• Charles L. Sawyers, M.D.

  • Chairperson, 2013

  • Chair, Human Oncology and Pathogenesis Program

  • Memorial Sloan-Kettering Cancer Center

  • New York, NY

  • Cory Abate-Shen, Ph.D.

  • Professor of Urology and Pathology & Cell Biology

  • Columbia University Medical Center

  • New York, NY

  • Kenneth C. Anderson, M.D.

  • Director, Jerome Lipper Multiple Myeloma Center

  • Dana-Farber Cancer Institute

  • Boston, MA

  • Anna D. Barker, Ph.D.

  • Professor and Director, Transformative Healthcare Networks

  • Arizona State University

  • Tempe, AZ

  • José Baselga, M.D., Ph.D.

  • Physician-in-Chief

  • Memorial Sloan-Kettering Cancer Center

  • New York, NY

  • Nathan A. Berger, M.D.

  • Director, Center for Science, Health & Society

  • Case Western Reserve University School of Medicine

  • Cleveland, OH

  • Margaret Foti, Ph.D., M.D. (h.c.)

  • Chief Executive Officer

  • American Association for Cancer Research

  • Philadelphia, PA

  • Ahmedin Jemal, D.V.M., Ph.D.

  • Program Director

  • American Cancer Society

  • Atlanta, GA

  • Theodore S. Lawrence, M.D., Ph.D.

  • Professor and Chair, Department of Radiation Oncology

  • University of Michigan

  • Ann Arbor, MI

  • Christopher I. Li, M.D., Ph.D.

  • Head, Translational Research Program

  • Fred Hutchinson Cancer Research Center

  • Seattle, WA

  • Elaine R. Mardis, Ph.D.

  • Co-Director, The Genome Institute

  • Washington University School of Medicine

  • St. Louis, MO

  • Peter J. Neumann, D.Sc.

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

  • Tufts Medical Center

  • Boston, MA

  • Drew M. Pardoll, M.D., Ph.D.

  • Professor, Department of Oncology

  • Johns Hopkins Kimmel Comprehensive Cancer Center

  • Baltimore, MD

  • George C. Prendergast, Ph.D.

  • Professor, President and CEO

  • Lankenau Institute for Medical Research

  • Wynnewood, PA

  • John C. Reed, M.D., Ph.D.

  • Head of Pharma Research and Early Development (pRED)

  • F. Hoffmann-La Roche Ltd.

  • Basel, Switzerland

  • George J. Weiner, M.D.

  • Director, Holden Comprehensive Cancer Center

  • University of Iowa

  • Iowa City, IA

AACR Staff

  • Shawn M. Sweeney, Ph.D.

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  • Philadelphia, PA

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  • Jon G. Retzlaff, M.B.A., M.P.A.

  • Managing Director, Science Policy and Government Affairs

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  • Mary Lee Watts, M.P.H., R.D.

  • Director, Government Relations

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  • Nicolle Rager Fuller

  • Illustrator

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  • Bellingham, WA

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

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

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

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

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

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

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

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

  • Charles L. Sawyers, M.D.

  • AACR President

  • Margaret Foti, Ph.D., M.D. (h.c.)

  • Chief Executive Officer

About the American Association for Cancer Research

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 advancing 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 over 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 eight major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Cancer Prevention Research; and Cancer Immunology Research. In 2012, 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.

  • AACR Headquarters

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  • Telephone: (202) 898-6499

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  • ©2013 American Association for Cancer Research.

Background

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

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

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

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

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

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

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

Prevention and Early Detection

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

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

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

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

Making Research Count for Patients: A Continual Pursuit

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

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

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

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

What is Required for Continued Progress Against Cancer?

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

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

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

The AACR Call to Action

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

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

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

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

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

Definitive Progress has Been Made Against Cancer

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

1,024,400

There have been 1,024,400 fewer cancer deaths since 1990 and 1991 for men and women, respectively, as a result of declining death rates (4).

The NIH

is 27 Institutes and Centers; funds 6,000 in-house scientists and 50,000 external grants annually; enables the work of more than 432,000 extramural researchers at more than 3,000 universities, medical centers, teaching hospitals, small businesses, and research institutions; and creates jobs in every state and around the world.

Figure 1:

Working Together Saves Lives. Progress against cancer has been and continues to be the result of the dedicated efforts of many individuals, agencies, and organizations. These include academic scientists and clinical researchers from a wide variety of specialties (microscope), citizen advocates and philanthropic organizations (megaphone), government (U.S. Capitol), regulatory agencies (FDA symbol), the biotechnology and pharmaceutical industries (pills), physicians (stethoscope), diagnostics companies (notepad), funding agencies and philanthropic organizations (National Institutes of Health building), and payers (health insurance card). Central to transformative advances against cancer are the patients and survivors themselves.

Figure 1:

Working Together Saves Lives. Progress against cancer has been and continues to be the result of the dedicated efforts of many individuals, agencies, and organizations. These include academic scientists and clinical researchers from a wide variety of specialties (microscope), citizen advocates and philanthropic organizations (megaphone), government (U.S. Capitol), regulatory agencies (FDA symbol), the biotechnology and pharmaceutical industries (pills), physicians (stethoscope), diagnostics companies (notepad), funding agencies and philanthropic organizations (National Institutes of Health building), and payers (health insurance card). Central to transformative advances against cancer are the patients and survivors themselves.

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Table 1:

Newly FDA-approved Drugs, Indications, and Technologies for the Treatment and Imaging of Cancer: Sept. 1, 2012-July 31, 2013

Newly FDA-approved Drugs, Indications, and Technologies for the Treatment and Imaging of Cancer: Sept. 1, 2012-July 31, 2013
Newly FDA-approved Drugs, Indications, and Technologies for the Treatment and Imaging of Cancer: Sept. 1, 2012-July 31, 2013

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

Figure 2:

I Will Survive. The number of cancer survivors alive in the United States has steadily increased since 1971 [blue bars] (1–3). During the same period of time, the proportion of our nation's population that is living with, through, or beyond a cancer diagnosis has more than tripled [gold line] (1–3, 6).

Figure 2:

I Will Survive. The number of cancer survivors alive in the United States has steadily increased since 1971 [blue bars] (1–3). During the same period of time, the proportion of our nation's population that is living with, through, or beyond a cancer diagnosis has more than tripled [gold line] (1–3, 6).

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

Even in the Face of Progress, Cancer Remains a Significant Problem

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

Table 2:

Select Cancer Incidence, Mortality, and Change in Death Rates (1999–2009)*

Select Cancer Incidence, Mortality, and Change in Death Rates (1999–2009)*
Select Cancer Incidence, Mortality, and Change in Death Rates (1999–2009)*
1 out of 2

Almost one out of every two people born today will be diagnosed with cancer (1).

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

1/3

One-third of cancer deaths are caused by tobacco use (1).

1/3

One-third of cancer diagnoses are related to patients being overweight or obese, physically inactive, and consuming a diet poor in nutritional value (1).

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

Figure 3:

Aging Baby Boomers Predicted to Drive up Cancer Incidence. The majority of all cancer diagnoses are made in those aged 65 and older (blue line) (1, 4). In 2010, individuals in this age group made up 13 percent of the U.S. population (6). In 2030, when the baby boomers will be aged 65 or older, this segment will be nearly 20 percent of the population (6). This change will dramatically increase the total numbers of cancers diagnosed each year, with a 67 percent increase in cancer incidence anticipated for the segment of the population aged 65 or over (bars) (7).

Figure 3:

Aging Baby Boomers Predicted to Drive up Cancer Incidence. The majority of all cancer diagnoses are made in those aged 65 and older (blue line) (1, 4). In 2010, individuals in this age group made up 13 percent of the U.S. population (6). In 2030, when the baby boomers will be aged 65 or older, this segment will be nearly 20 percent of the population (6). This change will dramatically increase the total numbers of cancers diagnosed each year, with a 67 percent increase in cancer incidence anticipated for the segment of the population aged 65 or over (bars) (7).

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

Cancer: An Expensive Disease. Biomedical Research: A Wise Investment

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

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

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

Five Molecularly Targeted Therapies

imatinib, dasatinib, nilotinib, bosutinib, and ponatinib — block the abnormal protein that causes most cases of chronic myelogenous leukemia, BCR-ABL.

