these cuts are put in place, it will destroy the cancer research and biomedical science enterprise, which is already confronting a situation where the opportunities for researchers to be awarded an NIH grant to uncover new scientific knowledge and make further substantial inroads against cancer have reached an all-time low. In testimony before Congress, NIH Director Francis Collins, M.D., Ph.D., described sequestration's impact on NIH as potentially “devastating,” and explained that NIH would be forced to fund 2,300 fewer grants than planned in fiscal year 2013. This scenario would be disastrous for our most precious national resource, the young investigators who are just beginning their professional careers in research with an eye toward making a difference. We are relying on these young investigators to continue to nourish the pipeline of new discoveries that will have an even greater impact on the welfare of patients and on public health as a whole.

As detailed throughout the Report, these funding constraints are coming at a time when the number of opportunities for exploiting our growing scientific knowledge against cancer has never been greater. The myriad advances in cancer research and biomedical science bring a sense of hope to all who face cancer or who love someone facing cancer, as poignantly illustrated by the personal stories shared in this Report. Clearly, as we observe the increasing incidence and mortality due to cancer not only in the U.S., but also around the world, we believe that our great Nation has a responsibility to step up to the plate and make a commitment to eradicating this devastating disease at the earliest possible time.

Sequestration can be prevented if Congress enacts legislation this year that provides alternative means to reduce the federal government's budget deficit. Therefore, we are urging all AACR members and the broader advocacy community to contact their representatives and senators in Congress to urge them to work in a constructive, bipartisan fashion to find a more balanced approach to address the federal deficit and prevent sequestration from occurring. We cannot compromise our ability to transform cancer care for the benefit of current and future cancer patients, for by doing so we risk losing the momentum we have already achieved in cancer science and medicine.

With the availability of new technological tools, cancer researchers are now able to find new and efficient ways to decipher the complexities of cancer. As a result, breakthroughs against human cancer are being discovered at an ever-increasing pace. Cancer survivors are coming together to speak with one voice about the urgency of finding new cures for patients today and for future generations. And Members of Congress have no other option but to recognize that they have the responsibility to invest in the health of our citizens.

By all of us working together – scientists, survivors and patient advocates, citizen activists, and legislators – we will accelerate further progress and we will defeat cancer.

• Frank McCormick, Ph.D., FRS, D.Sc. (hon.)

• AACR President

• Kenneth C. Anderson, M.D.

• Member, AACR Science Policy and Legislative Affairs Committee

• Anna D. Barker, Ph.D.

• Member, AACR Science Policy and Legislative Affairs Committee

• Margaret Foti, Ph.D., M.D. (h.c.)

• Chief Executive Officer

• Ernest T. Hawk, M.D., M.P.H.

• Member, AACR

• Peter W. Laird, Ph.D.

• Member, AACR

• David Piwnica-Worms, M.D., Ph.D.

• Member, AACR

No one who faces a diagnosis of cancer is ever fully prepared for the challenges that confront them and their loved ones. Hearing the words “you've got cancer” changes life, forever. Cancer remains in the forefront of our minds whether we are currently in treatment, living well beyond its diagnosis or coping with the loss of a loved one.

Cancer can strike anyone—no age, gender, race, ethnicity, socioeconomic status or political affiliation makes you immune. In fact, in the United States, one out of every three women and one out of every two men will receive a cancer diagnosis in their lifetimes.

As cancer survivors and advocates, we, like millions of others, battle this terrifying disease on a personal level through our own individual experiences. But it is also critical that everyone touched by cancer come together to advocate on a national level for the needs of those currently facing cancer and those who will face it in the future. Our drive to make a difference is why we wanted to be part of the AACR Cancer Progress Report 2012, to share our personal stories and put a face on the difference that cancer research has made and still needs to make.

To be honest, for many of us before we received a diagnosis of cancer, the National Cancer Institute (NCI) and its parent agency, the National Institutes of Health (NIH), were either unknown or seen as agencies that supported abstract research that was not terribly connected to our daily lives. Now, we understand and appreciate that, far from being abstract, these agencies serve a critical and irreplaceable role in stimulating scientific breakthroughs, which are the foundations for the medical treatments we all rely on today and which hold the promise for new cures and prolonged quality of life. Advances accrued over the past decades of cancer research supported by these agencies have fundamentally changed the conversations that Americans are having today about cancer.

From across the diversity of our cancer diagnoses, we are united in our belief that our greatest source of hope for healthier and longer lives for current cancer survivors and future generations is grounded in scientific discovery.

Sadly, despite the remarkable progress that has been made against cancer over the past four decades, a grim reality remains. Too many Americans are losing their battle with this disease that we now know is a collection of more than 200 different types of cancer. More than 1.64 million Americans will be diagnosed in 2012, and more than 570,000 will succumb to this disease. No matter which form of cancer has stricken us, we all know too well the horrific toll of a cancer diagnosis, the fear of what tomorrow might bring, and the pain and confusion that can follow is indescribable.

