Cancer Progress Report Writing Committee
Steering Committee Chair
Frank McCormick, Ph.D., FRS, D.Sc. (hon.)
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
Anna D. Barker, Ph.D.
Professor and Director, Transformative Healthcare Networks
Arizona State University
Margaret Foti, Ph.D., M.D. (h.c.)
Chief Executive Officer
American Association for Cancer Research
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
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.
Beth Israel Deaconess Medical School
Harvard Medical School
William S. Dalton, M.D., Ph.D.
President, Chief Executive Officer and Center Director
H. Lee Moffitt Cancer Center and Research Institute
Raymond N. DuBois, M.D., Ph.D.
Provost and Executive Vice President
UT MD Anderson Cancer Center
Olivera J. Finn, Ph.D.
Chair and Distinguished Professor, Department of Immunology
University of Pittsburgh School of Medicine
P. Andrew Futreal, Ph.D.
Professor of Genomic Medicine
UT MD Anderson Cancer Center
Todd R. Golub, M.D.
Director, Cancer Program
Broad Institute of the Massachusetts Institute of Technology and Harvard University
William N. Hait, M.D., Ph.D.
Global Head Janssen Research & Development, L.L.C.
Guillermina Lozano, Ph.D.
Chairman and Professor, Department of Genetics
UT MD Anderson Cancer Center
John M. Maris, M.D.
Chief, Division of Oncology
Children's Hospital of Philadelphia
William G. Nelson, M.D., Ph.D.
Johns Hopkins Kimmel Comprehensive Cancer Center
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
Margaret R. Spitz, M.D.
Professor, Department of Epidemiology
Baylor College of Medicine
Patricia S. Steeg, Ph.D.
Chief, The Women's Cancer Section
Laboratory of Molecular Pharmacology
National Cancer Institute
Mauro Ferrari, Ph.D.
President and CEO
Ernest Cockrell, Jr. Distinguished Endowed Chair
The Methodist Hospital Research Institute
Ahmedin Jamal, D.V.M., Ph.D.
Vice President, Surveillance Research
American Cancer Society
Bruce S. Kristal, Ph.D.
Department of Neurosurgery
Brigham & Women's Hospital
Joyce A. O'Shaughnessy, M.D.
Co-Chair, Breast Cancer Research
Baylor University Medical Center
Charles A. Sammons Cancer Center
Sudhir Srivastava, Ph.D., MPH
Chief, Cancer Biomarkers Research Group
Division of Cancer Prevention
National Cancer Institute
Francesco Versace, Ph.D.
The University of Texas MD Anderson Cancer Center
Shawn M. Sweeney, Ph.D.
Senior Program Administrator
Karen Honey, Ph.D.
Senior Managing Editor, Science Communications
Pamela Bradley, Ph.D.
Director, Science Policy
Director, Marketing and Creative Services
Jon Retzlaff, M.B.A., M.P.A.
Managing Director, Science Policy and Government Affairs
Mary Lee Watts, M.P.H., R.D.
Director, Government Relations
Mark Fleury, Ph.D.
Associate Director, Science Policy
Manager, Legislative Affairs
Nicolle Rager Fuller
A Message from the AACR
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.)
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.
Peter W. Laird, Ph.D.
David Piwnica-Worms, M.D., Ph.D.
The mission of the American Association for Cancer Research (AACR) is to prevent and cure cancer through research, education, communication, and collaboration. Founded in 1907, the AACR is the world's oldest and largest scientific organization dedicated to the advances in cancer research for the benefit of cancer patients.
Its membership includes 34,000 laboratory, translational, and clinical researchers who are working on every aspect of cancer research; other health care professionals; and cancer survivors and patient advocates in the United States and more than 90 countries outside the U.S. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, etiology, early detection, diagnosis, and treatment of cancer through innovative scientific and educational programs and publications. It funds innovative, meritorious research grants to both senior and junior researchers, research fellowships for scholars-in-training, and career development awards.
The AACR Annual Meeting attracts nearly 18,000 participants who share the latest discoveries and new ideas in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, ranging from the laboratory to the clinic to the population. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. In 2011, the AACR's scientific journals received 20 percent of the total number of literature citations in oncology.
The AACR also publishes a magazine,Cancer Today, for cancer patients, survivors, patient advocates, and their families and caregivers that includes essential, evidence-based information and perspectives on progress in cancer research, survivorship, and healthy lifestyle.
A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research, and the need for national policies that foster innovation and progress in the field.
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AACR Office of Science Policy and Government Affairs
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Telephone: (202) 898-6499
Fax: (202) 898-0966
An Appeal from Cancer Survivors and Their Loved Ones to Make Research a National Priority
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.
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
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.
Prevention and Early Detection
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.
Making Research Count for Patients
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.
What is Required for Continued Progress Against Cancer?
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.
The AACR Call to Action
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.
“Thousands of Americans lose their battle to cancer each year. But through the committed efforts of scientists and hospitals around the country, great strides are being made to discover cures and treatments to change this sad reality. By raising awareness about early detection and prevention as well as prioritizing research to treat and cure cancer, I am confident we will one day win this fight.”
Senator Kay Bailey Hutchison (R-TX)
Co-Chair of the Senate Cancer Coalition
A Snapshot of a Year of Progress
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 Status of Cancer in 2012
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.
While great strides have been made in cancer prevention and treatment, certain groups experience noticeably higher incidence of certain cancers than the general population and/or suffer significantly poorer treatment outcomes. A disproportionately higher burden of cancer falls on racial and ethnic minorities, as well as low-income and elderly populations. The causes of these disparities are numerous, complex, often interrelated and only partially understood. Chief among them are unequal access to quality health services; different behavioral, environmental and genetic risk factors; a lack of minority and elderly inclusion in the development of new therapies; and social and cultural biases that can negatively alter the relationship between patients and healthcare providers. Addressing these persistent cancer health disparities poses a significant challenge for researchers and policymakers.