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

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

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

The Origins of Cancer

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

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

The Virtuous Cycle of Biomedical Research

All biomedical research, including cancer research, is an iterative cycle, with observations flowing from the laboratory bench to the patient's bedside and back to the laboratory again. Essential to this cycle is the participation of not only basic scientists, physician-scientists, and clinical researchers, but also patients and their health care providers.

In short, the cycle is set in motion when observations are made and then questions are asked and tested. This can lead to discoveries that have the potential to be converted into a tangible tool, drug, or agent to be studied in the clinic. In addition, these discoveries can feed back through the research cycle. Testing of a discovery in the clinic can either lead to a new approach for the prevention, detection, diagnosis, or treatment of disease, or can generate a new observation to be run back through the research cycle.

Observations come from various sources. For example, basic scientists, physician-scientists, and clinical researchers study animals, cells, patients, patient samples, and/or molecules to learn how the body naturally functions and how these functions change during disease. Epidemiologists study groups of people looking for associations between patterns of risk factors or diseases and their relationship to health outcomes.

In each case, an observation helps generate a question, also known as a hypothesis. Researchers then try to answer this question through a series of tests or experiments. In preclinical testing, these experiments are carried out in the laboratory using experimental models of disease; while in clinical testing, the experiments are carried out primarily in patients and sometimes in animals that naturally develop human diseases.

Experimental models mimic what happens in healthy and disease conditions, and come in many forms ranging from isolated cells to whole animals. These cells can come directly from patients or may be more “permanent” cell lines that have been genetically engineered for the purpose at hand. Cells can be studied in isolation, together with other cell types, or combined with animal models for further testing. A number of animals are used in research including mice, zebrafish, flies, and worms.

The study and manipulation of experimental models — for example, exposing them to a potential new drug — can help identify useful approaches for disease 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.

Finally, before a tool, drug, or agent developed in the laboratory can be routinely used in patient care, it must be rigorously tested in clinical trials. To evaluate the safety and efficacy of a potential therapy, it is typically evaluated in a series of clinical trials, each with an increasing number of patients. Individuals participating in clinical trials are closely monitored using a variety of methods to determine if the therapy is effective against their disease, and to watch for any potential adverse outcomes.

If a therapy is deemed to be safe and effective, then it will be approved by the appropriate regulatory agencies for broader commercial use. It is also important to note, however, that all observations, positive or negative, are essential to the research cycle. For example, in cases where there is no immediate clinical benefit observed in a clinical trial, the knowledge amassed during the trial can be probed for insights into why and how a therapy may have failed to provide the expected effect. This can provide key insights into how the approach may be improved.

Because research is an iterative cycle, regulatory approval is not the end of the line. It is vital that what happens at patients' bedsides feeds back into the research cycle. For example, even if clinical trials indicate that an 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.

If the iterative cycle of research is to be truly successful, no segment of the research cycle or single research discipline can operate in isolation. Insights from all disciplines influence others, and discoveries in one disease area can offer new ideas for the conquest of other diseases (see Sidebar on Cancer Research at Work Against Other Diseases, p. 46).

The Genetic Basis of Cancer.

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

Crizotinib

The molecularly targeted therapy crizotinib blocks the abnormal protein that leads to about 5 percent of non-small cell lung carcinomas, EML4-ALK.

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

Figure 4:

Genomic Structure. The genetic material of a cell is made of deoxyribonucleic acid (DNA) strands, which are composed of four units called bases (A, T, C, and G). These bases are organized into genes, and the order, or sequence, of these bases provides the code for producing the various proteins a cell uses to function. The entirety of a person's DNA is called a genome. It is packaged together with proteins called histones into thread-like structures called chromosomes. The organization of DNA is similar to the way in which the letters of the alphabet are carefully ordered to form words and sentences. In this example, the bases form the words that comprise each verse of the patriotic song, America the Beautiful. The song contains four verses, each representing a gene. In this analogy, the entire song represents one chromosome, and each of the songs within a songbook would represent a chromosome within the genome.

Figure 4:

Genomic Structure. The genetic material of a cell is made of deoxyribonucleic acid (DNA) strands, which are composed of four units called bases (A, T, C, and G). These bases are organized into genes, and the order, or sequence, of these bases provides the code for producing the various proteins a cell uses to function. The entirety of a person's DNA is called a genome. It is packaged together with proteins called histones into thread-like structures called chromosomes. The organization of DNA is similar to the way in which the letters of the alphabet are carefully ordered to form words and sentences. In this example, the bases form the words that comprise each verse of the patriotic song, America the Beautiful. The song contains four verses, each representing a gene. In this analogy, the entire song represents one chromosome, and each of the songs within a songbook would represent a chromosome within the genome.

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

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

Figure 5:

Deciphering the Genetic Code. The genome carries the DNA blueprint that is deciphered by cells to produce the various proteins they need to function. Genes are decoded into proteins through an intermediate known as ribonucleic acid (RNA). Information directing which genes should be accessible for decoding in different cells of the body is conveyed by special chemical tags on the DNA, and by how the DNA is packaged with proteins into chromosomes, which also contains similar chemical marks. The pattern of these chemical tags is called the epigenome of the cell. Cell activity, proteins, and a special form of RNA called non-coding RNA, can feedback to alter each step of this process, and ultimately impact cell and tissue function in different ways.

Figure 5:

Deciphering the Genetic Code. The genome carries the DNA blueprint that is deciphered by cells to produce the various proteins they need to function. Genes are decoded into proteins through an intermediate known as ribonucleic acid (RNA). Information directing which genes should be accessible for decoding in different cells of the body is conveyed by special chemical tags on the DNA, and by how the DNA is packaged with proteins into chromosomes, which also contains similar chemical marks. The pattern of these chemical tags is called the epigenome of the cell. Cell activity, proteins, and a special form of RNA called non-coding RNA, can feedback to alter each step of this process, and ultimately impact cell and tissue function in different ways.

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

Figure 6:

The Impact of Genetic Mutations. Since a cell deciphers the DNA code to produce the proteins it needs to function (see Figure 5, p. 11), mutations in the code can result in altered protein amounts or functions, ultimately leading to cancer. It should be noted that not all mutations are harmful nor do they always lead to cancer. There are many different types of mutations that can cause cancer. Using the analogy of the written word (see Figure 4, p. 10), in the first line of America The Beautiful, a single letter (base) deletion has made the word spacious unreadable [1]; such a change would also affect how the remainder of the bases in the gene are read (not illustrated). Large deletions can also occur and alter the meaning of the verse (gene), like the deletion in the fourth verse [6]. In the second line of the song, a substitution mutation has changed the word grain to groin, thus changing the meaning of the line [2]. Not all substitution mutations change the meaning, as in the example in the third line [3]. Other mutations can lead to duplications, also known as amplifications, of an entire gene; here, the second verse has been amplified [4]. Chromosomes can also break and recombine, resulting in new genes and the production of entirely new proteins. The last verse has broken and recombined with a piece from a different song, leading to a completely new verse [7]. Changes in the epigenome can make regions of the genome accessible for use when they shouldn't be, or inaccessible when they should be available. If the page were folded on the dotted line, the third verse would lose five lines [5].

Figure 6:

The Impact of Genetic Mutations. Since a cell deciphers the DNA code to produce the proteins it needs to function (see Figure 5, p. 11), mutations in the code can result in altered protein amounts or functions, ultimately leading to cancer. It should be noted that not all mutations are harmful nor do they always lead to cancer. There are many different types of mutations that can cause cancer. Using the analogy of the written word (see Figure 4, p. 10), in the first line of America The Beautiful, a single letter (base) deletion has made the word spacious unreadable [1]; such a change would also affect how the remainder of the bases in the gene are read (not illustrated). Large deletions can also occur and alter the meaning of the verse (gene), like the deletion in the fourth verse [6]. In the second line of the song, a substitution mutation has changed the word grain to groin, thus changing the meaning of the line [2]. Not all substitution mutations change the meaning, as in the example in the third line [3]. Other mutations can lead to duplications, also known as amplifications, of an entire gene; here, the second verse has been amplified [4]. Chromosomes can also break and recombine, resulting in new genes and the production of entirely new proteins. The last verse has broken and recombined with a piece from a different song, leading to a completely new verse [7]. Changes in the epigenome can make regions of the genome accessible for use when they shouldn't be, or inaccessible when they should be available. If the page were folded on the dotted line, the third verse would lose five lines [5].

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

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

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

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

Beyond Genetics: The Role of Epigenetics.