With a burden so high, it is unbelievable to us that support for cancer research and biomedical science seems to be waning. The budgets of the NCI and the NIH have been falling over the past decade and are down in functional dollars by about 20%. We fear that the once determined resolve of our Nation to find a cure for cancer has eroded alongside these deteriorating budgets. We are extremely concerned that our nation's policymakers will not act to avert sequestration, which would make deep cuts to these programs, causing profound and catastrophic harm to the future of biomedical research in this country. These potential cuts threaten to compromise the progress we have made and destroy the hope for every one of us whose future depends on the breakthrough scientific discoveries that could lead to new and more effective treatments.

Our message is simple but earnest. Congress, help us continue the momentum necessary to combat the cancer epidemic, and make funding for cancer research and biomedical science a priority. There is no time to waste when, in the U.S. alone, we are losing one person every minute of every day to this devastating disease.

Signed:

Monica Barlow

Kathryn Becker

Congressman M. Robert Carr

S. Ward “Trip” Casscells, M.D.

Shaundra L. Hall

Wendy and Gavin Lindberg, Parents of Evan Lindberg

Amy Mulford, Mother of Brooke Mulford

Melanie A. Nix

Lori Redmer

Antoni Smith

Jill Ward

Cancer research saves lives, fueling the development of new and better ways to prevent, detect, diagnose and treat cancer in all age groups. The AACR Cancer Progress Report 2012 celebrates the many ways that we have made research count for cancer patients, highlighting important advances seen in the past year. Decades of prior research have provided the foundation for the progress that is helping to usher in a new day for patients with many forms of cancer. Indeed, scientific progress has spurred improvements in health care that have significantly reduced the burden of cancer and transformed the lives of a growing number of the 13.7 million cancer survivors in the U.S. and their families and other loved ones. These advances would not have been possible without the long-standing, bipartisan commitment of our Nation's policymakers to invest in research through the National Institutes of Health (NIH) and National Cancer Institute (NCI), the foundation of our Nation's biomedical research enterprise.

An estimated 577,000 Americans will die from cancer in 2012, despite these remarkable advances. Moreover, because cancer is predominantly a disease of aging, we face a future where the number of cancer deaths will increase dramatically. In fact, as an increasing proportion of the population is over the age of 65, cancer is predicted to soon become the number one killer of Americans, a trend that will also occur globally. Cancer is already the most costly disease to the Nation, and without major new research advances to facilitate the successful development of new preventive interventions and treatments, these trends will magnify the already huge economic burden that cancer manifests.

The dedicated work of thousands of cancer and biomedical researchers the world over has uncovered much about the complexities of cancer—we now know that cancer is, in fact, not a single disease, but 200 different diseases. This diversity exists at every level, from populations to the very genetic and molecular abnormalities that drive a patient's cancer. Although the complex, diverse nature of cancer is daunting, we have discovered that some common biological processes are involved in cancer. We have learned that changes in an individual's genes alter specific components of the molecular machinery of a cell to drive cancer initiation, development and spread (metastasis), and that therapies specifically targeting these defects are often beneficial to the patients while having less toxicity than older therapies.

With this new knowledge, we have never been better positioned to capitalize on our hard-won understanding of cancer—what causes it, what drives it—and there is enormous optimism that we can achieve our ultimate goal of defeating cancer. Unfortunately, continued progress in life-saving cancer research is in jeopardy, as investments in the NIH and NCI have been steadily declining since 2003. We are now facing the acute consequences of automatic budget-cutting sequestration, which will begin on Jan. 2, 2013, if Congress fails to find a more balanced approach to address the federal deficit.

This second AACR Cancer Progress Report to Congress and the American public seeks to again serve as a comprehensive educational tool that illustrates the astounding return on investment in cancer research and biomedical science supported by the NIH and NCI, while also specifically capturing the major advances that occurred in just the past year. Scientific momentum has brought the arrival of a new era in which we will be able to develop even more effective interventions and save more lives from cancer, but to do so will require an unwavering commitment on the part of Congress and the Administration to invest in our country's remarkably productive biomedical research enterprise led by the NIH and NCI.

One of the key areas of progress and promise is cancer prevention. As a direct result of our scientific understanding of the timing, sequence and frequency of the pivotal changes underlying cancer development and spread throughout the body, we now know there are points of intervention that can be exploited in order to stop certain cancers in their tracts, before they do irreversible damage that results in death. In fact, advances in cancer prevention and early detection have resulted in some of the greatest reductions in cancer mortality in recent decades. Implementing public health measures to reduce exposure to cancer-causing agents, intervening medically to treat or prevent infectious causes of cancer and introducing population-based screening practices have contributed to this progress.

