Special Feature on Five Years of Progress Against Cancer
Cancer Progress Report 2015: Contents
In this section you will learn:
Oncology is leading precision medicine efforts and transforming lives.
Genomics is the foundation on which precision medicine in oncology is built.
In the past five years, molecularly targeted therapeutics and immunotherapeutics have become part of routine care for patients with several types of cancer.
Big data show promise for increasing the number of precision therapeutics in our tool kit.
Genomically informed clinical trial designs are essential for moving precision medicine forward as quickly as possible.
To celebrate the fifth edition of the AACR Cancer Progress Report, included here is a special feature in which we highlight advances that have been made against cancer in the five years of publishing the report.
The year 2011 marked the 40th anniversary of the signing of the National Cancer Act of 1971, which focused the nation’s efforts and attention on the fight against cancer. Much changed between 1971 and 2011, and the AACR commemorated the amazing advances in cancer research made during that time with the publication of its inaugural AACR Cancer Progress Report.
In the four decades after 1971, we went from the concept that cancer is a single disease caused by viruses to the understanding that cancer is a vast collection of diseases, some of which are indeed caused by chronic infection with certain viruses, united by overgrowth of cells (see
Prevent Infection With Cancer-causing Pathogens). More important, however, was the discovery that cancer arises from a myriad of genetic changes within cells that accumulate with time (see
That discovery, coupled with advances in biology, chemistry, physics, and technology, set the stage for the new era of precision medicine. In fact, by January 2011, 20 therapeutics targeting specific molecules involved in the development and progression of cancer had been discovered and approved for patient benefit. Included in this list are not only therapeutics that target cancer-specific molecules, but also those that target the blood vessel growth that supports tumor development and some immunotherapeutics.
As described in this
Special Feature on Five Years of Progress Against Cancer, much has changed since January 2011.
Powered by fundamental research, our understanding of the inner workings of cancer has continued to explode. As we have learned more about the biology of cancer and both the normal and pathologic responses of the patient to cancer, we have been able to develop increasingly precise therapies that reduce the adverse effects of treatments while simultaneously enhancing their ability to eliminate certain forms of cancer, including some drug-resistant cancers.
Moreover, the pace at which this is being accomplished continues to accelerate year after year, providing a glimpse of an even brighter future. For example, from Jan. 1, 2011, through July 31, 2015, 32 additional therapeutics targeting molecules involved in the development and progression of cancer were discovered and approved for patient benefit, which is more than in the entire four decades prior.
Treating Cancer More Precisely
In 2001, the FDA approved the drug imatinib (Gleevec) for the treatment of Philadelphia chromosome–positive chronic myelogenous leukemia (CML).
This was a watershed moment.
Imatinib changed the standard of care for CML and transformed the lives of many patients with this previously fatal disease by increasing the five-year relative survival rate from 17 percent in the mid-1970s to 63 percent in 2007 (23). It also went on to become a very effective treatment for gastrointestinal stromal tumors (GIST), as well as several other forms of leukemia and myeloproliferative disorders. Equally important, imatinib helped to usher in the age of precision medicine by becoming the first chemical agent to target a cancer-specific protein, BCR-ABL.
What, then, is precision medicine?
Precision medicine, also known as personalized medicine, molecular medicine, or tailored therapy, is broadly defined as treating a patient based on characteristics that distinguish that individual from other patients with the same disease. Factors such as a person’s genome, his or her cancer genome, disease presentation, gender, exposures, lifestyle, microbiome, and other yet-to-be-discovered features are considered in precision medicine (24) (see
Figure 2). Currently, genomics is the predominant factor influencing precision medicine in oncology.
In essence, what precision medicine aims to do is identify the factors most unique to the disease state and use them for the purposes of preventing cancer, diagnosing disease, predicting patient outcomes, and directing therapy. Further, in the research and development setting, these characteristics are used to develop an ever-expanding toolkit of increasingly more precise anticancer therapeutics (see
Appendix Table 1). In other words, by understanding more about a particular disease, one should be able to develop “magic bullets” specific for that disease that would leave healthy tissue unharmed, a concept pioneered over 100 years ago by Paul Ehrlich, the father of chemotherapy for disease (25).
Over the course of more than 60 years, we have gone from a limited understanding of the specific factors that influence cancer development to a greater appreciation of the particular genetic mutations that can fuel a cancer (see
Figure 3 and
(Re)Setting the Standard of Care). With this more precise knowledge of cancer development, the tools used to prevent, detect, diagnose, and treat cancer have also become more precise.