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

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

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

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

Epigenetic Therapies

Patterns of DNA methylation and histone acetylation, which are epigenetic marks that control genome accessibility, are modified in many cancer cells. The FDA has approved the DNA methylation inhibitors azacitidine (Vidaza) and decitabine (Dacogen) for the treatment of myelodysplastic syndrome. Likewise, the histone deacetylase inhibitors romidepsin (Istodax) and vorinostat (Zolinza) are FDA-approved for the treatment of certain lymphomas.

Outside Influences

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

Figure 7:

Cancer Growth: Local and Global Influences. The initiation and growth of a cancer occurs locally and is largely due to accumulation of genetic changes that lead to defects in the molecular machinery of cells, permitting them to multiply uncontrollably and survive when normal cells would die (see The Origins of Cancer, p. 8). Uncontrolled proliferation occurs when normal control of a tightly regulated cellular process called the cell cycle is lost (A). Cancer is not only a local disease, but also a disease of the whole body, as interactions between cancer cells and their environment strongly influence cancer development and growth. For example, systemic factors in the circulation such as hormones and nutrients affect these processes (B), as does the cancer's ability to stimulate the creation of new blood vessels and lymphatic vessels, which bring in nutrients as well as provide a route for cancer cell escape to distant sites (metastasize) (C), and its capacity to manipulate the immune system (D). Importantly, none of these factors works in isolation, but altogether as a large network.

Figure 7:

Cancer Growth: Local and Global Influences. The initiation and growth of a cancer occurs locally and is largely due to accumulation of genetic changes that lead to defects in the molecular machinery of cells, permitting them to multiply uncontrollably and survive when normal cells would die (see The Origins of Cancer, p. 8). Uncontrolled proliferation occurs when normal control of a tightly regulated cellular process called the cell cycle is lost (A). Cancer is not only a local disease, but also a disease of the whole body, as interactions between cancer cells and their environment strongly influence cancer development and growth. For example, systemic factors in the circulation such as hormones and nutrients affect these processes (B), as does the cancer's ability to stimulate the creation of new blood vessels and lymphatic vessels, which bring in nutrients as well as provide a route for cancer cell escape to distant sites (metastasize) (C), and its capacity to manipulate the immune system (D). Importantly, none of these factors works in isolation, but altogether as a large network.

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

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

The Immune System.

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

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

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

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

Hepatitis C Virus Screening

In June 2013, the United States Preventive Services Task Force (USPSTF) recommended one-time hepatitis C virus (HCV) screening for those born from 1945 to 1965, as well as for individuals at high risk of infection, such as injection drug users and those who received blood transfusions before 1992.

Blood and Lymphatic Vessel Networks.

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

Blood Cancers

Cancers that begin in blood-forming tissues, such as the bone marrow, or in cells of the immune system are called hematologic cancers, or blood cancers. Examples include chronic myelogenous leukemia, non-Hodgkin lymphoma, and multiple myeloma.

Solid Cancers

Cancers that arise in tissues other than the blood can be grouped depending on the type of cell they originate from in that tissue. Examples include:

  • carcinomas, which begin in the skin or in tissues that line or cover internal organs;

  • sarcomas, which arise from cells of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue; and

  • blastomas, which derive from immature “precursor” cells or embryonic tissue.

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

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

Table 3:

Currently Approved Angiogenesis Inhibitors for the Treatment of Cancer

Currently Approved Angiogenesis Inhibitors for the Treatment of Cancer
Currently Approved Angiogenesis Inhibitors for the Treatment of Cancer

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

Developing Cancer

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

Figure 8:

How Bad is it? Staging describes the severity of a person's cancer. Most solid tumors except for brain and spinal tumors are staged using the TNM system; gynecological tumors use a variant of the TNM system. The system is based on tumor size (T), reach to local lymph nodes (N), and extent of spread in the body or metastasis (M). Each organ has a specific set of guidelines for determining stage using the TNM system. In the general example depicted here, the tumor gradually gets larger and extends to more lymph nodes as it becomes more advanced, ultimately metastasizing. Staging helps a patient's doctor select an appropriate treatment and estimate prognosis or predicted outcome. The TNM system provides a standard system for describing tumors, which helps health care providers and researchers compare different tumors and the results of various treatments.

Figure 8:

How Bad is it? Staging describes the severity of a person's cancer. Most solid tumors except for brain and spinal tumors are staged using the TNM system; gynecological tumors use a variant of the TNM system. The system is based on tumor size (T), reach to local lymph nodes (N), and extent of spread in the body or metastasis (M). Each organ has a specific set of guidelines for determining stage using the TNM system. In the general example depicted here, the tumor gradually gets larger and extends to more lymph nodes as it becomes more advanced, ultimately metastasizing. Staging helps a patient's doctor select an appropriate treatment and estimate prognosis or predicted outcome. The TNM system provides a standard system for describing tumors, which helps health care providers and researchers compare different tumors and the results of various treatments.

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

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

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

It's Never Too Late to Quit

using tobacco. Quitting even after a cancer diagnosis can reduce complications associated with cancer treatment and improve overall survival. The AACR recommends that healthcare providers assess tobacco use by cancer patients in all clinical settings and provide users with cessation treatment. The AACR also encourages researchers to study how tobacco use by clinical trial participants changes treatment outcomes in trials. Read more at: www.aacr.org/tobacco.

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

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

Healthy Living Can Prevent Cancer

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

Figure 9:

Risky Business. Research has identified numerous factors that increase an individual's risk for developing cancer. Not all factors have the same impact on cancer risk. The factors that have the biggest impact are tobacco use, obesity and being overweight, infection with one of several microorganisms, poor dietary habits, and lack of physical activity. Modifying personal behaviors could eliminate or reduce many of these risks (see Figure 10, p. 20), and, therefore, have a tremendous impact on our nation's burden of cancer. Data obtained from (10).

Figure 9:

Risky Business. Research has identified numerous factors that increase an individual's risk for developing cancer. Not all factors have the same impact on cancer risk. The factors that have the biggest impact are tobacco use, obesity and being overweight, infection with one of several microorganisms, poor dietary habits, and lack of physical activity. Modifying personal behaviors could eliminate or reduce many of these risks (see Figure 10, p. 20), and, therefore, have a tremendous impact on our nation's burden of cancer. Data obtained from (10).

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Figure 10:

Act Now to Reduce Your Cancer Risk. Decades of research have led to the identification of numerous factors that affect a person's risk of developing cancer (see Figure 9, p. 19). The factors with the biggest influence on cancer risk can be eliminated or reduced by modifying personal behaviors. For example, eliminating tobacco use; eating a healthy and balanced diet; increasing physical activity; reducing exposure to the sun and alcohol consumption; managing pre-existing medical conditions with the appropriate medications; and getting vaccinated against certain infectious agents are all actions one could take to reduce their risk of developing cancer. Despite this, many individuals find it hard to modify their behavior, and a great deal more research and resources are needed to understand how to best help individuals to change their lifestyle.

Figure 10:

Act Now to Reduce Your Cancer Risk. Decades of research have led to the identification of numerous factors that affect a person's risk of developing cancer (see Figure 9, p. 19). The factors with the biggest influence on cancer risk can be eliminated or reduced by modifying personal behaviors. For example, eliminating tobacco use; eating a healthy and balanced diet; increasing physical activity; reducing exposure to the sun and alcohol consumption; managing pre-existing medical conditions with the appropriate medications; and getting vaccinated against certain infectious agents are all actions one could take to reduce their risk of developing cancer. Despite this, many individuals find it hard to modify their behavior, and a great deal more research and resources are needed to understand how to best help individuals to change their lifestyle.

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Eliminating High-Risk Activities.

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

Tobacco Use and Cancer

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

Figure 11:

Beyond the Lungs: Cancers Caused by Tobacco Use. Tobacco use not only increases an individual's risk of developing lung cancer, but also of developing 17 other types of cancer (9). This is why tobacco use will be responsible for an estimated 30 percent of all cancer deaths that occur in the United States in 2013 (1).

Figure 11:

Beyond the Lungs: Cancers Caused by Tobacco Use. Tobacco use not only increases an individual's risk of developing lung cancer, but also of developing 17 other types of cancer (9). This is why tobacco use will be responsible for an estimated 30 percent of all cancer deaths that occur in the United States in 2013 (1).

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Table 4:

Anti-Tobacco Public Policies

Anti-Tobacco Public Policies
Anti-Tobacco Public Policies
More Than 20X

Tobacco smoke is a well-established carcinogen, with smokers more than 20-times more likely to develop lung cancer than nonsmokers (18). Research will help us better understand why some individuals develop cancer with relatively little exposure to smoke, while others are more resistant to cancer development.