Unfortunately, it is estimated that about two out of every three cancer deaths in the U.S. in 2012 will be due to preventable causes—most notably tobacco use, obesity, physical inactivity and failure to use or comply with interventions that treat or prevent infectious causes of cancer. These facts underscore the need for continued research to inform effective public educational campaigns and programs that can encourage and help people change their behaviors.

Population-based screening programs have been credited with dramatically increasing the five-year survival rates for the cancers that they detect because finding a tumor early makes it more likely that it can be treated successfully and with fewer side effects. There is concern, however, that this heightened surveillance can lead to overdiagnosis and overtreatment, potentially causing more harm than good. More research to address these problems is vital to ensure that the public has confidence in current screening guidelines and in any future recommendations that may be made. In addition, we need to develop screening strategies for those cancers that we cannot detect early, in particular, those that currently elude detection until they are at an advanced stage.

Decades of research have provided an understanding of the fundamental nature of cancer, and why and how cancer develops and spreads throughout the body. These major discoveries about the biology of cancer are beginning to be translated into new breakthrough therapies that are being used alongside the traditional triad of cancer patient care—surgery, radiotherapy and chemotherapy—to transform the treatment of patients with certain forms of cancer. In the past 12 months alone (September 2011 through the end of August 2012), the Food and Drug Administration (FDA) U.S. approved eight new drugs for the treatment of cancer, one new drug for the treatment of precancerous lesions, as well as new uses for three previously approved drugs, increasing the number of patients benefiting from these therapies. There are also numerous ongoing clinical trials testing other agents, several of which are showing promise for near-term clinical advances.

The majority of the cancer therapies approved by the FDA in the past 12 months are more effective and less toxic than older treatments that have been the mainstay of patient care. As a result, these new therapies are not only saving the lives of countless cancer patients, but are also improving their quality of life. Rapid advances in this area are likely in the near future, as we learn more about patient characteristics that predict their response to a certain therapy. Patients identified as likely to respond will receive treatment, while those determined to be very unlikely to respond will be spared any adverse side effects from the course of therapy. Moreover, definitive stratification of patient populations can also provide healthcare savings by avoiding the futile use of ineffective courses of cancer treatments and the treatment costs associated with their adverse effects.

Unfortunately, progress has not been uniform for all forms of cancer, and this highlights the great need for continued cancer research. Large-scale analyses of the genetic underpinnings of cancer are now guiding the development of new cancer drugs and are directing the repurposing of proven therapies to treat novel cancer types. Further innovation is needed, however, if genetic/genomic analysis is to become part of standard practice, and if most cancer treatment and prevention strategies are to be based on both a person's genetic makeup and the genetic makeup of their specific cancer.

While the altered genomes of cancer cells can have a profound effect on the development and spread of cancer, factors at all levels—from molecules to cells to humans—are involved. Understanding all of these influences will help to determine which can be exploited to most significantly impact patient care. In addition, it is vital that we learn not only how these factors work in isolation, but also how they affect each other. While progress is beginning to be made in several areas, it will take a concerted effort from all in the cancer research community to deliver future breakthroughs.

Congressional support for the NIH and NCI has enabled extraordinary progress against cancer, and in doing so has saved countless lives while catalyzing the development of the biotechnology industry and economic growth in America. The research-fueled explosion of both knowledge and technological innovation, as well as our ever-increasing understanding of how to apply this new information, has provided new ways to reduce the global burden of cancer. However, there are many challenges to overcome if we are to realize our goal of defeating cancer.

If we are to make a quantum leap in our progress against all cancers, we must continue to pursue a comprehensive understanding of cancer. With new tools, new analytics, new ways of thinking and new ways of working together, we will gather speed in furthering our knowledge base and develop new approaches to cancer prevention, detection, diagnosis and treatment.

We live in a time of unprecedented scientific opportunities, afforded to us by past investments in cancer research and biomedical science. Researchers and their partners in the cancer research community possess the steadfast resolve to seize the day and forge ahead to the finish line—to the day when cancer is removed a major threat to our Nation's citizens and to future generations. Realizing this bright future requires that Congress and the general public stand firm in their commitment to the conquest of cancer. At a time when budgets are constrained and there is the looming threat of sequestration, scarce federal dollars must be invested wisely. Funding cancer research and biomedical science through the NIH and NCI is a wise choice for our Nation's future.

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

• Work in a constructive, bipartisan fashion to find a more balanced approach to address the federal deficit and prevent sequestration from occurring on Jan. 2, 2013; and

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

While it is imperative that Congress take action to stop the threatened sequestration and once again make NIH and NCI funding a national priority, the responsibility is not theirs alone. The AACR also urges the citizens of this great Nation, who benefit from this life-saving research, to urge their legislators to support cancer research and biomedical science.

