Personalized Cancer Medicine
Cancer Progress Report 2011: Contents
Genomics and Molecular Biology are Transforming Patient Care
The advanced technologies that researchers are using today to sequence cancer genomes, identify altered genes and proteins, and analyze the wealth of information from these technologies are making it increasingly possible to link specific defects in the molecular machinery of cells and tissues to the development of cancer.
As a result, we now have the ability to identify mutations in an individual patient’s tumor and use that information to select cancer therapies precisely targeted to these cancer-causing mutations. These discoveries are moving us from an era of one-size-fits-all cancer care to an exciting era of personalized cancer treatment. Knowing the molecular defects in a cancer also promises to identify individuals or populations who may be at increased risk of developing certain types of cancers, thereby reshaping and strengthening our efforts in cancer prevention.
This new era of molecularly based cancer medicine is the culmination of many successes in fundamental or laboratory research and applied research. This progress represents a clear-cut example of the significant return on investment from such research.
We currently stand at a defining moment in our ability to conquer cancer. The molecular biology revolution set the stage for the rapid pace of innovation that has defined the recent decades of cancer research. Exciting fundamental discoveries are occurring at an ever-accelerating rate, and further improvements in cancer patient care and survival will depend in large measure on continued progress in all areas of cancer research.
Molecular Classification of Cancer Subtypes:
The Foundation of Personalized Cancer Medicine
As described above, tumors are now being detected using standard imaging methods, like mammography, MRI, and colonoscopy, as well as more advanced imaging techniques like FDG-PET, DC-MRI, and CT. Once detected, a tumor sample that has been obtained by a biopsy is examined by pathologists, who help determine the cancer’s stage and grade based on changes in cell shape. We now know that this approach, which has served us for many years, is insufficient when used alone to determine the best course of treatment for most cancers.
Thanks to advanced technologies and progress in genomics and molecular biology, we can now identify the unique molecular characteristics of cancer cells, known as biomarkers. Previously, the organ of origin, such as the lung, brain, etc., defined an individual’s cancer. Now, a cancer can be defined by what intrinsic molecular changes drive it. Our ability to identify the genes and molecular pathways that are disrupted in these diseases is providing a new foundation for classifying them into specific molecular subtypes, thus permitting more precise treatment strategies.
To this end, a number of large-scale efforts, such as TCGA, are now underway to identify all of the genomic alterations within specific types of cancer to provide support for the development of biomarkers for these cancers. Early results from TCGA have already revealed previously unknown underlying causes of ovarian cancer and glioblastoma, opening up opportunities for the development of new, much needed treatment strategies for these two cancers that are too often fatal due to the difficulties associated with detecting and treating them (see
Molecular biomarkers, which may correlate with specific clinical aspects of the tumor, are ushering in a new paradigm for designing and developing more effective and less harmful drugs, known as targeted drugs or therapeutics. Further, these biomarkers are having an impact on all aspects of cancer care including prevention, early detection, diagnosis, treatment, and drug development. As a result, we are now beginning to understand why two patients with a disease like lung cancer may have two very different diseases at the molecular level, requiring two entirely different courses of treatment. The development of targeted cancer therapies based on an individual’s molecular subtype is progressing quickly and, in doing so, is driving the development of a new generation of clinical trials and providing new hope for cancer patients at high risk for recurrence following standard therapies.
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Molecularly Based Drug Design
The development of lifesaving or life-improving cancer drugs is essential to our ability to control cancer. Traditionally, cancer drugs were made by chemists and then tested in models where they were evaluated for their ability to stop cancer cell growth. If these tests were passed, the compounds entered clinical trials. Because these traditional chemotherapy drugs were developed to stop both rapidly dividing healthy and cancer cells, unfortunately, due to toxicity, they have debilitating short- and long-term side effects.
Our increased understanding of cancer biology, which has been made possible by advances in genomics and molecular biology, has forever changed the way cancer drugs are developed and tested, and it has created research opportunities to develop more effective drugs that have the potential to increase survival in many cancers that previously eluded treatment. These drugs are available to patients because of the investment of hundreds of millions of dollars by the pharmaceutical and biotechnology industries.