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

Smokeless Tobacco

Tobacco comes in many forms. While smoking rates in the United States have declined, the use of smokeless tobacco has increased. Individuals are increasingly consuming both forms of tobacco, smokeless tobacco in settings where smoking is prohibited and cigarettes elsewhere. This “dual use” may actually increase tobacco exposure while reducing the effect of smoking bans and the likelihood of tobacco cessation.

10 Years

You are 50 percent less likely to die of lung cancer 10 years after stopping smoking.

Five Years

You are 50 percent less likely to develop mouth, throat, esophageal, and bladder cancer five years after stopping smoking.

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

Melanoma

accounts for the majority of skin cancer deaths in the United States but less than 5 percent of skin cancer cases (1).

Exposure

Experts recommend 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.

Outdoor and Indoor Tanning and Cancer

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

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

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

Cancer-associated Infectious Agents.

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

Table 5:

Infectious Causes of Cancer

Infectious Causes of Cancer
Infectious Causes of Cancer

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

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

HPV Vaccine Usage

The Centers for Disease Control and Prevention (CDC) tracks vaccination coverage in the United States. It reported that in 2012 (35):

  • Almost 54 percent of girls aged from 13 to 17 had received one dose of HPV vaccine.

  • Just 33 percent of girls in this age group had received the recommended three doses of HPV vaccine.

  • Of the girls who began the HPV vaccine series, almost 40 percent did not receive all three doses.

In addition, the CDC reported (37) that in 2010:

  • Completion of the three-dose HPV series was lower among blacks and Hispanics than whites.

  • Health insurance coverage for three doses of HPV vaccine was lower for those living below poverty.

  • Poor and minority teens were less likely to receive all three recommended doses of the HPV vaccine.

  • Fewer than 2 percent of males aged from 13 to 17 had received at least one dose of HPV vaccine.

Despite the low vaccine uptake, a recent report indicated that cervical infection with the strains of HPV targeted by the vaccines has decreased by 56 percent among females aged from 14 to 19 since the vaccine was introduced in 2006 (36).

Sleep Disturbances and Cancer

There is accumulating scientific evidence that qualitative and quantitative sleep disturbances increase a person's risk for developing cancer. Moreover, it appears that sleep disturbances increase cancer risk directly and indirectly through their link to obesity and type 2 diabetes.

Reports that shift workers have a higher incidence of breast, colorectal, prostate, and endometrial cancers support the link between sleep disturbances and cancer (38–41). Further evidence to support this link comes from two studies that indicate that short sleep duration and frequent insomnia increase postmenopausal women's risks for colorectal and thyroid cancers, respectively (42, 43).

In addition, recent studies indicate that sleep apnea, which is a well-established risk factor for cardiovascular mortality, is also linked with increased cancer mortality (44).

Research indicates that there are multiple ways in which sleep disturbances may influence the development of cancer. One indirect way is that sleep disturbances increase a person's chances of being obese and having type 2 diabetes (45, 46), both of which increase cancer risk. More directly, sleep disturbances may increase cancer risk as a result of the disruptions to an individual's circadian rhythm (47); decreases in melatonin levels (48); and disturbances in DNA repair processes (49, 50). Research into the role of circadian rhythms and disease is an active area of current investigation.

A recent study showed that close to a third of full-time workers in the United States get six or fewer hours of sleep each night (45). Sleep disturbances are, therefore, likely to become a significant contributor to cancer incidence. Clearly, more work is needed to completely understand the causes and develop potential interventions for this underappreciated cancer risk factor.

Moreover, it is becoming increasingly clear that cancer incidence and outcomes are profoundly affected by excess energy reserve accumulation. Importantly, many of the factors that lead to this accumulation and the consequences of this accumulation — including obesity, diabetes, metabolic syndrome, and inflammation — can be corrected by changing personal behaviors (51). Thus, restoring energy balance has the potential to reduce an individual's risk of developing cancer and improve outcomes for individuals already diagnosed with the disease.

It seems likely, however, that a multipronged approach will be required to disrupt the link between excess energy reserve accumulation and cancer because behavior change is challenging for many individuals, for many reasons. As we discuss below, a promising area of research in this context seeks to understand how factors affecting energy balance influence cancer development and outcome (51, 52).

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

Energy Balance: Weighing in on Cancer.

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

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

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

Sunbeds

Did you know that sunbed use before the age of 35 almost doubles your risk of melanoma (26)

How Do Physicians Know if I am Obese?

Body mass index (BMI), which is calculated as weight in kilograms divided by height in meters squared, is used to define healthy weight, overweight, and obesity. In adults:

  • BMI of 18.5–24.9 kg/m2 is considered healthy weight;

  • BMI of 25.0–29.9 kg/m2 is considered overweight; and

  • BMI of ≥30 kg/m2 is considered obese.

In children and adolescents, the definitions of overweight and obese are based on the 2000 CDC BMI-for-age-and-sex growth charts:

  • BMI of ≥85th percentile to <95th percentile is considered overweight; and

  • BMI ≥95th is considered obese.

Obesity and Cancer

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

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

Figure 12:

Getting the Balance Right. “Energy balance” refers to the difference between the number of calories consumed and the number burned. Tipping of this balance so that a person accumulates excess energy reserves plays a crucial role in promoting cancer. Energy balance is a complex dynamic that is not only influenced by calorie consumption and physical activity, but also by other factors such as genetics, diet composition, body weight or body composition, and sleep. How changes in energy balance promote cancer is an area of intense research investigation. Depicted here are some of the interrelated factors researchers have recently implicated in the process.

Figure 12:

Getting the Balance Right. “Energy balance” refers to the difference between the number of calories consumed and the number burned. Tipping of this balance so that a person accumulates excess energy reserves plays a crucial role in promoting cancer. Energy balance is a complex dynamic that is not only influenced by calorie consumption and physical activity, but also by other factors such as genetics, diet composition, body weight or body composition, and sleep. How changes in energy balance promote cancer is an area of intense research investigation. Depicted here are some of the interrelated factors researchers have recently implicated in the process.

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

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

Type 2 Diabetes Mellitus and Cancer

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

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

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

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

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

Physical Activity and Cancer

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

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

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

Physical Activity Guidelines

The U.S. Department of Health and Human Services issues the Physical Activity Guidelines for Americans, which provides science-based guidance to help Americans aged 6 and older improve their health through appropriate physical activity. The most recent version of the guidelines was published in 2008.

Key Guidelines for Children and Adolescents
  • Children and adolescents should do 60 minutes or more of physical activity daily.

  • Most of this time should be either moderate-to-vigorous-intensity aerobic physical activity like running, and should include vigorous-intensity physical activity at least three days a week.

  • Muscle- and bone-strengthening exercises like pushups or jumping rope, respectively, should be a part of daily physical activity and occur at least three days of the week.

Key Guidelines for Adults
  • All adults should avoid inactivity. Some physical activity is better than none, and adults who participate in any amount of physical activity gain some health benefits.

  • Adults should undertake at least 150 minutes a week of moderate-intensity activity like a brisk walk, or 75 minutes a week of vigorous-intensity aerobic physical activity like running, or an equivalent combination of the two. Aerobic activity should be performed for at least 10 minutes at a time, and be spread throughout the week.

  • Ideally, adults should increase their aerobic physical activity to 300 minutes a week of moderate intensity, or 150 minutes a week of vigorous-intensity, aerobic physical activity, or an equivalent combination of the two.

  • Adults should also undertake muscle-strengthening activities that are moderate or high intensity and involve the legs, hips, back, abdomen, chest, shoulders, and arms on two or more days a week.

For older adults, those who are pregnant, and or those with disabilities, these guidelines are modified; see http://www.health.gov/paguidelines/guidelines/summary.aspx for further details.

For cancer survivors, it is recommended that they follow the 2008 Physical Activity Guidelines for Americans with specific exercise programming adaptations based on disease and treatment-related adverse effects (65, 66).

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

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

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

Looking for Cancer: Who, When, and Where

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

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

Table 6:

FDA-Approved Medicines for Cancer Risk Reduction or Treatment of Precancerous Conditions*

FDA-Approved Medicines for Cancer Risk Reduction or Treatment of Precancerous Conditions*
FDA-Approved Medicines for Cancer Risk Reduction or Treatment of Precancerous Conditions*
Table 7:

Surgeries for the Prevention of Cancer

Surgeries for the Prevention of Cancer
Surgeries for the Prevention of Cancer

Classifying Risk.