In short, if we are to ultimately transform scientific discoveries into therapies that improve the lives of cancer patients, an unwavering commitment on the part of Congress and the Administration to invest in our country's biomedical research enterprise is urgently needed.

It is a new day for cancer research and for cancer patients. Rapidly evolving technology is enabling extraordinary advances in cancer research that deepen our understanding of how cancer develops, grows and threatens the lives of millions. By exploiting this growing body of knowledge about cancer biology, we can be more strategic and innovative than ever before in the way we attack cancer. This is quickening the pace of developing new ways to prevent, detect, diagnose and treat cancer.

The AACR Cancer Progress Report 2012 celebrates the many ways that we have made research count for cancer patients, particularly in the past year alone. Decades of research, in large part thanks to our Nation's long-standing investment in cancer research and biomedical science by the National Institutes of Health (NIH) and the National Cancer Institute (NCI), have provided the foundation for the progress that is helping usher in this new day for patients with many forms of cancer.

Highlighted in this Report are treatment advances approved by the U.S. Food and Drug Administration (FDA) in the past 12 months alone:

• A new drug for treating precancerous lesions of the skin

• Eight new drugs for treating a variety of types of cancer, of which two are entirely new classes of drugs

• Four new uses for previously approved cancer drugs, one of the four uses being an alternative administration to reduce side effects

There are many cancer therapeutics showing tremendous potential in clinical trials. Some of these are currently being reviewed by the FDA and could provide widespread patient benefit in the near term; others require further study in larger populations before they can be considered by the FDA. Several promising cancer treatments are discussed herein, but this Report should not be considered an exhaustive summary of potential areas of future progress.

The Report also presents new discoveries that are forming the foundation of tomorrow's progress. Scientists at institutions in every state across the Nation continue to report a myriad of basic science breakthroughs that are revealing novel insights that may well offer the key to the next major advances.

Unfortunately, continued progress against cancer is in jeopardy due to the current crisis in funding for cancer research and biomedical science at the federal level. Without action to avert further cuts, our Nation's ability to seize today's scientific momentum and capitalize on prior investments in cancer research, spur innovation, and most importantly, save lives is at risk. Because of a decade of essentially flat budgets, compounded further by biomedical inflation, the NIH and NCI have effectively lost $6 billion or nearly 20% of its ability to support life-saving research. Sequestration, with its automatic budget cuts, threatens to set these agencies back to budget levels last seen in 2004.

As a reminder of why it is so critical for the Nation to prioritize cancer research and biomedical science, the 2012 Report describes the exciting research progress and scientific opportunities ahead. Also, to put a face on the realities of cancer, we have chronicled the experiences and the sentiments of eleven cancer survivors, and as well as a mother and father who suffered unimaginable grief when their seven-year-old child died of neuroblastoma.

The number of cancer survivors in the United States (U.S.) continues to increase year after year, from 3 million in 1971, the year the U.S. Congress passed the National Cancer Act, to approximately 13.7 million in 2012 (1, 2). This success is the result of several factors – the investments in research by the federal government as well as philanthropic individuals and the private sector, and behavioral changes. The decades of investments in basic and clinical cancer research and biomedical science, in particular the investments supported by public funds through the National Institutes of Health (NIH) and the National Cancer Institute (NCI), have spurred the development of new and better ways to prevent, detect, diagnose and treat cancer in all age groups, leading to decreases in incidence; cures for some patients with certain types of cancer; and higher quality, longer lives for many of those individuals whose cancers cannot yet be prevented or cured.

Now, more than any other time in our history, cancer researchers are maximizing the impact of the fundamental discoveries made during the past four-plus decades and are translating them into improved patient care. In the past 12 months alone (September 2011 through August 2012), the Food and Drug Administration (FDA) approved one new drug for treating precancerous lesions, eight new drugs for treating cancers and four new uses for previously approved drugs (see Table 1).

However, the vast complexity of cancer, which is in fact not one disease but more than 200 different diseases, has meant that advances have not been uniform for all forms of cancer (see Table 2 p. 15). The good news is that the five-year survival rate for all cancers is now about 65%. Significant progress has been made against some cancers, such as breast cancer. The five-year survival rate for female breast cancer patients is now 90% compared with 63% in the early 1960s (3). Another example is childhood acute lymphocytic leukemia, where the five-year survival rate is now greater than 90% versus 58% in the mid-1970s (3). In contrast, the five-year survival rates for other cancers, such as pancreatic, liver and lung cancers, remain very low at 6%, 14% and 16%, respectively (3). Moreover, the burden of cancer is not distributed evenly across the population, due to numerous interrelated factors (see Sidebar on Cancer Health Disparities in America, p. 16). These differences in survival rates underscore the great need for continued research in discovery, translation and dissemination science.