Access and utilization of health services ranging from screening to treatment are perhaps the most readily identifiable causes of disparities in cancer outcomes. In the U. S., access is greatly affected by insurance coverage, and while nationally 14% of the population is uninsured, 37% of Latinos lack insurance, and 20% of African Americans are uninsured (122, 123). Even when the lack of insurance does not create a barrier to care, the availability of local providers and healthcare facilities can create barriers. Furthermore, when care is available, social and cultural biases can often inhibit patients from accessing care (124), and when individuals seek care, the care they receive can often depend on their race (125). Lastly, most cancer therapies are derived from focused research that culminates in clinical trials that determine whether experimental therapies should be approved for general use, and while enrollment in cancer trials is low for all patient groups, racial and ethnic minorities, and the elderly are significantly under-represented in cancer clinical trials. This means that therapies often enter widespread use without thorough evaluation of their efficacy in all populations.
While access to healthcare can help explain differences in treatment outcomes between certain groups, many cancer disparities emanate from differences in cancer incidence. Groups vary in both genetic and behavioral risk profiles, and it can often be difficult to untangle the effects of the two since some racial and ethnic groups share not only similar inherited genes, but also similar cultural practices like diet. Increased access to genetic sequencing should make it easier for future researchers to tease apart the contributions of the two.
Mutations in the BRCA genes are but one example of a genetic risk factor that is more prevalent in a specific ethnic group than others, which creates cancer disparities. For example, approximately 2.0–2.5% of women with Ashkenazi Jewish ancestry have one of three specific mutations in the BRCA1 and BRCA2 genes, which is about five times the prevalence of this mutation in people of other ethnicities (126). As a result of these mutations, women of Ashkenazi Jewish ancestry are at increased risk of developing BRCA-related cancers as compared to the general population (127, 128).
Continued research will undoubtedly reveal other similar genetic risk factors that disparately either drive cancer incidence or inhibit effective treatment. Where genes are not the cause of disparities, research will still be critical to identify causes and develop sound evidence-based interventions to address cancer health disparities.
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.
Why 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.
Metastasis is the spread of cancer cells from a primary tumor to other areas of the body where they establish new tumors. It is responsible for more than 90% of the morbidity and mortality associated with cancer. Studying the fundamental properties of metastasis is essential to conquering cancer, because it is only through research that we will be able to identify important targets for the development of new therapies to prevent or treat metastasis, and learn how to predict who will develop metastatic cancer and require these therapies.
Already we have learned a great deal about this deadly process, some of which explains why metastatic disease is so difficult to treat. For example, virtually every step of the metastatic process can be achieved through multiple different means, giving the cancer cells many opportunities to metastasize. This also means that blocking only one pathway therapeutically will not be sufficient. In addition, we know that cancer cells can travel to other parts of the body and then lie dormant in this new location for years, becoming active again later in life. A greater understanding of the factors that contribute to tumor cell dormancy could lead to the development of new therapies that have the potential to prevent these dormant cells from reawakening.
Metastatic disease is a dire situation that requires an immediate and complete therapeutic response in order to prevent almost certain death. While recent research has revealed that there is a genetic basis for susceptibility or resistance to metastasis, creating new avenues for the development of effective therapies, much more work is needed if we are to develop a comprehensive understanding of this complex process and make significant progress against cancer and toward saving lives.
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.
Cancer Research: From Concept to Patient and Back Again
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.
Experimental Models of Cancer.
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.
Probing Cancer Models: Generating and Testing Ideas.
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.
One of the greatest advances in cancer research was the discovery that changes, or mutations, in genes can cause cancer. The “genetic code”, carried in deoxyribonucleic acid (DNA) units called bases is packaged into chromosomes that are passed from parents to offspring. The entirety of a person's DNA is called a genome. The genetic code within our genome is decoded to produce the various proteins that our cells use to function; (see Fig. 4, p. 22).
In cancer, chromosomes sometimes break and recombine causing large-scale changes within the genome. Genes can also be altered by single mutations in DNA units. Over the years, researchers have determined that cancer-associated genetic mutations are often found in one of two classes of genes: oncogenes and tumor suppressor genes. Oncogenes can drive the initiation and progression of cancer by producing abnormal proteins that permit cancer cells to ignore normal proliferative regulatory signals. Tumor suppressor genes encode proteins that normally stop the emergence of cancer. Mutations in these genes result in proteins that fail to function properly, enabling cancer cells to proliferate unchecked.
The correlation of genetic mutations with specific malfunctions of cellular molecular machinery that result in cancerous cell behaviors has provided the impetus for the development of many molecularly targeted cancer drugs, bringing the prospects of a new day for cancer prevention, detection, diagnosis and treatment closer to reality.
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).
Moving Cancer Research into the Clinic.
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.
“In this time of severe budget constraints, Americans need to know that today's basic research is the engine that powers tomorrow's therapeutic discoveries. They need to know that basic research is the type of science that the private sector, which requires rapid returns on investment, cannot afford to fund. They need to know that, because it is impossible to predict whence the next treatment may emerge, the nation must support a broad portfolio of basic research.”
Francis Collins, M.D., Ph.D.,
Director, National Institutes of Health
Clinical Outcomes Go Back to the Laboratory.
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.
Learning healthcare systems generate and collect evidence from the delivery of health care in everyday clinical settings. This evidence is used to determine which interventions work best and for whom when placed into broad clinical practice, with the results feeding back into the data system to continually and iteratively improve clinical care delivery. Thus, learning healthcare systems complement the clinical trials process and its goals by examining the effectiveness of interventions or their utility in a real-world setting, rather than their efficacy or use in the restricted populations and idealized settings involved in clinical trials. In addition, although regulatory agencies like the FDA require proof of efficacy for drugs and biologics before they can be used clinically, other interventions such as imaging, surgery or off-label drug use do not require the same scientific scrutiny for efficacy, let alone demonstrations of effectiveness, before entering widespread use. Learning from everyday healthcare delivery is becoming a reality because of the contributions of contemporary health information technology, informatics, and the availability of real-time data and analytics. The continual evaluation and modification of healthcare interventions enabled by a learning healthcare system ensure that the care delivered to patients is effective and efficient, saving patients unnecessary treatment, wasted time and added costs.