Prevention and Early Detection of Primary Tumors

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

Table 8:

Inherited Cancer Risk

Inherited Cancer Risk
Inherited Cancer Risk
How do I Know if I am at High Risk for Developing an Inherited Cancer?

If, in your family there is/are:

  • many cases of an uncommon or rare type of cancer (such as kidney cancer);

  • members diagnosed with cancers at younger ages than usual (such as colon cancer in a 20 year old);

  • one or more members who have more than one type of cancer (such as 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 a set of siblings (such as sarcoma in both a brother and a sister);

  • a close relative, like a parent or sibling, with cancer; and/or

  • a history of a particular cancer among those on the same side of the family.

Adapted from: http://www.cancer.org/Cancer/CancerCauses/GeneticsandCancer/heredity-and-cancer.

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

The Honorable Debbie Wasserman Schultz

Age 47

Weston, Fla.

Breast Cancer Survivor Since 2007

For as much as I knew as an advocate in the fight against breast cancer over my 20-year legislative career, I quickly realized in late 2007 that there was much I didn't know when I found a lump just six weeks after a clean mammogram — it was breast cancer, and I was only 41. At the time, I did not know that as an Ashkenazi Jew, I was five times more likely to have the BRCA 1 or BRCA2 gene mutation. I did not know that carriers of the BRCA gene mutations have up to an 85 percent lifetime chance of getting breast cancer and up to a 60 percent chance of getting ovarian cancer. I found out that I do have the BRCA2 mutation. I was fortunate that I found the tumor early, but I didn't find my tumor through luck. I found it through knowledge and awareness.

It was also made plainly clear to me that despite the perception that breast cancer is something older women need to worry about, young women can and do get breast cancer. Sharing this knowledge is critical because young women's breast cancers are generally more aggressive, are diagnosed at a later stage, and result in lower survival rates. One reason they are diagnosed at a later stage is because many young women simply don't think they can get breast cancer. And even if they do suspect something is wrong, too many physicians dismiss their concerns because they also believe that the woman is simply too young to have breast cancer.

After experiencing the importance of early detection firsthand, I knew that I had to introduce legislation to help other young women facing this terrible disease. That is why, as soon as I was cancer-free, I introduced the Breast Health Education and Awareness Requires Learning Young Act, or the EARLY Act. I'm proud to report that the EARLY Act became law in 2010 as part of the Affordable Care Act and is already being implemented.

The EARLY Act focuses on a central tenet: that we must empower young women to understand their bodies and speak up for their health. It creates an education and outreach campaign that highlights the breast cancer risks facing women 45 and under, and empowers them with the tools they need to fight this deadly disease. It helps educate and sensitize health care providers about the specific threats and warning signs of breast cancer in younger women that lead to early detection, diagnosis, and survival.

Looking to the future, I am committed to finding those gaps in cancer treatment and awareness and working on legislative solutions to fill those voids. I think of all the women who have fought the breast cancer battle as my sisters in survival, united and made that much stronger by these difficult experiences. I could not be more grateful to everyone who has chosen to join us in this fight, so that we can support each other, and eliminate cancer, once and for all.

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

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

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

USPSTF Cancer Screening Guidelines

The U.S. Preventive Services Task Force (USPSTF) is an independent group of experts that makes evidence-based recommendations about clinical preventive services such as screenings, counseling services, or preventive medications. Importantly, recommendations can be revised if research uncovers new evidence.

The USPSTF has made numerous recommendations related to population-based screening for early detection of several cancers. Here we highlight its recommendations, as of Aug. 1, 2013, for generally healthy individuals.

  • Breast cancer:

    • For women aged 50 to 74 years, screening mammography once every two years.

    • For women younger than 50, the decision to start regular screening should be an individual one.

  • Cervical cancer:

    • For women aged 21 to 29 years, a Pap test every three years.

    • For women aged 30 to 65 years a Pap test every three years or a Pap test and human papillomavirus (HPV) testing every five years.

  • Colorectal cancer:

    • For adults aged 50 to 75 years, fecal occult blood testing, sigmoidoscopy, or colonoscopy.

  • Draft lung cancer recommendation:

    • For adults aged 55 to 79 years, annual low-dose computed tomography for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years, etc.).

Not listed are the screening programs the USPSTF believes there is insufficient evidence to recommend for or against (e.g., screening for ovarian cancer).

70% Decrease

There was a 70 percent decrease in cervical cancer deaths from 1955 to 1972, largely as a result of the Pap test (31)

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

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

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

Colorectal Cancer Screening

If the proportion of individuals following colorectal cancer screening guidelines increased to slightly more than 70 percent, researchers estimate that 1,000 additional lives per year could be saved (79).

Cancer Health Disparities in America

Cancer health disparities are differences in the incidence, treatment, and outcomes of cancer that exist among specific populations in the United States. These populations are often racial and ethnic minority groups, but can also include individuals with low socioeconomic status, residents in certain geographic locations, the elderly, and individuals from other medically underserved groups. Differences in access to healthcare and healthy foods, behavioral factors, and health literacy are well-documented causes of disparities, but genetic, environmental, and social and cultural factors, including those that can that can negatively alter the relationship between patients and health care providers, contribute to disparities as well.

Research plays a key role in the identification of disparities and in the untangling of their complex and interrelated causes, ultimately leading to the development of effective interventions. An example of an evidence-based intervention is Delaware's cancer control program (see Prevention and Early Detection of Primary Tumors, p. 28), which eliminated colorectal cancer disparities between African-Americans and non-Hispanic whites through the creation of a comprehensive statewide screening program that included coverage for screening and treatment and patient navigators to help guide patients through the screening, treatment, and follow-up processes (81).

The Delaware initiative is a success story, but unfortunately new interventions, including new therapeutics, are not always adequately tested in all of the populations that could benefit from them. For example, racial and ethnic minorities are significantly under-represented in cancer clinical trials. This means that therapies may be approved with little evidence as to their effect in minority populations. In an effort to address this potential source of disparities, several federal agencies, including the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH), have been working to increase minority representation in clinical trials, and a number of independent advocacy efforts have also been launched to address hurdles to minority participation in clinical research.

The demographic changes that are anticipated over the next few decades highlight the importance of addressing cancer health disparities in America. By 2050, it is expected that 30 percent of the population will be Hispanic and 15 percent will be African-American (5, 82). Cancer is already the leading cause of death for Hispanics, accounting for approximately 21 percent of deaths overall and 15 percent of deaths in children, and African-Americans are more likely to die from cancer than any other racial group (1, 5). Therefore, the future health of these groups, and all Americans facing cancer, will require the continued generation of new insights into the underlying causes of cancer health disparities, and the implementation of effective interventions for the elimination of those disparities.

The causes of disparities are complex and interrelated, making it difficult to isolate and study the relative contribution of each. However, below are a few examples of factors that have been shown to play a strong role in differences in cancer incidence and mortality.

Differences in Treatment: For example, only 60 percent of African-Americans diagnosed with early-stage lung cancer are likely to receive recommended surgical resection compared with 76 percent of their white counterparts. African-Americans correspondingly suffer a 25 percent greater mortality in lung cancer (83, 84).

Genetics: For example, the incidence of breast cancer in Hispanic women is nearly 30 percent less than for non-Hispanic whites, but research has found that the more European ancestry Hispanic women have, the more likely they are to develop breast cancer (5, 85)

Environment/behavior: For example, stomach cancer incidence in Japanese Americans is less than half that of Japanese who reside in Japan, showing how changed environment can affect cancer risk (12, 86).

Access to Healthcare: For example, Hispanic women are 1.5 times more likely to die of cervical cancer than non-Hispanic whites. The cervical screening rate among uninsured Hispanic women is only 53 percent compared to 63 percent for uninsured non-Hispanic whites. Hispanics are uninsured at a rate over 2.5 times that of non-Hispanic whites (41 percent versus 15 percent) (5, 87).

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

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

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

Prevention and Detection of Tumor Recurrence

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

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

Cancer Survivorship

According to the National Cancer Institute (NCI), a cancer survivor is anyone living with, through, or beyond a cancer diagnosis. While we use the term “cancer survivor” here in this report, it is important to note that not all people with a cancer diagnosis identify with it.