Despite significant improvements in survival from many cancers, it is estimated that more than 577,000 Americans will die from cancer in 2012. Cancer will account for nearly one of every four deaths, making it the second most common cause of death in the U.S. If current trends continue, it will not be long before cancer is the leading cause of death for Americans. It is therefore urgent that our Nation continues to invest in the scientific research necessary to develop effective preventive interventions and treatments.

More than 1.6 million Americans will be diagnosed with cancer in 2012 (3), and it is estimated that more than 41% of individuals born today will be diagnosed with cancer at some point during their lifetimes, which is nearly one out of every two Americans (4). The number of cancer diagnoses is likely to increase dramatically in the next few decades because cancer is predominantly a disease of aging. The majority of all cancer diagnoses are among those aged 65 years and older (4, 5), a rapidly expanding segment of the population (6, 7); see Fig. 1, p. 18). Compounding the problem is the growing prevalence of obesity and the declining, but still significant, use of tobacco, which are linked to an increased risk for several cancers (8). The combination of these trends will magnify the already huge economic burden of cancer.

The latest estimates from the NIH indicate that the overall economic cost of cancer in the U.S. in 2007 was $226.8 billion (3), making cancer the most costly disease to the Nation. Unless more successful preventive interventions, early detection tools and treatments can be developed, this cost will rise dramatically during the next two decades.

Cancer prevention, in particular, is an area of great promise because research has shown that about two out of every three cancer deaths in the U.S. are due to preventable causes (3). Almost one third are caused by tobacco use; about one third are related to patients being overweight or obese, physically inactive and consuming a diet poor in nutritional value; some are caused by infectious agents for which we have vaccines; and many of the deaths from melanoma are a result of prior excessive sun exposure or use of indoor tanning facilities. Developing evidence-based approaches to cancer prevention, including research related to tobacco cessation, remains an area of active investigation.

The number of newly diagnosed cases of cancer is rising not just in the U.S., but throughout the world, with global numbers predicted to rise from 12.7 million new cases in 2008 to 22.2 million by 2030 (9). Without major new advances in cancer research to facilitate the successful development of effective preventive interventions and treatments, this will translate into more than 13 million lives claimed by cancer in 2030 (10). Moreover, of all causes of death worldwide, cancer has the greatest economic impact from premature death and disability. This global economic toll is 20% higher than that from any other major disease, at $895 billion in 2008 (11), not including the direct costs of treating cancer. Collaborations between U.S. cancer researchers and the international cancer research community are essential to sharing knowledge and leveraging resources to hasten the reduction in cancer burden and improvement of global health.

At this point in time, continued progress in life-saving cancer research is in jeopardy. NIH and NCI budgets have been declining since 2003, and many promising scientific projects are not being funded. This report captures many of the remarkable recent advances that are the direct result of the dedicated work of thousands of researchers who are now poised to exploit the current scientific momentum to save more lives from cancer. This will only be achieved if Congress provides the required support for cancer research.

Research is our best defense against cancer. The Nation's investments in cancer research and biomedical science during the past four-plus decades have produced remarkable progress in our understanding of the events which initiate a number of cancers at the molecular, cellular and tissue levels. Advances in cancer research are now transforming patient care. We would not be on our current path to revolutionizing cancer care if not for the extraordinary endeavors of individuals working in numerous research disciplines and technologies.

Today, we know that because cancer is extremely heterogeneous, it is in fact not a single disease, but likely consists of over 200 diseases. Further, we are beginning to understand that due to this heterogeneity, nearly all cancers are comprised of a number of different cancer subtypes, meaning that every person's cancer is unique in its composition. Despite the apparent complexity that this diversity brings, decades of research have established that there are a number of basic biological principles that underpin cancer initiation, growth and spread to other sites in the body.

One of the most fundamental traits of cancer cells is their ability to multiply uncontrollably. Normal cells only proliferate when the balance of numerous factors instructs them to do so, by progressing through a process called the cell cycle (see Fig. 2 p. 20). Various inputs determine whether or not a cell will enter this cycle; these include the balance of growth-stimulating and growth-suppressing factors; the energy state of the cell, including nutrient and oxygen levels; and the status of the environment that surrounds the cell, called the microenvironment. This biological system is dysfunctional in cancer cells.

A second characteristic central to cancer cells is their ability to invade and destroy normal tissue surrounding them and to move to and grow in other areas of the body, called metastasis. Metastasis is the most lethal attribute of cancer cells. It is responsible for more than 90% of the morbidity and mortality associated with cancer (see Sidebar on Metastasis). Local invasion and metastasis are complex processes, fueled by changes in the cancer cells and in their interactions with their environments.