Tools Used in a Learning Healthcare System:
Health Information Technology (HIT): Data collection and analysis infrastructure that enables digital recording of patient information, diagnosis and treatment history along with outcomes. These systems allow easier and more widespread data access, opening up the possibility of secondary data use for research purposes.
Observational studies: Research that infers links between treatments and outcomes based on natural—as opposed to experimental—variations in treatment delivery. These analyses are often applied in retrospect in a learning healthcare system
Pragmatic clinical trials: Randomized experiments designed to test effectiveness of an intervention in normal clinical settings with attendant natural confounding factors.
Registries: Databases organized around specific diseases or interventions (e.g., cancer or implanted defibrillator) that record patient and outcome information.
Patient-reported outcomes: Effects of treatment as reported directly by a patient (e.g., pain, fatigue, mood, mobility, quality of life, etc.)
Quality measures: Standardized metrics that indicate the degree of attainment of idealized treatment or outcomes goals.
Prevention and Early Detection
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.
To Know Your Risk, Know the Causes of Cancer
Causes of Cancer You Can Avoid.
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].
Tobacco Use and Cancer: Smoking-Gun Evidence
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].
Obesity and Physical Inactivity Weigh in on Cancer
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.
Ultraviolet Light: Reflecting on a Cause of Cancer
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.
Increasing the price of tobacco products has been proven to reduce tobacco use, as indicated by the strong relationship between increases in cigarette prices in the U.S. from 1970 to 2007 and decreases in consumption (129, 130). This approach is particularly effective for children, who are two to three times more price sensitive than adults (131). In addition, it has been estimated that the April 2009 federal tobacco excise tax increase of 61 cents per pack reduced the number of smokers among middle and high school students in May 2009 by approximately 220,000–287,000 (132).
However, price increases alone will not stop all individuals from using tobacco products, and a comprehensive, evidence-based tobacco control policy employs price deterrents in combination with other proven measures in public education such as school-based programs or public advertising campaigns; federal, state, and regional regulations regarding the pricing or restricted sale or use of tobacco products; and clinical programs to provide the full range of cessation services or facilitate smokers' connections to public resources such as quitlines.
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).
Faced with the overwhelming scientific evidence that tanning bed use increases an individual's risk for developing skin cancer and that the risk increases with younger age (30), some states, counties and cities in the U.S. have enacted legislation banning minors from using tanning beds. In other regions, however, similar initiatives have fallen short of approval (31).
Preventing skin cancer by protecting skin from intense sun exposure and avoiding indoor tanning would not only limit the morbidity and mortality caused by these conditions, but would also save enormous amounts of money. For example, it has been estimated that the total direct cost associated with the treatment of melanoma in 2010 was $2.36 billion in the U.S. (32). Given that melanoma incidence rates continue to increase (3), all sectors with a stake in reducing skin cancer burden—from patients, to researchers, to politicians seeking to balance their budgets—need to come together to develop and implement more effective policy changes and media campaigns.
Infectious Agents: Catching a Cause of Cancer
Research has revealed that infection with one of several microorganisms is an important cause of some cancers. The latest data indicate that worldwide, more than 16% of the new cancer diagnoses made in 2008, amounting to approximately 2 million affected individuals, were attributable to infections [(33); see Fig. 12, p. 32]. In the U.S. and other developed countries, this fraction was lower (7.4%) than in less-developed countries (22.9%). Several infection-associated cancers have high mortality rates, and preliminary estimates suggest that up to 20% of cancer deaths, or 1.5 million deaths, in 2008 were attributable to infections (33).
The International Agency for Research on Cancer lists 10 microorganisms in its highest cancer-risk category, “carcinogenic to humans” [(34); see Table 3]. These include the bacterium Helicobacter pylori; human papillomavirus (HPV); hepatitis B virus (HBV); hepatitis C virus (HCV); Epstein-Barr virus (EBV); human T cell lymphotropic virus type 1 (HTLV-1); human herpes virus type 8 (HHV-8; also known as Kaposi's sarcoma herpes virus); the parasitic liver flukes Opisthorchis viverrini and Clonorchis sinensis; and the parasite Schistosoma haematobium. Recently, researchers have identified Merkel cell polyomavirus as the seventh virus directly linked to human cancers (35). Human immunodeficiency virus (HIV) is also associated with an increased risk for several types of cancer, but it is not considered carcinogenic because its effects are indirect—they are due to the effects of the virus on the immune system (see Cancer-Predisposing Medical Conditions, p.41).
The knowledge that infection with certain microorganisms can cause specific cancers has had a substantial effect on cancer prevention strategies. It has enabled the identification of individuals at elevated risk for developing cancer as well as the development of new methods for prevention and treatment. One of the best examples of how scientific discovery can lead to both of these key aspects of cancer prevention relates to HPV which is estimated to have been responsible for almost 39,000 new cases of cancer in the U.S. in 2010 and more than 9,500 deaths (36).
As a result of several decades of research, we now know that persistent infection with certain strains of HPV can cause cervical cancer, a substantial proportion of anogenital cancers, and some head and neck cancers (33). This information led to the development of a clinical test that detects the presence of cancer-causing types of HPV. The test, when combined with a standard Papanicolaou (Pap) test for cervical cancer, enables earlier identification of women at high risk for cervical cancer and safely extends cervical cancer screening intervals (37).
Determining which strains of HPV can cause cervical cancer also fueled the development of vaccines to prevent persistent infection with these HPV types. The FDA has approved two vaccines for use in females aged nine to 25 years old for the prevention of cervical cancer caused by high-risk HPV strains. Both vaccines are highly effective at preventing precancerous cervical lesions caused by these HPV strains (36). The FDA also approved one of the vaccines, Gardasil, for use in females aged nine to 26 for the prevention of vulvar and vaginal precancerous lesions as well as for the prevention of HPV-associated anal cancer in both males and females aged nine to 26 (see Sidebar on HPV Vaccine Usage). Future studies will determine whether the vaccines also reduce the risk for head and neck cancers caused by HPV.