As a result of advances in cancer research more people are surviving longer and leading fuller lives after their initial cancer diagnosis. In fact, the number of cancer survivors living today in the United States is estimated to have risen to more than 13.7 million, which is approximately 4 percent of our nation's population (2).

This is a growing population; in fact, it is estimated that the number of cancer survivors in the United States will reach 18 million by 2022 (2). This expansion can be attributed to numerous factors including earlier cancer detection, which increases the chance for curative treatment; more effective and less toxic treatments, particularly for advanced and metastatic disease; and the aging and growing population.

Also increasing is long-term survivorship. However, survivorship rates vary considerably depending on cancer type, patient age at diagnosis, and other characteristics. In the United States in 2012, an estimated 64 percent of survivors were diagnosed with cancer five or more years ago, and 15 percent were diagnosed 20 or more years ago (2). Among children diagnosed with cancer, the chances of long-term survival are even greater: three out of every four American children receiving a cancer diagnosis are alive 10 or more years later (95).

There are at least three distinct phases associated with cancer survival, each accompanied by its own unique set of challenges. These phases include the time from diagnosis to the end of initial treatment, the transition from treatment to extended survival, and long-term survival. Here, we focus on the issues facing long-term cancer survivors, which vary depending on the age of the survivor.

While some cancer survivors experience few, if any, health-related challenges, many suffer serious and persistent adverse outcomes. Some of these effects may start during cancer treatment and continue long term, but others can appear months or even years later. These long-term and late effects may be emotional and/or physical. For example, cancer survivors are at increased risk for anxiety and depression as well as damage to the heart, lungs, and kidneys, cognitive impairment, and infertility.

Further, many survivors live in fear that their cancer will return at some point. In fact, cancer survivors are at risk for recurrence of the original cancer and for the development of a new, biologically distinct, second cancer, with risk dependent on the original type of cancer, stage of disease at diagnosis, and treatments received.

The almost 60,000 pediatric cancer survivors (aged from 0 to 14 years) estimated to be living in the United States often face an increased risk of serious negative long-term and late effects as a result of treatments received while their bodies are still developing (2). Adolescents (ages 15 to 19 years) and young adults (ages 20 to 39 years) also have to confront a distinctive set of concerns, including adapting to long-term cancer survivorship while beginning careers and thinking about families of their own.

It is clear that a person diagnosed with cancer may be faced with critical problems that diminish their quality of life for many years. Thus, a new focus for cancer research is to help the increasing number of cancer survivors achieve a higher quality of life by avoiding or diminishing the potential long-term and late effects of successful treatments. By gaining a better understanding of these issues confronting cancer survivors, the cancer research and advocacy community can continue to play an integral role in meeting the needs of survivors, their loved ones, and future Americans navigating the cancer journey.

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

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

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

Making Research Count for Patients: A Continual Pursuit

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

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

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

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

Mary (Dicey) Jackson Scroggins

Age 62

Washington, D.C.

17-Year Ovarian Cancer Survivor and Advocate

I am a 17-year ovarian cancer survivor. The knowledge that my survival depended so heavily on chance and good luck fueled my desire to spread awareness about gynecologic cancers, cancer health disparities, and the need for more research funding.

I was 46 years old when I was diagnosed with stage 1a ovarian cancer. For about two years, I had experienced symptoms that could have suggested ovarian cancer — abdominal bloating, weight gain, frequent urination, and excessive menstrual bleeding. I know my body and knew something wasn't right, so I changed gynecologists during this period to find answers and get relief, but none of us ever suspected cancer.

To remove fibroid tumors and an ovarian cyst, I had a hysterectomy in September 1996. During the surgery, my gynecologist discovered the tumorous ovary and contacted a gynecologic oncologist to complete the surgery. In so doing, she probably saved my life and surely increased my chances of recurrence-free survival.

When my gynecologic oncologist called with the pathology report, he told me he had good and bad news. The good news was that I had stage 1a ovarian cancer, which is the earliest and most treatable stage. The bad news was that it was clear-cell, the most aggressive and least well understood ovarian cancer type.

Although my cancer was early-stage, primarily because it was clear-cell, I received six cycles of chemotherapy — paclitaxel (Taxol) and cisplatin (Platinol). The side effects from the chemotherapy were typical — slight nausea and fatigue for a few days after each cycle and hair, taste, and appetite loss — but overall, except for one bad reaction to anti-nausea medication, my treatment was pretty uneventful.

I finished chemotherapy in February 1997 and have not had a recurrence of the disease. For this I am truly thankful. And although I am still very careful about my health care, the frequency of my follow-up CT scans has decreased.

My oncology nurse, Alice Beers, was vital to my early recovery. She was also instrumental in connecting me with other women who had gynecologic cancers, and I joined the Ovarian Cancer National Alliance, which along with my family became a lifeline. The connection to survivors who understood the disease and who were active in helping others — even as they waged their own battles — was empowering.

Although I had always been active in my community, these connections sparked my advocacy efforts in the cancer community. And since I passionately believe that no one's survival and well-being should be driven by ZIP code, race or ethnicity, or socioeconomic status, one of the initiatives closest to my heart is the elimination of cancer health disparities. There is no acceptable level of the unnecessary and selective suffering and death experienced by medically underserved populations.

A powerful mechanism for reducing and ultimately eliminating cancer and other health disparities is research. As a matter of good science and of good conscience, that research must be anchored with clinical trials that include participants from all segments of the population.

We are all touched by cancer, and we must have the will as a nation to ensure that every citizen will receive the level, length, and depth of care that is appropriate for her or his condition. To do so, we must act on what we already know and on what we learn through research.

One of the reasons that I advocate for others and share my experience is to spread awareness that ovarian cancer can strike any woman, at any age, of any race, and that it is neither silent nor necessarily a death sentence.

The Honorable Michael Fitzpatrick

Age 50

Levittown, Pa.

Five-year Colorectal Cancer Survivor

At first, the symptoms were familiar — not disabling — not much to worry about. We pick up a virus now and then, it makes us sick for a few days, and it's over. But there was a day in spring 2008 when the “virus” had not subsided. The symptoms were even more pronounced by the time I relayed this to my wife. In retrospect, the symptoms were similar to what we know about colon cancer, but I chose to ignore them — I was having a couple of busy weeks.

It was obvious this was not a virus. At my wife's insistence, not my better judgment, I went to the doctor for screening and soon after I was told I had colon cancer — later learning it was stage 3.

There are many things I know now about recognizing symptoms, as well as family history. In my case, four grandparents died from cancer; both my parents are cancer survivors, and a sister.

My first thoughts on hearing the news: I was 44 years old, a father of six, seemingly in good health. Two words come to mind: disbelief and incomprehensible. Needless to say, life changed that day and I was forced to focus on my health and the future. Two other words came to mind: cure or not.

I began treatment at our local community hospital with a great team of physicians, nurses, and technicians administering chemotherapy and a “lifetime dose” of radiation. I was scheduled for four months of very aggressive treatment, beginning in June 2008, leading up to surgery scheduled for October that same year.

Following the mandatory, presurgery examination, I was surprised to learn that the tumor was gone — “melted away,” someone said. I had a choice to have the surgery, regardless, or just post-surgery chemotherapy. I opted for the latter. From October 2008 to March 2009, I underwent the prescribed treatment, and during this nine-month period of treatment at the hospital, I watched the health care bill being debated in Congress. At that point, it was personal.

I was often asked how I felt while undergoing treatment. I suppose it is different for each of us. I was tired, not feeling great most days, but I never missed a day at the law office. I even tried a case in court. Maybe it was a “life goes on” effort, but it worked.

With my illness in remission, I decided I should get back in the game, and in January 2010 I announced that I would run for my old congressional seat. I made the announcement in front of the hospital where I had been treated, with the port in my chest reminding me the cancer could return.

In the aftermath, I look at life knowing I've been given a second chance. Of course, I always appreciated my family, my wife and six kids, seven siblings, parents — but facing your own mortality somehow changes the view. What we take for granted, soars. I even decided to have another run at Congress — and regained my former seat.

In my chosen profession now, I believe this experience has made me a better advocate for the rights of citizens dealing with cancer. I am much more passionate about debating the need for additional money for cancer research so this disease can be thoroughly beaten.

Thus far, I've been spared, and I'm forever thankful to God and the wonderful care I received, and continue to receive, in follow-up visits. I have the utmost respect for those in the healing profession — the physicians and scientists who have chosen this path so others may live. They have my heartfelt gratitude.