The development of cancer is largely due to the accumulation of genetic changes that lead to malfunctions in the molecular machinery of cells, permitting them to survive when normal cells would die and to multiply uncontrollably and metastasize. In addition, interactions between cancer cells and their microenvironment profoundly affect these same processes. Cancer-influencing factors that comprise the tumor microenvironment include the matrix of proteins outside the cancer cell that support the structure and function of the tissue in which the cancer is growing; the creation of new blood and lymphatic vessels; hormones; nutrients; and the immune system (see Fig. 2 p. 20).

Insight into the importance of inflammation, established by certain cells of the immune system, in promoting cancer progression has increased dramatically in the past few years. Persistent inflammation—for example, that driven by infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), or by continual exposure to toxins like alcohol or asbestos—has been known for some time to create an environment that fosters cancer cell survival, proliferation, local invasion and metastasis. More recently, it has become apparent that chronic inflammation in an organ or a region of the body enables cells in that area to acquire the characteristics needed for cancer formation.

In addition to better understanding the concept of tumor-promoting inflammation, the last several decades of research have also established the importance of the components of the immune system that participate in antitumor defense. That knowledge has stimulated developments of drugs designed to boost patients' antitumor immunity.

Although we have learned a great deal about the unifying principles that underpin cancer, translating this knowledge into cures remains challenging because of the diversity of cancer types. Currently, many areas of research are rapidly evolving, in part as a result of technological advancements that are increasing our ability to probe the genetic and molecular defects that drive cancer. With continued federal investments, these endeavors will yield new discoveries that improve the ways we prevent, detect, diagnose and treat cancer.

If cancer research is to be truly successful, it must be an iterative cycle, with observations flowing from the bench to the bedside and back again (see Fig. 3). The participation of patients and their health care providers is essential to this cycle because observations made in clinical trials also help define areas for future study, including the identification of new drug targets and the refinement of treatment. Finally, cancer research does not operate in isolation from other fields of research. Insights into the biology of cancer and the identification of ways to prevent, detect, diagnose and treat its many forms offer new ideas for the conquest of other diseases.

The concept of taking an observation, making a discovery, turning it into a tangible tool, drug or agent to be studied in the clinic, testing the discovery in the clinic and ending up with a viable approach for cancer prevention, detection, diagnosis or treatment is sometimes called target-based discovery. It is not the only strategy for developing new ways to reduce the tremendous burden of cancer, but increasingly the advances reaching the clinic are the result of target-based discovery programs (see Making Research Count for Patients, p. 46). The following focuses on some of the more frequently used ways in which those involved in basic and clinical cancer research take an idea all the way to the patient.

 In the laboratory, researchers study patient samples as well as cells and animals that mimic what happens in healthy and cancerous conditions.

A wide variety of cell types are used in cancer research. Some cells can be grown continuously in the lab in such a way that each is genetically identical, and these are called cell lines. Others are primary cells, which are genetically diverse because they are obtained directly from tissues. The tissues can be healthy or cancerous and isolated from a human or animal. Cells can be studied in dishes in the laboratory or after having been transferred into animals.

Mice constitute the most commonly utilized animal models in all areas of cancer research. Zebrafish have recently emerged as a useful model for melanoma, the most deadly form of skin cancer, and for leukemias. Other animals are also used, but largely for specific cancer types. For example, because some dog breeds naturally develop certain cancers, they are good models for studying the equivalent human diseases.

 The study and manipulation of these models—for example, exposing them to a potential new drug—can help identify useful approaches for cancer prevention, detection, diagnosis or treatment that can then be tested in the clinic. Various techniques are used to probe cancer models, including but not limited to: genetic, biochemical and cellular analyses.

The genetic code carries a blueprint that is deciphered by the cell to produce the various proteins that it uses to function (see Fig. 4, p. 22). Some genetic alterations result in the generation of abnormal proteins that can fuel the development of cancer. Alternatively, they may lead to the loss of other critical proteins that usually maintain normal cellular functions (see Sidebar on the Genetic Basis of Cancer). Tremendous technological advances in recent years have made it possible to rapidly sequence the entire genome of a cancer to reveal which genetic alterations are present. Furthermore, these technologies can also detect changes in the cancer's epigenome, which is how the DNA is modified and packaged into chromosomes.

Whether or not the observed genetic and epigenetic changes contribute to cancer can be examined further by engineering cells or animals to express the modification and by observing the resultant changes in cell or animal behaviors. Previously, researchers studied individual pieces of DNA, proteins and cell metabolites as they pertain to cell function. Now, as a result of innovative large-scale approaches, researchers can study the entire set of DNA, proteins and metabolites in a sample. These new approaches complement more traditional biochemical methods to rapidly enhance our understanding of the structure and function of cancer-associated proteins and their effects on cell behavior.

Laboratory studies enable researchers to identify changes in genes and proteins linked to cancer. Converting these discoveries into a tool, drug or agent to be tested in the clinic can take many different forms. Some of these validated discoveries identify biological indicators, or biomarkers, which may be clinically useful (see Fig. 5, p. 25), while others can be developed into a potential drug (see Fig. 6).