Our increasing knowledge about infectious causes of cancer provides opportunities for tremendous progress in reducing the health care and economic burden of certain cancers, like that experienced by Shaundra L. Hall. Continued research in this area holds great promise for our conquest of certain cancers, but it will not have the desired effects without comprehensive approaches to public education and public health policy implementation—both of which are essential if cancer prevention advances are to be deployed to all those who could benefit.
Coverage for one dose of HPV vaccine for girls increased by only 4.4 percentage points to about 49 percent (48.7% in 2010 vs 44.3% in 2009).
For girls who received the recommended three doses of HPV vaccine, coverage increased five points to just 32 percent (32% in 2010 vs. 26.7% in 2009).
Of the girls who began the HPV vaccine series, 30% did not receive all three doses.
Completion of the three-dose HPV series was lower among blacks and Hispanics than non-Hispanic whites
Health insurance coverage for three doses of HPV vaccine was lower for those living below poverty.
Poor and minority teens are less likely to receive all three recommended doses of the HPV vaccine.
The CDC estimates that 1.4% of males age 13–17 years have received at least one dose of HPV vaccine.
Adapted from the CDC National Immunization Survey – 2010 Teen Survey available here: http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm6033a1.htm?s_cid=mm6033a1_w
I am a 14-year cervical cancer survivor whose experience ignited a passion for educating the public—and parents in particular—about gynecological cancers and the fact that FDA-approved vaccines can now prevent many of these cancers.
In 1999, I was diagnosed with stage I squamous cell carcinoma of the cervix, when I was just 28 years old. My husband and I were trying to start a family, and after no success for about 10 months, I returned to my gynecologist for testing. I am very thankful that I did, because in the approximately 10 months since my previous clean Pap test, an aggressive tumor had grown on my cervix.
I had always been vigilant about having Pap tests each year, and for the prior four years, my results had been normal. Previously, I had had many years of abnormal Pap test results, leading to various procedures to remove affected cervical tissue, but I was still surprised to find out that I had developed invasive cancer. I now understand that I must have been suffering from persistent HPV infection for many years, even though there was not a lot of information published about the link between HPV and cervical cancer at that time.
Unlike several friends who had previously gone through cancer treatment, I did not have any chemotherapy or radiotherapy after my surgery. I really questioned that decision. However, my clinical team was confident that the surgical intervention was adequate, and now that I know more about chemotherapy, I recognize that it was the appropriate decision at that time. I did have follow-up Pap tests and scans every three months for a few years to check for any recurrence or metastasis, but now I am happy to say my only maintenance includes my yearly well-woman exam and Pap test.
Regrettably, I never received reproductive counseling. As a result, I was not aware until several years later that it would have been possible to have some of my eggs frozen, so that my husband and I could have had biological children with the help of a gestational carrier (surrogate). Even though the treatment left me unable to have children, I have been in remission for more than 14 years now and I am so thankful that I am able to live a very robust and fulfilling life.
Thanks to my status as a cancer survivor, I am able to act more effectively as a patient advocate. I volunteer for the National Cervical Cancer Coalition (NCCC) and use my cancer experience positively to educate people about gynecological cancers in particular. Cervical cancer, anal cancer, vulvar cancer and penile cancer are cancers that people do not particularly like to talk about, and it is important to let people know that these are not anything to be ashamed of. We are all in this together, as many of these cancers are often caused by HPV infection. My journey also led me to my career at Cancer Treatment Centers of America in Arizona, where I am fortunate to work and help others in their fights against cancer.
It is so vital that we educate the public about the FDA-approved HPV vaccines. This is one of my passions because it is critical parents understand the available information so they are able to make an educated decision along with their child's physician as to what the best course is for their child. I know that if I had children, I would absolutely have them vaccinated. I encourage any parent looking for more information regarding HPV or the FDA-approved vaccines to contact the NCCC (www.nccc-online.org) or the American Social Health Association (www.ashastd.org).
Diet and Cancer: You Are What You Eat and Drink
Dietary factors are important, but they do not appear to be uniformly relevant to all forms of cancer. The strongest scientific evidence is for alcohol intake, which has been linked to an increased risk for developing mouth, throat, larynx, esophagus, liver, colorectal and breast cancers (8). For each of these cancers, the risk increases with the amount of alcohol consumed, as highlighted by a recent study showing that even a few alcoholic drinks per week increase a woman's breast cancer risk (38). Developing and implementing more effective public health policies, media campaigns and education initiatives will be key to decreasing alcohol consumption, with the latter being particularly important given that almost 39% of high school students report current alcohol use (29).
For dietary factors other than alcohol, only limited research conducted thus far supports a direct link to cancer risk (8). Red meat and processed meat are both clearly associated with an increased risk for colorectal cancer, but for other cancers, their influence on risk is less certain scientifically. Moreover, no unequivocal evidence of preventive effects exists for any dietary factor, although some studies indicate the risk for some cancers is reduced through the consumption of fruits, vegetables and fiber.
The complexities of the relationship between food and nutrient intake and cancer risk are a key reason for the lack of a strong evidence base in this area. Designing scientific studies to determine the contribution of a single dietary component is very challenging. Despite this, it is imperative that we continue to build upon our knowledge of the causes of cancer and increase the number of cancers that we can prevent.
Causes of Cancer That Are Hard to Avoid.
We have discussed cancer risk factors that are possible to avoid, but there are other risk factors that are more difficult to elude.
Ionizing Radiation: Energizing Cancer
Extensive epidemiological and biological evidence links exposure to ionizing radiation with the development of cancer, in particular, leukemias and breast, lung, brain and thyroid cancers (39). Ionizing radiation is emitted from both natural and man-made sources (see Fig. 13, p. 34). In the U.S., 82% of annual exposure to ionizing radiation is composed of natural background radiation; the remaining 16% comes from man-made sources (39).