Special Feature on Immunotherapy: Decades of Research Now Yielding Results for Patients

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

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

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

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

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

Releasing the Brakes on the Immune System.

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

Key Players in the Immune System

White blood cells, or leukocytes, are the cells of the immune system that work together to protect the body from pathogens. Some can also recognize cancer cells as dangerous to the body and attack and destroy them. Here, we provide a very brief description of the unique functions of some of the white blood cells that have a central role in this process.

T cells, or T lymphocytes, are divided into two main types: those that have the protein CD4 on their surface (CD4+ T cells) and those that have the protein CD8 on their surface (CD8+ T cells). CD4+ and CD8+ T cells both “identify” their target through a groups of proteins on their surface called T-cell receptors.

CD8+ T cells are sometimes called cytotoxic T cells or killer T cells. When they are called into action, they attack and destroy their targets.

CD4+ T cells respond differently to CD8+ T cells when called into action. They do not kill their targets, rather they orchestrate multiple other types of immune responses. For example, they release factors, or cytokines, that direct the function of other immune cells. CD4+ T cells that produce the cytokines interleukin-12 and interferon-γ, which help CD8+ T cells function, are called T helper 1 cells, or Th1 cells.

A distinct subset of CD4+ T cells keeps other immune cells in check, preventing them from attacking our own normal cells and from over responding to pathogens. These cells are called regulatory T cells, or Treg cells. Some cancers actively recruit Treg cells to help shut down the anticancer immune response.

B cells, or B lymphocytes, respond to pathogens and cancer by releasing factors called antibodies. Each B cell makes a single antibody. Monoclonal antibodies, one of the most important classes of anticancer therapy, are derived from the progeny of a single B cell selected to produce one antibody with high specificity for the therapeutic target of interest.

Dendritic cells have a central role as sentinels in the immune system. They alert T cells to the presence of disease-causing pathogens or cancer cells, triggering the T cells' responses.

Natural killer cells, or NK cells, macrophages, and neutrophils are additional specialized immune cell types that are some of the “first responders” of the immune system. When called into action, they release factors that kill their targets.

Drew Pardoll, M.D., Ph.D.

Professor of Oncology, Director of Cancer Immunology

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Md.

Immunotherapy as a treatment for cancer is a dream that is more than 110 years old. But we have now reached an inflection point: in the past three years, a number of immunotherapies have emerged that work in different ways to achieve amazing, long-lasting responses that can be measured in years not months.

It all started in the 1890s, when William Coley noticed that the immune system's response to a bacterial infection seemed to spill over and cause tumor regression in some cancer patients. So, he began to treat his cancer patients by infecting them with certain kinds of bacteria. Although Coley reported some successes, his approach to cancer treatment was never widely adopted.

Since Coley's efforts, we have gained immense scientific insight into the pathways, molecules, and cells that regulate the immune system and execute its functions. Integrating this understanding of the immune system with our knowledge of the biology of cancer is beginning to allow us to intelligently design immunotherapies that are working for a significant number of patients.

This progress is very recent. Before 2010, which is when the FDA approved the first therapeutic cancer vaccine, sipuleucel-T (Provenge), for the treatment of prostate cancer, investigational immunotherapies would cause tumor regression in a few patients, but not enough patients for the immunotherapies to become established treatment options.

In the past, the development of immunotherapies called therapeutic cancer vaccines was plagued by failure in large phase III clinical trials despite some positive patient responses. But now that immunologists have gained more knowledge of the molecules and cells involved in activating the immune system, I believe that over the next three years, therapeutic cancer vaccines will become a core component of cancer immunotherapy combinations.

Therapeutic cancer vaccines like sipuleucel-T act as if you are pushing on the accelerator of your car. We also have immunotherapies that disable the “parking brake”! Ipilimumab (Yervoy), the first of this class of cancer immunotherapy, was approved by the FDA for the treatment of metastatic melanoma in 2011.

The development of ipilimumab resulted directly from a series of milestone discoveries by scientists in the field of immunology. What is most exciting about ipilimumab, is that some patients who responded are still alive three, four, five years after receiving their treatment. This is something that has rarely happened before for patients with metastatic melanoma, and it indicates that even after their treatment was stopped, these patients' immune systems are still keeping their tumors in check.

In 2012 and 2013, the results of early-stage clinical trials testing immunotherapies that disable a second immune-system brake, called PD1, showed even more dramatic results. These studies reported frequent clinical responses not only for patients with metastatic melanoma, but also for those with kidney or lung cancer. Although these PD1-targeted treatments are not approved by the FDA currently, patients' responses seem to be long-lived, and everyone involved in the development of these drugs expects that they will soon become widely available.

In the past, insufficient scientific understanding of the immune system has been a barrier to advancing immunotherapy as a treatment for cancer. Now that we have expanded our knowledge, we are no longer shooting in the dark; we are using science to guide the development of new approaches. Particularly exciting is the idea of combining immunotherapies that work in different ways. We have already seen this in the clinic, where a small clinical trial has confirmed the scientific prediction that a combination of ipilimumab and a PD1-targeted immunotherapy would be better than either treatment alone.

There is also a lot of reason to believe that some molecularly targeted therapies combined with epigenetic therapies will have huge effects on how the immune system interacts with a tumor. This opens the door to the possibility that combining these treatments with immunotherapies will provide additional clinical benefit.

When I was an oncology fellow, I was taught that there were three pillars of cancer treatment: surgery, radiotherapy, and chemotherapy. In the late 1990s, we added a fourth pillar, therapies that target specific cancer-driving defects. I have such confidence in the potential of immunotherapy that I think the years from 2010 to 2015 will be looked at historically as the time that immunotherapy became the fifth pillar of cancer treatment.

There are barriers to this becoming a reality, but they are not scientific. They are regulatory and financial. To use a military analogy, we have the weapons but not the funds to test or manufacture them quickly enough.

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

Figure 13:

Stepping Toward the First Checkpoint Blockade. Ipilimumab (Yervoy) is an immunotherapy that works by counteracting brakes on the immune system called immune checkpoint proteins. It was the first drug of its kind to be approved by the U.S. Food and Drug Administration (FDA). Almost 25 years of basic, translational, and clinical research underpinned the development of ipilimumab. The story began in 1987, when researchers discovered a gene that they called CTLA4. It then took nearly eight years before the function of CTLA4 was uncovered, and another 16 years before this knowledge was translated into ipilimumab. There are now several other drugs in development against another checkpoint protein called PD1 (see Table 9, p 41).

Figure 13:

Stepping Toward the First Checkpoint Blockade. Ipilimumab (Yervoy) is an immunotherapy that works by counteracting brakes on the immune system called immune checkpoint proteins. It was the first drug of its kind to be approved by the U.S. Food and Drug Administration (FDA). Almost 25 years of basic, translational, and clinical research underpinned the development of ipilimumab. The story began in 1987, when researchers discovered a gene that they called CTLA4. It then took nearly eight years before the function of CTLA4 was uncovered, and another 16 years before this knowledge was translated into ipilimumab. There are now several other drugs in development against another checkpoint protein called PD1 (see Table 9, p 41).

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Therapeutic Antibody

A protein that attaches to a defined molecule on the surface of a cell. These agents can exert anticancer effects in several different ways.

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

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

Table 9:

PD-1- or PD-L1-targeted Therapeutics Under Development

PD-1- or PD-L1-targeted Therapeutics Under Development
PD-1- or PD-L1-targeted Therapeutics Under Development

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

FDA Designations

To ensure the safety and efficacy of every drug in America, Congress established the U.S. Food and Drug Administration (FDA) in 1906. The FDA approves drugs after a rigorous evaluation process that can take many years to complete. In an effort to accelerate the pace at which new drugs reach patients with serious and life-threatening conditions like cancer, the FDA has introduced several new regulatory and review strategies.

Breakthrough Therapy

Since 2012, experimental therapies that show substantial improvement over available treatments in early clinical studies are eligible for the breakthrough therapy designation. A drug that receives this designation is eligible for all of the features of fast track designation (see below) and additional guidance from the FDA throughout the drug development process. As of July 31, 2013, six anticancer drugs had received this designation, including two immunotherapies: Lambrolizumab for the treatment of advanced melanoma and obinutuzumab for the treatment of chronic lymphocytic leukemia.