 Before a tool, drug or agent developed through many years of work in the laboratory can be used routinely in patient care, it must be rigorously tested in clinical trials, which provide each patient with the best care available. This step from the bench to the bedside involves a vast array of approaches. The discussion here only highlights some examples of how this step toward reducing the burden of cancer is implemented.

In the case of a potential therapeutic for cancer treatment, clinical trials with increasing numbers of patients are undertaken to determine the safety and effectiveness of the potential therapy (see Fig. 7, p. 25). Individuals participating in clinical trials are monitored extremely closely. For example, levels of known cancer markers in the urine or blood can be regularly checked to provide information as to whether or not the drug is effective. Currently, however, the predominant criteria used to determine whether a new drug for cancer treatment benefits patients are: Does it stop tumor growth or reduce its size? Does it increase the length of time to renewed growth or spread, as assessed by tumor imaging? And does it increase patient survival time?

In many clinical trials, tumor imaging is done using computed tomography (CT) scanning, but other technologies can be used, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using a radiolabeled tracer called ¹⁸fluorodeoxyglucose (FDG; see Fig. 8, p. 26). As progress is made in enhancing imaging capabilities, these scans can be incorporated into clinical trials. It is hoped that as advances are made, they can be used to shorten the process of drug development, with significant reductions in tumor burden visible by imaging techniques being used as a measure of drug effectiveness. This is a very active area of cancer research, with multiple other approaches being actively assessed for their utility in the same context.

 It is vital that what happens at the bedside is not the end of the cancer research trail. Even if clinical studies indicate that the agent, drug or tool can help reduce the burden of cancer and it is adopted into routine clinical practice, continued monitoring of its safety and benefits provides important information for improved use and further innovation (see Fig. 3, p. 21 and Sidebar on Learning Healthcare Systems, p. 27). For example, some tumors learn to bypass initially efficacious treatments, and how that happens needs to be determined in order to develop new and improved therapies. In cases where there is no immediate gain observed in the clinic, the knowledge amassed during the trial can be probed for insights into why and how the treatment failed to have the expected effects and how to improve upon it.

Advances in cancer prevention and early detection have resulted in some of the greatest reductions in cancer mortality, and these have been achieved with remarkable impact by translating scientific discoveries into actions by two complementary strategies: public health initiatives involving education and policy, and personalized initiatives applied in the clinic. Public health measures have included public education regarding common cancer risks (such as physical inactivity and unhealthy diets) and policy development to minimize harmful exposures (such as smoke-free workplaces or asbestos remediation laws). Clinical preventive advances include improved screening practices (e.g., colonoscopy to detect and remove precancerous colorectal polyps) and targeted interventions (e.g., administering vaccines for infectious diseases associated with cancer risk).

This progress has come from decades of research that have led us to our current understanding of how cancers develop. We know that cancer is a complex process that takes place over a period of time, sometimes several decades. Most, if not all, tumors arise as a result of a series of changes in our genes or in the molecules that control how and when our genes are expressed. Our knowledge of the timing, sequence and frequency of the pivotal changes underlying tumor development is increasing, as is our insight into the specific implications of these changes. This provides us with unique opportunities for earlier identification of aberrations and therefore new prospects for developing the means to prevent cancer onset or to detect it and intervene earlier in its progression. We have also learned that cancer risk factors are varied, complex and interrelated, making it challenging, but not insurmountable, to deliver on the promise of cancer prevention. The identification of research priorities along with the necessary funding will help to accelerate progress in this important area.

 Through the identification of numerous factors germane to cancer, scientists have come to the conclusion that almost two thirds of the more than 577,000 cancer deaths expected to occur in the U.S. in 2012 will be related to preventable causes [(3); see Fig. 9, pg. 29].

One of the most successful examples of how scientific progress can inform public policy and educational efforts to measurably reduce cancer incidence and death rates is the 29% decline in lung cancer death rates among men that occurred between 1990 and 2008, which is directly attributable to the decrease in smoking prevalence (4). The scientifically established causal relationship between smoking and cancer, which began with epidemiological observations, gained prominence in the public arena in 1964 when the U.S. Surgeon General's Report on Smoking and Health was published (12). This report set in motion major U.S. policy changes, media campaigns and other measures to combat cigarette smoking (see Fig. 10, pg. 30). As a result of these efforts, the prevalence of smoking in the U.S. decreased from 42% of the population in 1965 to 19% in 2010 (13). This decrease has been credited with saving millions of lives that would otherwise have been lost not only to lung cancer, but also to 17 other types of cancer directly related to tobacco use, including head and neck, stomach, pancreas, cervical and other cancers (13), as well as to many other often fatal diseases.