The main natural source of ionizing radiation is radon gas, which is released from the normal decay of certain components of rocks and soil. It usually exists at very low levels outdoors, but can accumulate to dangerous levels in areas without adequate ventilation, such as underground mines and home basements. Radon gas is the second leading cause of lung cancer after smoking and is responsible for between 15,000 and 22,000 deaths from lung cancer per year (40). This information led to policies for reducing exposure through home and business inspections and methods to contain or eliminate the source when possible. Increased awareness, along with further deployment of mitigation strategies, should further reduce the incidence of lung cancer caused by these exposures.
The predominant man-made source of ionizing radiation is medical equipment, treatments and diagnostic agents. Experts are concerned about the recent dramatic rise in the frequency of X-ray use for diagnostic purposes, such as CT scans (39). Thus, approaches are underway to limit radiation exposure from diagnostic CT scans with the use of new low-dose scanners. Also, educational programs have been launched to reduce the number of these procedures and to reduce radiation doses to what is medically essential.
“[This] is the time to reaffirm our further commitment to finding treatments, cures and better tools for prevention, building on the momentum of recent years. As the members of the American Association for Cancer Research and their partners continue their quest for cancer prevention and cures, Congress must stand behind them and invest in our research infrastructure.”
Representative Lois Capps (D-CA-23rd)
Co-Chair of the House Cancer Caucus
According to the NCI, a cancer survivor is anyone living with, through or beyond a cancer diagnosis. Over the past several decades, tremendous advances have been made in the field of cancer research, and as a result, a large and growing community of cancer survivors now exists. For example, prior to 1970, being diagnosed with cancer during childhood was considered a universally fatal disease, whereas there are now approximately 300,000 survivors of pediatric cancer in the U.S, and the five-year survival rate is over 80%. Progress has been made against many other cancers as well, and the number of people living today with a history of cancer has risen to over 13.7 million — a significant increase from the 3 million survivors living in 1971 (1).
Long-term survivorship is also increasing: in the U.S. in 2012, an estimated 64% survivors were diagnosed with cancer five or more years ago and 15% were diagnosed 20 or more years ago. Nearly 50% of the current survivor population is 70 years of age or older, while only 5% are younger than 40. Earlier cancer detection and more effective treatments, along with the aging population, are expected to further increase the number of individuals living well beyond a cancer diagnosis.
While rising survivorship in and of itself is a sign of progress against cancer, survivors may suffer serious and persistent long-term adverse outcomes. Cancer survivors are at increased risk for and develop psychosocial and physiologic long-term and late effects of cancer treatment, including but not limited to: anxiety, depression, fear of cancer recurrence, damage to the heart, lung and kidney, cognitive impairment and infertility. Additionally, survivors are at risk for recurrence of the original cancer or the development of a new, biologically distinct, second primary cancer.
Adolescent and young adult oncology (AYAO) survivors, age 15–39 years, along with pediatric cancer survivors, face a unique set of challenges compounded by their stage of life. For the AYAO population, two out of every three childhood cancer survivors will develop at least one complication due to their prior therapy, and one out of every three will develop serious or life-threatening complications. Further, recent studies have concluded that AYAO survivors are at higher risk for engaging in risky health behaviors known to increase cancer risk, such as smoking and drinking, which puts them at higher risk for developing additional cancers (133).
Following treatment, a person diagnosed with cancer may be faced with critical problems that diminish quality of life. The new research focus on cancer survivorship promises to play a significant role in the reduction of long-term and late effects. After decades of focus on cancer treatments and the attendant successes emerging from those efforts, researchers now face the challenge of helping the increased number of survivors achieve a higher quality of life by avoiding or diminishing the potential late adverse health consequences of successful therapies. By gaining a better understanding of the issues confronting cancer survivors, the cancer research community can continue to play an integral role in meeting the needs of survivors, their loved ones and future Americans diagnosed with this dreaded disease.
Although high-dose radiation therapy is clearly beneficial for cancer treatment, patients are at increased risk for developing a second cancer, particularly pediatric patients. Given that the number of cancer survivors in the U.S. alone is now estimated at more than 13.7 million (3), this is a growing concern (see Sidebar on Cancer Survivorship). Research is needed to determine ways to identify those patients who are most sensitive to the negative health effects of radiation.
Environmental Pollutants: A Murky Link to Cancer
The identification of environmental and workplace agents that cause cancer continues to be an important area of epidemiological and toxicological research. One of the most well-established links between an environmental pollutant and cancer is that between inhalation of asbestos and mesothelioma (41), an aggressive form of cancer for which new treatment options are urgently needed. The scientific determination of this causal relationship led to the use of preventive interventions and the implementation of important public health policies. However, asbestos remains a relevant risk factor today because it is still used in some commercial products within the U.S. In addition, not all the asbestos used in the last century has been removed. Moreover, erionite, a natural mineral fiber from volcanic ash that is similar to asbestos, is more potent than asbestos in causing mesothelioma and has been used in paving products in certain parts of the U.S. (42).
Many other environmental agents are classified as “likely to be cancer-causing” or “known to be carcinogenic” (41, 43). These agents include arsenic; pesticides; solvents used in the dry-cleaning industry and in paint thinners, paint and grease removers; dioxins, which are unwanted byproducts of chemical processes such as paper and pulp bleaching; polycyclic aromatic hydrocarbons, which primarily come from burning wood and fuel for homes but are also contained in gasoline and diesel exhaust; and heavy metals like those contained in rechargeable batteries. Further study is required if we are to remain vigilant in our detection of cancer-causing agents in our environment and workplaces and to enhance our ability to determine who has been exposed, to what agents and through which routes, in an effort to prevent future exposures and subsequent cancer development
Hormones: A Natural Boost to Cancer
Scientific evidence has established that hormones modify a woman's risk for breast, ovarian and endometrial cancers; however, their effects are complicated by a number of factors. In particular, natural hormonal and reproductive factors that expose breast tissue to high levels of hormones for longer periods of time—beginning menstruation at an early age, experiencing menopause at a late age, first becoming pregnant at a late age and not having children at all—are linked to a small increase in breast cancer risk. Knowing these facts is a key component in determining a woman's likelihood for developing breast cancer.