Although precision medicine is not unique to the practice of oncology, oncology is leading such efforts largely because of our immense knowledge of the role of genetic mutations in the development and progression of cancer (see
Developing Cancer). When this fact is coupled with our increasing ability to read all parts of a person’s genome faster than ever before, it becomes clear that genomics is and will continue to be a key driver of precision medicine. It should be noted, however, that genetics is but one of the many factors relevant to precision medicine (see
Figure 2). As our ability to analyze all aspects of these other characteristics rapidly catches up with our current genomic prowess, we can expect faster and broader implementation of precision medicine in the near future, not only in oncology, but also in the treatment of other diseases.
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(Re)Setting the Standard of Care
Numerous advances over the past five years have greatly benefited patients. Chief among these has been a change in the standard of care for many types of cancer, as well as the addition of entirely new therapeutic modalities. Together with those that have been the mainstay of cancer treatment for many years, these new therapies give patients and their physicians many more options to treat, manage, and hopefully overcome their cancers.
In the not-so-distant past, there were three “pillars” of cancer treatment to effectively treat disease—radiotherapy, surgery, and traditional chemotherapy (see
With the advent of molecular biology, we began to understand various cancers at the molecular level and to develop new therapeutics that targeted those molecules that were closely associated with the root cause of the disease. Some of the earliest examples of such “molecularly targeted” therapeutics, which became the first generation of precision therapeutics, include rituximab (Rituxan) for the treatment of B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin) for the treatment of HER-2–positive breast cancer; and imatinib for the treatment of CML.
This first generation of precision therapeutics added a fourth “pillar” of cancer treatments, and provided new, less-toxic options for physicians treating patients with these cancers (see
Figure 4). Unfortunately, at the time, for patients for whom these drugs were ineffective, or for those who developed resistance, there were no other precision medicine treatment options. Fortunately, today this is different for patients with many, but not all, types of cancer.
Melanoma is the deadliest form of skin cancer, with only 16 percent of patients with metastatic disease surviving five or more years after diagnosis (6). The first new treatment option for melanoma in 30 years was approved by the FDA in 2011. Prior to that, the standard of care for patients with metastatic melanoma was dacarbazine, a traditional chemotherapeutic, and high-dose aldesleukin (Proleukin), an immune stimulant; however, neither agent had demonstrated a significant effect on overall survival in randomized trials (27).
Since January 2011, the FDA has approved six systemic therapeutics for treating patients with metastatic melanoma, three of which more precisely target the cancer than any other agents previously used to treat patients with this deadly disease (see
Figure 5). Two of these novel agents, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), are so precise that they are effective only against the approximately 50 percent of melanomas that harbor mutant forms of BRAF. These therapeutics have transformed the lives of many patients with metastatic melanoma and show the power of this approach to cancer treatment.
In addition, there are now six precision therapeutics for the treatment of CML, including an agent that targets the common T35I mutation (see Ref. 28 for more details). Similarly, chronic lymphocytic leukemia (CLL) patients have an equally extensive selection of precision therapeutics to treat their disease, including two new agents that were approved in 2014 (see Ref.1 for more details). Importantly, patients with melanoma, CLL, or CML are not the only individuals with numerous precision therapeutic options, as this is rapidly becoming the rule rather than the exception.
Undoubtedly, as we continue to learn more about the biology of those types of cancer for which no, or relatively few, precision therapeutic options currently exist, we will be able to develop equally impressive and deep toolkits of therapeutic options for patients with these diseases.
A New Pillar
During the past five years, another major advancement in cancer treatment was the addition of a fifth “pillar” of cancer treatment: immunotherapy (see
Figure 4). The concept of using a patient’s own immune system to eliminate his or her cancer is not new, but in the past five years we have finally been able to effectively translate knowledge about the immune system into revolutionary advances in patient care (see
Treatment With Immunotherapeutics).