Despite this progress, tobacco use will still be responsible for an estimated 30% of all cancer deaths that occur in the U.S. in 2012 (3). The Surgeon General's 31st report on tobacco (14), released in 2010, concludes that there is no safe level of exposure to tobacco smoke. Yet, 70 million Americans regularly use tobacco products, and every day in 2010, 6,500 Americans aged 12 years and older smoked their first cigarette (15). It is not only the lives of those who use tobacco products that are at risk; scientific evidence has shown that exposure to secondhand tobacco smoke also causes cancer. Although this has led to some important public health policies restricting smoking in public places, countless lives could be saved in the future through continued research to develop and implement effective tobacco prevention, cessation and control strategies such as those described in “Tobacco and Cancer: An AACR Policy Statement” [(16); see Fig. 11, pg. 30 and Sidebar on Tobacco Tax, pg. 31].

Data from numerous epidemiological studies have revealed that obesity is clearly linked to an increased risk for the adenocarcinoma subtype of esophageal cancer and to pancreatic, colorectal, kidney, endometrial and postmenopausal breast cancers (8). Mounting evidence indicates that obesity is also associated with an increased risk for other cancers, including gallbladder and liver cancers (8). In line with the dramatic increase in incidence of obesity, incidence of several of these cancers, including pancreatic, kidney and liver cancers, have increased during the past 10 years (17). Independent of weight, a lack of regular physical activity is associated with an increased risk for colon, endometrial and postmenopausal breast cancers and also may be associated with lung, pancreatic and premenopausal breast cancers (8).

Obesity and physical inactivity are not just associated with increased cancer risk. They also negatively impact tumor recurrence, metastasis and patient survival for several types of cancers (17). Among patients with breast cancer (18), colorectal cancer (19) or prostate cancer (20), excess weight is associated with poorer outcomes; conversely, physical activity in patients with these diseases has been shown to improve outcomes (21, 22).

Although trends in the prevalence of obesity in the U.S. finally seem to be stabilizing, the number of individuals classified as obese is still at an all-time high. The latest figures indicate that more than 35% of adults and almost 17% of children and adolescents are obese (23). Similar proportions of individuals are considered physically inactive (17). These unparalleled levels of obesity and physical inactivity are important, avoidable contributors of approximately one third of cancer deaths (3).

Research on a number of fronts indicates that if Americans were to modify their lifestyle to include regular physical activity, a balanced diet and a healthy weight, millions of people could reduce their risk of a cancer diagnosis. In recent years, several cities and states have adopted public policies to enable people to make healthier choices. However, additional research is required to develop and implement effective policy changes and media campaigns. In addition, continued fundamental research efforts are needed to better understand the biological mechanisms that link obesity and insufficient physical activity with cancer. Armed with this information, we may be able to develop clinical and pharmacological interventions to reduce the cancer burden resulting from obesity. Population and clinical studies that complement basic science endeavors will be necessary to determine the optimum body type, body composition and exercise program to reduce cancer risk and recurrence.

Researchers have clearly established a causal relationship between excessive exposure to ultraviolet (UV) light, which is a form of radiation emitted by the sun, sunlamps and tanning beds, and all three of the main types of skin cancer—basal cell carcinoma, squamous cell carcinoma and melanoma. Skin cancer is the most prevalent of all cancers in the U.S. Researchers have estimated that in 2012, there will be more than 2 million new cases of basal cell and squamous cell carcinoma (24) and 76,250 new cases of melanoma (3). The majority of non-melanoma skin cancers are highly curable when treated early, although a small fraction will progress to life-threatening metastatic tumors [see Donna Johnson's Story, p59; (25)]. Melanoma, although accounting for less than 5% of skin cancer cases, is the predominant cause of skin cancer death (3).

The overwhelming majority of skin cancers could be prevented if everyone avoided intense sun exposure. Thus, experts have recommended that people seek shade and limit time in the sun, especially around midday; cover up with a shirt; wear a wide-brimmed hat; use sunglasses for eye protection; and apply a sunscreen rated SPF15 or higher at least every two hours. Adopting sun-safe habits is undoubtedly an important cancer prevention approach, as indicated by research showing that daily sunscreen use can cut the incidence of melanoma in half (26). However, more risk communication needs to be done to bring this to the attention of the general public.

The International Agency for Research on Cancer (IARC), an affiliate of the World Health Organization, includes UV tanning devices in its highest cancer-risk category, “carcinogenic to humans” (27), alongside agents such as plutonium, cigarettes and solar UV radiation. Avoiding the use of tanning beds and sunlamps would therefore decrease the incidence of skin cancer. However, tens of millions of Americans visit tanning salons each year (28). According to a 2011 report from the Centers for Disease Control and Prevention, this number includes more than 13% of all high school students and 21% of high school girls (29).