In addition to the estrogen and progesterone produced by their own bodies, women are exposed to these hormones when they use oral contraceptives (birth control pills) or medications to treat symptoms of menopause and other gynecological conditions. Epidemiological studies clearly indicate that oral contraceptive use decreases the risk for endometrial and ovarian cancer, and researchers have estimated that during the past 50 years, 200,000 cases of ovarian cancer and 100,000 deaths from the disease were prevented worldwide through the use of oral contraceptives (44).
The contribution of menopausal hormone therapy to cancer risk is an area of ongoing investigation. Several large epidemiological studies, including the Women's Health Initiative and the Million Women Study, revealed that therapies containing both estrogen and progestin, a synthetic form of the hormone progesterone, increase breast cancer risk in postmenopausal women who have a uterus (45, 46). Subsequent studies suggest, however, that the risk increase is not uniform for all women. More research is needed to clarify this issue.
The role of hormones in cancer causation is complicated further by environmental estrogens. Some epidemiological evidence indicates that plant-based, weak estrogens, such as those derived from soy products, may be beneficial, but only when consumed over a lifetime and perhaps only in Asian populations (47). Furthermore, new research is examining the influence of hormone-like substances in the environment, like those found in plastic containers and metal food cans. This emerging area of research illustrates the power of our biological and epidemiological knowledge of carcinogenesis in the evaluation of potential harm from modern-day products.
If, in your family there is/are:
Many cases of an uncommon or rare type of cancer (like kidney cancer).
Members diagnosed with cancers at younger ages than usual (like colon cancer in a 20 year old).
One or more members that have more than one type of cancer (like a female relative with both breast and ovarian cancer).
One or more members with cancers in both of a pair of organs simultaneously (both eyes, both kidneys, both breasts).
More than one childhood cancer in siblings (like sarcoma in both a brother and a sister).
A close relative, like a parent or sibling, with cancer.
A history of a particular cancer among relatives on the same side of the family.
Adapted from: http://www.cancer.org/Cancer/CancerCauses/GeneticsandCancer/heredity-and-cancer
Inheritable Causes of Cancer.
Inherited Risk: It's in Your Genes
We now know that most, if not all, tumors arise from several genetic mutations that have accumulated in one cell of the body during the patient's lifetime. Unfortunately, in some families, several members can inherit a genetic mutation linked to cancer and have an increased risk for certain forms of the disease from birth. The NCI estimates that about 5% to 10% of all new cases of cancer in the U.S. each year, which is approximately 50,000 cases, are associated with an inherited mutation ((48); see Table 4, p. 38).
Retinoblastoma is one of the first cancers documented to be caused by an inherited, cancer-predisposing genetic mutation in some individuals (49). Retinoblastoma is a cancer of the eye that usually develops in early childhood, typically before the age of five. Although it is a rare cancer, diagnosed in just 250 to 350 children in the U.S. per year, analysis of retinoblastoma in the 1970s and 1980s revealed several of the tenets that underpin our current understanding of all cancers. For example, research demonstrated for the first time that mutations in a tumor suppressor gene, in this case the RB1 gene, could initiate tumor formation. The important role that these findings played in advancing cancer research highlights the need to study all cancers, even those that affect very few people.
Cancers linked with inherited mutations in the tumor suppressor genes BRCA1and BRCA2 are much more prevalent than those associated with RB1mutations. They constitute about 5% to 10% of breast cancer cases, such as Melanie A. Nix's, and 10% to 15% of ovarian cancer cases (50). A woman who has inherited a cancer-susceptibility mutation in one or both of these genes is about five times more likely to develop breast cancer and more than 10 times more likely to develop ovarian cancer compared with a woman who does not have such a mutation (51). Men who inherit these mutations are also at increased risk for developing breast cancer as well as pancreatic cancer and an aggressive form of prostate cancer.
Currently there is no way to correct inherited cancer-susceptibility mutations. However, the knowledge that an individual is in a high-risk category can encourage him/her to modify their behaviors to reduce risk from other factors, such as the use of tobacco and alcohol consumption; intensify participation in screening or early detection programs; or under certain circumstances, consider the options of taking a preventive medicine or having precautionary surgery to remove organs that are at greatest risk for cancer, as Melanie A. Nix did. At least some of these options are available to all patients who know they have a cancer-associated mutation, but additional research is needed to define the most comprehensive strategies for cancer risk reduction in different patient populations.
Despite clear advances in our understanding of inherited cancer risk, much remains to be learned. For example, although we know that a family history of cancer is a sign that a person may have inherited a cause of cancer (see Sidebar on How Do I Know If I Am at Risk for Developing an Inherited Cancer?), in most cases we do not know what the inherited genetic mutation is. Furthermore, we need to understand the genetic underpinnings of the inherited risk, which is one of many components contributing to the differences in cancer incidence and mortality between racial and ethnic groups (see Sidebar on Cancer Health Disparities in America, p. 16). Defining the root causes of all cancers with an apparent inherited component, whether it is undiscovered genetic mutations or complex environmental and genetic interactions, is imperative if we are to break the cycle of disease for future generations.
University Park, Md.
I have been around breast cancer for most of my life. My mother was diagnosed with the disease when I was just eight years old. I also remember my grandmother being diagnosed with it when I was very young, and each of my three aunts has been affected by either breast cancer, ovarian cancer or both.
Given my family history, I knew I was at very high risk for developing breast cancer. After discussing this with my gynecologist in early 2008, he suggested that we needed to monitor my health much more aggressively and that I should begin by getting MRI screens rather than mammograms and by being tested for the BRCA gene mutations linked to breast and ovarian cancers.