Presently, once a molecular alteration fueling a cancer’s growth is identified, drugs to target this precise alteration can be developed. This method of drug development, called rational drug development, differs significantly from the development of traditional chemotherapies in that the compounds are designed using computers to most closely match their intended targets. Rationally developed drugs approach a level of precision that has never before been seen in medicine. Because of this precision, rationally designed cancer drugs that target cancer cells specifically lessen and, in many cases, eliminate drug toxicity. Today’s advances in drug development, clinical trial design, and treatment are the result of our ability to identify the biomarkers associated with the molecular subtypes of cancer and rationally design drugs to precisely target them.
However, to fully realize the advantages of biomarkers in research and care, the fundamental problems inherent in turning discoveries into drugs that benefit patients must be addressed. Typically, drug development is complex, high-risk, and time-consuming, and all too often new promising agents never make it through to full development into the clinic, becoming lost in a gap that some refer to as the “valley of death.” This gap arises when promising discoveries lack sufficient investment to develop them into new FDA-approved therapeutics or diagnostics. Steps must be taken to address this challenge.
One potentially effective way to bridge this gap would be to increase pre-competitive collaboration among all sectors in the field - academia, government, the biotechnology and pharmaceutical industry, philanthropic organizations, patient advocacy groups, and the patients themselves - that are involved in the drug development process. Other potentially synergistic, worthy ideas almost certainly exist and need to be vetted in order to effect real change in this complex problem.
The research that underpinned advances in genomics and powered the molecular biology revolution has demonstrated what is possible when a country agrees to invest in science, technology, and innovation. However, this visionary strategy also underscores the need to develop the infrastructure necessary to support molecularly based medicine: a robust network of high-quality, clinically annotated tissue samples, or biospecimens, collected using global standards in privacy protection and archiving; and platforms in genomics and proteomics with the accompanying informatics for data analysis and communication between research laboratories. The effectiveness of both molecular classification of tumors and targeted drug development, for the benefit of patients everywhere depends on the availability of biospecimens that are properly consented, collected and annotated.
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The Dawn of Molecularly Driven Drug Design
A powerful example of the dramatic changes in drug development which we are now witnessing began not long after the signing of the National Cancer Act, when researchers discovered that a molecular defect due to a chromosomal translocation in a majority of patients with chronic myelogenous leukemia (CML) correlated with the production of a novel signaling enzyme, called a kinase, that caused the overproduction of certain blood cells. This discovery propelled researchers across disciplines to collaborate on the development of both a detailed computational analysis of protein structures and a large collection of new agents that could block these abnormal kinases. Through this process, the first rationally designed oncology drug, imatinib (Gleevec), was developed (see
Imatinib proved that drugs could be purposefully developed to block the activity of a specific kinase target, and its success was the catalyst for the 13 FDA-approved kinase inhibitors now being used to treat a variety of cancers, as well as other drugs now in development or in clinical trials. Kinase inhibitors are part of a much larger family of drugs, called small molecule inhibitors, many of which are being developed using a similar rational design approach. The development of imatinib for the treatment of CML revolutionized drug development, spawning several classes of new drugs that are now being used in the clinic to treat cancer and other diseases.
The Use of Biological Agents to Treat Cancer
Some of the cancer biomarkers that researchers have discovered are proteins, called growth factor receptors. These receptors sit on the surface of cells, where they interact with proteins on the outside of the cell and relay signals into the cell. Within the cell, each signal is relayed across an extensive network by kinases, ultimately resulting in changes in the cell’s behavior.