There are numerous types of immunotherapeutics (see sidebar on
How Immunotherapeutics Work). The first immune-checkpoint inhibitor, ipilimumab, was FDA approved in 2011, with two others approved by the FDA in 2014, and many more in various stages of clinical development and regulatory review (see
Releasing the Brakes on the Immune System). The first therapeutic vaccine for the treatment of cancer, sipuleucel-T (Provenge), was also FDA-approved in 2011 for the treatment of metastatic prostate cancer. Now, some groups are using genomics to develop precision therapeutic vaccines (see
The past few years have also brought forth the concept of engineering a patient’s immune cells to specifically attack his or her cancer. This promising technique has resulted in chimeric antigen receptor (CAR) T–cell therapy, which has been shown in early clinical trials to successfully treat both pediatric and adult patients with several types of blood cancer (see
Boosting the Killing Power of the Immune System). Two CAR T–cell therapies recently received FDA breakthrough designations for the treatment of acute lymphoblastic leukemia (ALL), which will help this new form of immunotherapy reach patients as quickly as possible (see
Our understanding of this powerful class of therapeutics and the newest addition to the pillars of cancer treatment is just beginning. We will undoubtedly uncover even more effective and precise ways of using these tools in the near future (see
What Progress Does the Future Hold?).
As discussed above (see
Developing Cancer), cancer is characterized by alterations of the genome. We are now able to use these alterations to more precisely diagnose disease, predict patient outcomes, develop therapies, and direct treatment. Although the causes of cancer are far more complex than a collection of genetic mutations (see sidebar on
Cancer Growth: Local and Global Influences), genetic sequencing is one of our most effective tools for analyzing cancer. Consequently, many researchers have begun to investigate the possibility of using genetic sequencing to increase the relative precision of some non–genetic-based anticancer therapeutics.
As discussed in
What Progress Does the Future Hold?, several groups are actively using genomic sequencing to determine which patients are most likely to respond to various types of immunotherapeutics. Others are investigating whether genomics can be used to identify ways to develop more precise anticancer vaccines (29).
The earliest traditional chemotherapeutic was based on nitrogen mustard gas and was found to cause damage to DNA, leading to early death of rapidly dividing cells, such as cancer cells. The success of this and compounds like it led to the development of dozens of traditional chemotherapeutics that function to damage DNA (see
Appendix Table 1). Although these drugs are relatively imprecise, some groups have been using genomics to identify patients who have cancers that, due to certain genetic mutations, cannot efficiently repair damage to their DNA and stand to benefit the most from DNA-damaging agents (see
Ways to Use Radiotherapy and Traditional Chemotherapy More Precisely). In this manner, physicians can use genomics to more precisely deliver a class of otherwise relatively imprecise anticancer therapeutics.
Another way to increase the precision of a traditional chemotherapeutic is to link it to an antibody that recognizes and attaches to a specific protein on the surface of a certain type of cancer cell. Because this new therapeutic, called an antibody–drug conjugate, more precisely delivers the traditional chemotherapeutic to the cancer cells compared with conventional systemic infusion of the traditional chemotherapeutic, it is less toxic and causes fewer side effects. There are two FDA-approved anticancer antibody–drug conjugates, ado-trastuzumab emtansine (Kadcyla) and brentuximab vedotin (Adcetris), but many more of this emerging category of anticancer therapeutics are currently being tested in clinical trials.
These are but a few examples of how we are learning to use genomics and other molecularly based tools not only to enhance our knowledge of cancer but also to increase the precision with which we use our existing tools and therapies.
There are many uses for genomics. Two uses have the potential to convert small successes into benefit for much larger groups of patients (see sidebar on
Transforming Lives One Sequence at a Time). These are the use of genomics to assign a patient to a therapeutic not previously FDA approved for his or her cancer type, known as drug repositioning, and the use of genomics to determine why a few patients’ cancers either responded, known as rare-responders, or failed to respond, to a particular therapy.
The AACR Cancer Progress Report 2014 featured one such drug-repositioning story (1). At just 5 years of age, Zach Witt was diagnosed with anaplastic large cell lymphoma (see sidebar on
Transforming Lives One Sequence at a Time). His team of physicians at Children’s Hospital of Philadelphia performed genomic sequencing of his tumor and found that it contained a mutation in a gene called ALK. Because the FDA had already approved the ALK-targeted therapeutic crizotinib (Xalkori) for treating patients with non–small cell lung carcinoma (NSCLC) harboring ALK mutations, Zach’s physicians had recently initiated a clinical trial testing crizotinib as a treatment for childhood cancers carrying ALK mutations. Zach’s parents enrolled him in the trial, and thanks to crizotinib, he has been cancer free for several years. Successes like this have the potential to benefit the 10 to 15 percent of children whose lymphomas harbor the ALK mutation, if they are borne out in larger-scale clinical trials.