Fast Track

Fast track is designed to facilitate the development of drugs that fill an unmet medical need. This designation can be granted solely on the basis of preclinical data, or data from nonhuman studies. Fast track applications may be evaluated through a “rolling”, or continual, review procedure that allows sponsors to submit to the FDA parts of the application as they are completed, rather than waiting until every section is finished. Ipilimumab (Yervoy), a treatment for metastatic melanoma, was approved through fast track in March 2011.

Accelerated Approval

It can take many years to learn whether a drug improves or extends the lives of patients. To speed the evaluation process, the FDA will, in some cases, grant accelerated approval based on whether or not a drug affects a surrogate endpoint. Surrogate endpoints are scientifically validated measures likely to predict the treatment will have the intended clinical benefit (e.g., extending survival) and may include physical signs such as tumor shrinkage. Drugs approved based on surrogate endpoints must undergo additional testing to verify that they provide clinical benefit. Ponatinib (Iclusig), a treatment for chronic myeloid leukemia (CML), was approved under this pathway in December 2012.

Priority Review

Drugs that have the potential to significantly improve safety or effectiveness may be granted priority review, which allows them to be assessed within six months as opposed to the standard ten months. The designation is granted after all clinical trials are completed, when the drug's safety and efficacy can be reliably evaluated. Radium-223 dichloride (Xofigo) was granted priority review and approved for the treatment of prostate cancer that has spread to the bones in May 2013.

Andrew (Andy) Messinger

Age 61

Short Hills, N.J.

Beating Advanced Melanoma Since 2005

When I was diagnosed with melanoma eight years ago, I was shocked: I had never been a sun worshipper. In 2007, scans showed that the cancer had spread to my lungs, and in 2009, it spread to my brain. As a result of the brain lesion, I became eligible to participate in a clinical trial testing ipilimumab (Yervoy). I have been receiving ipilimumab through the clinical trial ever since and I am thankful every day that it has worked for so long.

It was 2005 when I first noticed a mark on my chest and went to see my dermatologist. He thought it was a blood blister so we were both very surprised when the biopsy revealed that it was melanoma.

My dermatologist referred me to Memorial Sloan-Kettering Cancer Center in New York, where I had the lesion surgically removed. I also had a sentinel lymph node biopsy. Unfortunately, this showed the cancer had spread to my lymph nodes and I had to have a second surgery to have lymph nodes removed. Although scans showed no sign of metastases in my body, the fact that the cancer was in my lymph nodes meant that my diagnosis was advanced disease.

At that point, there were limited treatment options available to me. It was do nothing and observe or treat with interferon. Although the use of interferon was very controversial, after speaking with multiple doctors to get their opinions, I decided that it was right for me. Psychologically, I just felt I needed to be treated.

Fortunately, I was able to get the initial interferon treatments locally, in suburban New Jersey. That helped a lot. After that, I continued with self-injection of interferon every other day for a year. During that time, I recuperated from my surgeries and resumed my life.

About a year after stopping interferon, scans showed tumors in my lungs. During the surgery to remove the affected parts of my lungs, the surgeon also removed several lymph nodes that were obviously cancerous. In an effort to slow the disease, I was treated with granulocyte-macrophage colony stimulating factor, or GM-CSF. It helped me for a few months, but then scans revealed more tumors in my lungs.

At that point, early 2008, I was not eligible for clinical trials testing a new therapy called ipilimumab that was being talked about on all the patient information blogs. So, I began four rounds of interleukin-2, or IL-2. The tumors shrank measurably. However, IL-2 was tough on my body, and then, in 2009, scans showed new tumors in my lungs and a lesion in my brain.

The brain lesion was a turning point, and if anyone can ever say they are lucky to have cancer in their brain, then I was very fortunate. I became eligible for a two-year clinical trial to study the effectiveness of ipilimumab on brain metastasis. I immediately enrolled. I experienced side effects and actually missed a round of treatment as a consequence, but my lung metastases disappeared. Ipilimumab was ineffective against my brain lesion, but this was successfully treated with radio-surgery. I also had radiation therapy to eliminate some lingering cancer in my humerus.

At the end of the two years, I had expected to stop ipilimumb treatment. After all, I had been receiving ipilimumab for two years, and the standard treatment for melanoma patients is four doses over the course of a year. However, the trial was extended for a number of individuals, including me, who had responded well to treatment. Because the goal is to determine whether continuing ipilimumab treatment provides benefit, I still receive ipilimumab quarterly.

Because I am benefiting so much from a clinical trial, I do everything I can to help move clinical research forward. In fact, I participated in clinical trials testing new advances in radio-surgery and radiotherapy during the course of my treatment.

I wish I had not had this experience, but I have, and I want people to understand that cancer is manageable, even deadly cancers like mine, and that there are reasons to be optimistic, even in the face of tough prognoses. The speed of progress in cancer research is such that the situation for patients can change very quickly. But to keep up the momentum, government needs to step up and fund cancer research in a much bigger way.

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

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

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

Boosting the Killing Power of the Immune System.

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

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

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

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

Pancreatic Cancer

kills more than 90 percent of patients within five years of diagnosis (1).

Maddison (Maddie) Major

Age 8

La Plata, Md.

Battling Acute Lymphoblastic Leukemia for More Than Half her Life

A message from Robyn Major, Maddie's mother

My daughter Maddie was diagnosed with acute lymphoblastic leukemia (ALL) when she was just three years old. She has been treated with all kinds of caustic chemotherapies and head-to-toe radiation therapy. But in January 2013, she received a therapy unlike any other she has been treated with: a T-cell therapy that is helping her own body fight the leukemia without serious side effects.

It all started in 2008. As we watched the July 4th fireworks in the summer heat, Maddie complained of being cold and tired. On top of this, a small bruise on her hip got bigger by the day until it looked like she had been beaten with a broom handle. Maddie's pediatrician suggested we take her straight to the emergency room at Children's National Medical Center in Washington, D.C., and blood tests there showed she had leukemia.

A bone marrow biopsy narrowed down the type of leukemia to B-ALL. She began the standard treatment for children with B-ALL, which is six months of intensive chemotherapy followed by two years of maintenance chemotherapy.

Unfortunately, Maddie's body did not respond well to the intensive chemotherapy. She spent two months in the intensive care unit on a ventilator and battling two life-threatening conditions: tumor-lysis syndrome, which caused liver failure; and sepsis, which was caused by an infection in the blood stream. When she finally came home, she had to relearn how to walk and talk.

Maddie, then 5, received her last dose of maintenance chemotherapy in October 2010, but life without treatment did not last long. We found out in February 2011, that she had relapsed.

Within days, Maddie started relapse therapy. This involved six months of even more intense chemotherapy than she had received previously, whole-body radiation therapy, cranial radiation, and a bone marrow transplant.

In August 2012, at just seven years old, Maddie relapsed for a second time. Further chemotherapy had no effect on Maddie's disease, and by December 2012, the doctors at Children's National Medical Center told us that there was not much more they could do. We were devastated.

But a few days later, Maddie's oncologist called and said that she might be able to get Maddie enrolled in a clinical trial at Children's Hospital of Philadelphia. My first response was: You mean that was real? Several people had sent me links to stories on the internet about an experimental treatment at Children's Hospital of Philadelphia that had transformed the life of another girl with leukemia. I hadn't even read past the headlines thinking it was too good to be true.

It wasn't until after just Christmas that we went to see Dr. Grupp at Children's Hospital of Philadelphia. The wait had been excruciating and we had been afraid that it would be our last Christmas with Maddie. But the news he gave us — that the T-cell therapy might possibly be curative — blew us away. I remember thinking, if only we had known this 10 days ago, our Christmas would have been much happier.

In January 2013, we went back to Philadelphia so the doctors could collect Maddie's T cells. Then we faced another excruciating wait, which was about three weeks, as the T cells were genetically altered and grown in the lab. On Jan. 22nd, she got her T cells back. With the exception of a fever, headache, and some confusion, all of which resolved in a few days, she has experienced no side effects. It was such a different experience to all her other treatments.

Since then, the researchers have found no sign of leukemia in her blood or bone marrow and she is living the life she should. She swims, takes horseback riding lessons, and will start second grade on Aug. 19th; it will be the first time she has been in school since February 2012, when she was in kindergarten.

Maddie's experience has made me an advocate for research into pediatric cancers. The drugs that are used to treat many of these cancers are so toxic that they leave the children with a lifetime of problems: they stunt growth and lead to learning disabilities, heart problems, kidney problems, liver problems. These children are our future. We need a better way, and research holds the answers.

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

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

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

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

Flagging Cancer Cells for the Immune System.

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