Antibodies are also proteins that are naturally made by a type of immune cell, called a B-cell. Their role in normal cells is to identify and kill foreign invaders, such as viruses and bacteria. Researchers undertook a strategy to block the activity of the specific receptors driving certain cancers by developing therapeutic antibodies that block receptor function and thereby halt tumor growth. The increased function of these receptors and their signaling networks are the result of genetic changes specific to the cancers in which they occur. Therapeutic antibodies can be used alone, or in combination with chemotherapy, to treat different types of cancers. Researchers have also devised ways to attach chemotherapy drugs or radiation-emitting particles to therapeutic antibodies in order to deliver them directly to the cancer cells and avoid damaging normal cells.
The innovative technologies that researchers use to produce large quantities of human antibodies in mammalian cells have made it possible for researchers to develop an entirely new class of drugs, called therapeutic antibodies. Now more than a dozen therapeutic antibodies have been approved by the FDA for use against a number of cancers, and many more are in clinical trials. Moreover, researchers have discovered that some of the antibodies used for oncology could be used to treat other diseases, like rheumatoid arthritis, providing an enhanced and unexpected return on investments in cancer research.
Molecularly Based Treatment Advances
Our enriched understanding of cancer biology is providing insights into the differences between normal cells and cancer cells. A detailed understanding of the intricate network of signals that control how a cancer cell functions, combined with advances in drug development, now makes it possible to precisely target these differences in order to treat only the cancer cells while minimizing damage to healthy cells. Using molecular tests, we can increasingly match patients to targeted drugs with pinpoint accuracy, and we are at the initial stages of learning how to predict which of these patients will respond best to which drugs. All of these advances have already made a real difference in the lives of a growing number of cancer patients, the 12 million cancer survivors in the U.S., and their families and loved ones.
Epigenetics is the study of how the DNA is modified and packaged into chromosomes within a cell. The discovery that epigenetic changes can drive cancer has resulted in 4 new FDA-approved drugs that target epigenetic processes for the treatment of certain leukemias, cutaneous T-cell lymphoma, and myelodysplastic syndrome, the latter of which occurs when cancer of the stem cells within the bone marrow fail to produce adequate numbers of normal blood cells. For the treatment of myelodysplastic syndrome, these epigenetic drugs are now the standard of care. Moreover, several Phase I and II clinical trials have shown promising results using these drugs in combination with other molecularly targeted therapeutics. The future of epigenetic therapies is considered to be quite promising.
Cell Signaling Targets
As described above, the success of imatinib (Gleevec) guided the development of subsequent drugs that block various components within signaling networks. As a result, 14 chemically based kinase inhibitors have been approved by the FDA to treat an ever-expanding array of cancers, while more are currently in all phases of clinical trials, and still others are in the final stages of approval.
Among these are 3 FDA-approved drugs for patients with CML in which the tumors have a specific chromosomal translocation, called the Philadelphia chromosome, that makes the BCR-Abl kinase. For these patients who comprise 95% of all CML patients, these drugs, which are now the standard of care, have transformed a cancer diagnosis that was previously a death sentence into one with a 5-year survival of 86%. More recently, they have also been found to be effective in the 5% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) patients who also have this chromosomal translocation.
Further, 2 FDA-approved kinase inhibitors are now the standard of care for non-small cell lung cancer; 4 are now used to treat renal cell carcinoma; 2 each are used to treat gastrointestinal stromal tumors and pancreatic neuroendocrine tumors; and 1 each are used to treat metastatic breast cancers and medullary thyroid cancers. Additionally, a very unique small molecule inhibitor, called bortezomib (Velcade), is now the standard of care for patients with multiple myeloma. This interesting drug works by blocking the breakdown of proteins, which leads to the disruption of multiple pathways that are necessary for tumor cell proliferation.
The small molecule inhibitors, like imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) have rendered all but a few blood cancers chronic rather than lethal conditions. Unfortunately, for many patients with solid malignancies, these new precision drugs are used to treat their disease after it has already progressed on less precise therapies. However, these new, more precise drugs provide new hope for long-term survival. With more progress, it is likely that, in the near future, precision therapies like the ones described here will be the first choice of treatment for all appropriate patients.