I found out in July 2008 that I was BRCA-positive, with a mutation in my BRCA1 gene that was most likely handed down to me from my mother. An MRI in November of that year revealed an area of concern, and a subsequent biopsy showed that I had stage I breast cancer. Further, it was triple-negative breast cancer, a very aggressive form of breast cancer that disproportionately affects African American women and younger women.
I was just 38, a wife and a mother of two young children. For the best chance of long-term, cancer-free survival, I decided to have a bilateral mastectomy, so that in addition to having my left breast with the cancer removed, I also had my right breast removed to reduce my risk for the disease emerging again in the future. Then, after 16 rounds of chemotherapy and breast reconstruction surgery, I had both my ovaries removed (a prophylactic bilateral oophorectomy) to further reduce my risks for cancer in the future.
I sometimes regret not having been tested for the BRCA gene mutations sooner, but there were a few things that held me back. Some of it was fear and anxiety about my future insurability, but much of it was that I was pretty sure that if I tested positive, I would be aggressive in my approach to preventing disease and would opt for a preventive bilateral mastectomy and oophorectomy. In preparing to have and breast-feed my second child, I held off getting tested.
My BRCA status is often at the forefront of my mind because I know that I am going to have to explain it to my children, in particular my daughter, when they get a little older. When the time comes, I will need to educate her about her cancer risks and how to monitor her own health. I will also have to teach her about her options for preventing the disease—whether or not to be tested for the mutation and what to do if she is positive.
I am very fortunate to be an almost four-year cancer survivor. Although I have not had any treatments since those I received right after my diagnosis, I will be under the care of an oncologist for the rest of my life. Right now, I see him every six months. In an effort to keep my risks for further cancer as low as possible and to contain any side effects of my treatments, such as osteoporosis, in addition to conscientiously going to my doctors' appointments, I exercise regularly, am very careful about my diet and take vitamin supplements.
As a result, I continue to thrive. I work with a childhood friend who was diagnosed with triple-negative breast cancer just before me to provide support and comfort for breast cancer patients who are going through treatment. I also volunteer with breast cancer advocacy and support organizations, because it is important that we raise awareness of this disease and the triple-negative form of it in particular. There is still so much to learn.
For some cancers, researchers have used known risk factors to devise mathematical models that predict the likelihood that a person will develop these diseases. For example, the Gail and Claus models are used to determine a woman's risk of breast cancer.
Risk estimates derived using the Gail model are based on a woman's natural hormonal and reproductive history, family (first-degree relatives only) breast cancer history, race/ethnicity, breast biopsy history and the presence/absence of prior breast tissue abnormalities51. The Claus model considers only family history, but it incorporates maternal and paternal breast cancer history, first- and second-degree relatives and age of affected family members at breast cancer diagnosis. Each has its own strengths and limitations.
Cancer-Predisposing Medical Conditions
A number of medical conditions have been linked to an increased risk for certain types of cancer. Among these are the two major inflammatory bowel diseases, ulcerative colitis and Crohn's disease, and hereditary pancreatitis. Central to these conditions being cancer predisposing is the persistent inflammation that they cause. Patients with ulcerative colitis and Crohn's disease have inflammation of the lining of the colon, and they are six times more likely to develop colorectal cancer compared with the general population (52). The most effective strategy for reducing colorectal cancer risk in patients with inflammatory bowel disease remains unclear (52), and this is an area of active investigation. The options currently available include increased screening for early detection and precautionary surgery to remove all or part of the colon.
Research has shown that medical conditions that suppress the normal function of the immune system increase risk for certain types of cancer. For example, people with HIV/AIDS and patients taking immunosuppressive drugs after solid organ transplantation are more likely than healthy individuals to develop Hodgkin's lymphoma (53).
Stratifying Risk to Improve Health Care for Everyone
Our increasing knowledge of risk factors for certain types of cancer provides unique prospects for reducing the burden of these intractable diseases by identifying those individuals at highest risk prior to disease onset and intervening earlier. For example, when this understanding is employed alongside our expanding awareness of the molecular profile of cancer development, specific prevention programs can be tailored to each high-risk patient's needs. It might be enough to assist patients in modifying their behaviors to reduce risk from other factors, such as tobacco use, or it might be necessary to increase their participation in screening or early detection programs or to recommend they consider taking a preventive medicine or having precautionary surgery to remove those organs at greatest risk for cancer.
Currently, there are few ways to reliably assess an individual's cancer risk without medical intervention. The most concrete approach is to classify as high-risk those individuals with an extensive family history of cancer and those with a cancer-predisposing medical condition (see Sidebar on How Do I Know If I Am at Risk for Developing an Inherited Cancer?, p. 39). Among the former, if it is suspected that disease in affected relatives could be caused by a known inherited cancer-susceptibility mutation, genetic testing can more specifically stratify each family member's individual risk. In this way, relatives who carry the familial mutation can take appropriate risk-reducing measures, while those without the mutation can avoid unnecessary and costly medical procedures.
“For me, this is personal. I have lost two sisters to breast cancer, one brother to prostate cancer, and another brother to thyroid cancer. Tens of millions of Americans and their loved ones also have been touched by cancer. This is why I have long been an advocate of robust funding for cancer prevention and research.”
Senator Tom Harkin (D-IA)
For the broader population, researchers have devised models to predict the likelihood that a person will develop certain cancers, with the goal of selecting those who may benefit from additional screening (see Sidebar on Modeling Cancer Risk, p. 41). These models are based on known risk factors, but are imperfect. The Gail and Claus models for determining a woman's risk for breast cancer are the most used commonly used in the clinic (54, 55). Further research to develop models that not only more accurately quantify risk, but also estimate the benefits of modifying risk factors (e.g., through reducing alcohol consumption) is urgently needed if we are to target preventive interventions to the people who would benefit most.
Many researchers are seeking to identify biomarkers that could be used to stratify an individual's cancer risk—for example, biomarkers signifying exposure to a cancer-causing agent (see Fig. 5, p 23). Ideally these biomarkers would be measurable in small amounts of accessible material such as blood, urine or saliva. Current research in this area aims to harness recent technical advances and powerful analytical platforms to discover such biomarkers.