One rare responder, Warren Ringrose (see sidebar on
Transforming Lives One Sequence at a Time), is teaching physicians and researchers about how best to use sorafenib (Nexavar), which targets multiple molecules involved in angiogenesis and related signaling pathways that drive cell multiplication and survival. Warren was diagnosed with olfactory neuroblastoma and enrolled in a clinical trial testing sorafenib as a treatment for head and neck cancers. Warren was among the few individuals who responded to sorafenib, and continues to respond nearly two years later. In the not-so-distant past, Warren would have simply been considered “lucky,” an interesting medical anecdote. However, over the past five years, physicians and researchers have been increasingly turning to genomics to determine what makes patients like Warren “lucky.” By using genomics to learn about Warren’s success, physicians and researchers want to help make others like Warren the rule rather than the exception.
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As discussed above, there are numerous characteristics of a person and their cancer that need to be considered when implementing precision medicine (see
Figure 2). During the past five years, rapid technological progress has allowed us to analyze a person’s microbiome, hormones, genome, and epigenome at wholesale scales, a stark contrast from the past, when each would have been analyzed one at a time.
Coupling these advances with recent improvements in our ability to image the body and its contents more quickly, with higher resolution and increasing speed, we have made significant and rapid progress against cancer. This progress, however, brings its own challenges. We are now generating enormous amounts of data per patient, and this will only “balloon” as one scales these types of analyses across more patients to entire populations. Implementation of precision medicine for the treatment of cancer is, therefore, a “big data” problem (see
What are “big data”?
Big data are defined as data sets that are so large and complex that they cannot easily be analyzed using traditional methods. For big data to truly benefit patients, researchers must be able to convert this mass of data into meaningful knowledge. As the use of precision medicine, particularly genomics, moves closer to becoming the standard of care for everyone, the need to understand and manipulate big data will become even greater. Thus, researchers from all areas of the biomedical research enterprise need to work together to prepare for the coming tsunami of data.
In the United States and elsewhere, an experimental therapy must be tested in clinical trials and undergo evaluation by the relevant ruling regulatory body to ensure that it is both safe and effective. During the past five years, the pace of progress against cancer has accelerated dramatically. As the research landscape has changed, the regulatory and clinical trial landscapes have adapted to keep pace.
All Trial, No Error
Several changes relating to clinical trials have occurred during the past five years.
The first of these includes a shift in perception about clinical trials. Once viewed as the “last hope” for a given patient, they are now beginning to be considered as a normal part of cancer care. Although there remains room for improvement in attitudes toward and participation in clinical trials (see
Building Blocks to Furthering Precision Medicine), this change is helping to deliver novel treatments to the right patients as quickly as possible.
A major change to the conduct of clinical trials, particularly in the past five years, has been the use of genomics and adaptive trial designs to identify the patients most likely to benefit from a given therapy (see
Biomedical Research). These strategies seek to reduce the number of patients required to enroll in a clinical trial to demonstrate that a given therapy is effective.
These trials largely fall into one of two categories: basket studies and umbrella studies (see
Figure 7). Basket studies are those that test a given therapy on a group of patients who all have the same type of genetic mutation, irrespective of the anatomic site of origin of the cancer, whereas umbrella studies aim to identify the best therapy for different types of genetic mutations all within the same anatomic cancer type.
Whatever these types of studies are called, they are essential for moving precision medicine forward as quickly as possible. The conduct of clinical trials has been revolutionized in a few short years, and undoubtedly we can expect this revolution to continue as precision medicine moves forward at an ever-quickening pace.
As discussed above, the revolution in cancer research can be meaningful for patients only if the governing bodies that approve the resultant novel therapies adapt as the research landscape changes. In the United States, the FDA has done just that by developing numerous new strategies to get safe and effective therapies to patients as quickly as possible (see sidebar on
FDA’s Expedited Review Strategies).
In addition to these expedited review strategies, in 2012 the FDA initiated a new path to enhance the pace at which experimental breast cancer therapeutics are approved (see (1) for more details). In 2013, pertuzumab (Perjeta) became the first therapeutic to be approved under this new regulatory path, and the molecularly targeted therapeutic is now benefiting patients with HER-2–positive breast cancer.
These are but a few examples of how the FDA is working to transform patients’ lives as safely and quickly as possible.
The past five years have been an amazing period of change in cancer research and medicine, and the examples presented here are surely but a small sampling of what we can expect in the next five years.
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Progress Report 2015 Contents