Clearly, stratifying risk is important for reducing the morbidity and mortality of cancer in high-risk individuals, but it also has the benefit of decreasing the complications and cost of unnecessary health care interventions for those at low risk for disease. Every medical procedure, even a seemingly harmless approach for screening for early detection of certain cancers, carries with it some risk for an adverse effect. Eliminating the need for low-risk individuals to be exposed to these procedures also reduces health care costs, providing additional impetus to expand our research efforts to develop new, accurate and reliable ways to discern an individual's cancer risk.
Screening to Spot Cancer Early.
Finding a tumor early, before it has spread to other parts of the body, makes it more likely that the cancer can be treated successfully with fewer side effects and a better chance of survival.
Many cancers, particularly those that arise in tissues other than the blood, are progressive in nature. They begin with a series of genetic changes that translate into defined cellular changes that cause normal cells to develop into precancerous lesions, known as intraepithelial neoplasia (see Fig. 14, p. 42). As the genetic and cellular changes accumulate, the precancerous lesions may evolve into cancerous lesions contained within the tissue and ultimately into advanced metastatic disease. These processes typically take place over a period of many years, and improvements in our understanding of these changes and our ability to identify them have allowed us to detect some precancers and intercept them before they become advanced disease.
Population-based screening programs, which test generally healthy individuals for potential disease, provide opportunities to intervene in the cancer process as early as possible. For many years now, screening has been routinely conducted for the early detection of cervical cancer using the Pap test, for colon cancer using several approaches including colonoscopy, for breast cancer with mammography, and for prostate cancer using prostate-specific antigen (PSA) tests. Individuals at increased risk for cancers for which there are routine population-based screening programs are often advised to start screening at an earlier age or to be screened more frequently than those at average risk.
To be successful, a screening program must result in a decrease in the number of deaths from the screened cancer; all population-based screening programs are continually evaluated to ensure they meet this criterion. Effective screening programs must be well organized and must assess the majority of at-risk individuals. Screening for the early detection of cervical cancer using the Pap test is one of the best examples, as research has shown that reductions in cervical cancer incidence and mortality are proportional to the fraction of the population screened (56). In the U.S., widespread use of the Pap test contributed significantly to the almost 70% reduction in the number of deaths from cervical cancer between 1955 and 1972 (57) and has contributed to the further declines since then, particularly among African American women.
Colonoscopy has contributed significantly to the dramatic declines in colorectal cancer incidence seen since 1998 (58). However, only about 59% of Americans aged 50 years and older, the group for whom testing is currently recommended, get tested (59, 60). If the proportion of individuals following colorectal cancer screening guidelines increased to slightly more than 70%, researchers estimate that 1,000 additional lives per year could be saved (60). Clearly, innovative ways to increase the number of individuals following colorectal cancer screening guidelines are needed. The maximum impact is likely to be achieved with a diverse set of strategies, including public health and education initiatives and the development of alternative, less invasive screening strategies.
Regular screening for breast cancer with mammography is an effective, noninvasive way to detect the disease at an early stage, when treatment is more effective and a cure is more likely. Since the onset of regular mammography screening, the mortality rate from breast cancer has steadily decreased, and this has been attributed to both early detection through screening and improvements in treatment (3, 61). However, it is important to note that studies to date have not shown a benefit from regular screening mammography in women younger than the age 40. In addition, the use of routine mammography screening among those older than the age of 40 has become a hotly debated topic, because there is concern that it can detect breast tumors that will never cause symptoms or threaten a woman's life. That is, it can potentially lead to overdiagnosis of the disease and subsequent overtreatment with its associated risks.
“Awareness and access to screening are half the battle when it comes to battling breast cancer. It's important to celebrate the advances we've made when it comes to detection and treatment.”
Representative Sue Myrick (R-NC-9th)
Co-chair of the House Cancer Caucus and a breast cancer survivor
Almost 20 years after its introduction in the U.S., the use of the PSA test for early detection of prostate cancer is still controversial. The most recent analyses of two ongoing large-scale studies failed to conclusively indicate whether or not routine PSA screening is useful (62, 63). In one study, although annual PSA screening identified prostate cancers that would not otherwise have been detected, it did not reduce the number of prostate cancer deaths (62). In the other study, men undergoing a PSA screen once every four years had a 21% reduced risk for death from prostate cancer (63). Reconciling these data to generate guidelines for screening is difficult, and it is currently recommended that men, starting at age 50, talk to a doctor about the pros and cons of testing so they can decide if it is the right choice for them. Beyond the lack of clarity as to whether PSA screening saves lives from prostate cancer, screening may also lead to overdiagnosis and subsequent overtreatment, and therefore can cause harm.
The issue of overdiagnosis and overtreatment is relevant not only to mammography and PSA screening, but also to all approaches to early detection of cancer. Research to address the problem is vital to ensure that the public has confidence in current screening guidelines and any future changes in these guidelines. Moreover, it is evident that clinicians urgently need a way to distinguish among screen-positive patients—some may require treatment, while others can undergo surveillance and safely forego immediate curative interventions. One recent advance is the July 2012 FDA approval of the Prostate Health Index (phi), a blood test that can detect prostate cancer more accurately than the PSA test (64), thereby reducing the number of unnecessary medical procedures. This index can also help predict which prostate cancer patients need treatment (65). However, additional work is required if we are to comprehensively reduce the burden of overdiagnosis and overtreatment while ensuring that those with significant disease are identified when curative treatment options are available.
For cancers other than cervical, colorectal, breast and prostate cancers, there are no routine screening strategies for individuals with an average risk for disease. Researchers have made some advances recently for early detection of lung cancer in current and former heavy smokers. In this population, researchers have reported that low-dose CT screening reduces lung cancer mortality by 20% because it identifies small tumors (66). However, this is an early result. More work is required to identify those current and former smokers at highest risk for developing lung cancer, because screening all of the estimated 94 million current and former smokers in the U.S. would be cost prohibitive.
Clearly, screening can greatly redu