While the above-mentioned drugs work by targeting components inside cells, signaling networks can also be blocked from outside the cell, which is achieved by using drugs, called therapeutic antibodies. For patients with non-Hodgkin’s lymphoma, the first-in-class rituximab (Rituxan), which targets a blood cell-specific surface protein, was a great advance. Trastuzumab (Herceptin), which is used to treat the approximately 20% of breast tumors that are HER2-positive, has improved survival for these women by about 24% (meet cancer survivor and trastuzumab patient
Bonnie Olsen). For those patients with EGFR-expressing metastatic colorectal cancer, panitumumab (Vectabix) expands their treatment options.
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Targeting the Cancer Cell’s Environment
Clinical experience has taught us that targeting cancer cells alone is not sufficient to completely treat a patient’s cancer. Fundamental research has identified that the tissue surrounding the tumor plays a role in cancer progression, thus offering new drug targets including the tumor vasculature and the immune system.
The Tumor Vasculature
Five FDA-approved drugs work by blocking the growth of the new blood and lymphatic vessels that a tumor needs to grow and thrive; these are now regularly used to treat patients with renal cell carcinoma, medullary thyroid cancer, gastrointestinal stromal tumors, non-small cell lung cancer, metastatic colorectal cancer, and pancreatic neuroendocrine tumors. Clinical trials are now underway to determine if other types of cancers can be effectively treated with these therapies.
Harnessing the Patient’s Immune System
Recently, it was discovered that many cancers are able to inactivate a patient’s immune system. This finding led to the development of the therapeutic antibody, ipilumumab (Yervoy), which helps to re-activate the patient’s immune cells (meet cancer survivor and ipilumumab patient
Andrew Messinger). This drug is a new and welcomed advance for patients with metastatic melanoma, an aggressive type of skin cancer with few active treatment options. Clinical trials are now underway to test its effectiveness for the treatment of prostate and non-small cell lung cancer.
Immunotherapy, using a vaccine to program the immune system to attack cancer cells, is another new development. The cancer vaccine, sipuluecel-T (Provenge), is now being used to treat patients with metastatic prostate cancer. This strategy is currently being studied in a number of clinical trials to see if it is effective against other cancers. Finally, other immunotherapeutic strategies are in their early stages of development and are showing great promise (meet cancer survivor and immunotherapy patient
These clinical advances are the direct result of our increased understanding of cancer biology and our current ability to develop drugs that specifically target these processes. This approach has made it possible to develop entirely new classes of drugs that are more effective and less toxic than the treatments that have been the mainstay of patient care for many years.
Tumor Heterogeneity and Its Effect on the Response to Cancer Therapy
The complexity of cancer at the level of an individual tumor is the root cause of our failure to completely eliminate many tumors with current drug therapy.
Over the past 40 years, we have learned that a single tumor contains many subpopulations of cancer cells, meaning that a tumor is heterogeneous. The rapid pace of cell division, coupled with the malfunctioning DNA repair systems of cancer cells, results in unstable and error-prone genomes; together, these are the primary drivers of tumor heterogeneity.
As a result, some tumor cell subpopulations may be actively proliferating while others are not; a different subpopulation may contain one genetic alteration leading to rapid proliferation, while another may contain several distinct molecular defects. Heterogeneity is what drives insensitivity to treatment of both cytotoxic and molecularly based therapeutics, a problem that is magnified exponentially when considering both primary and metastatic lesions.
In some cases, a patient’s tumor may initially shrink or stop growing in response to a treatment, stop responding to that treatment, and then begin to grow again. Thus, following treatment, some portion of the tumor cells will be eliminated; however, the cells that do not respond to therapy will continue to proliferate and replace the cells that have been eliminated. As such, the entirety of the tumor can become resistant to a therapy that was previously successful; this is known as acquired resistance. This form of resistance can be caused by new mutations within the cancer cells themselves or the inherent redundancy in the signaling networks that cause cancer (see
Drug Resistance Sidebar).
In other cases, a patient is resistant to the therapy from the outset, referred to as innate resistance (see
Drug Resistance Sidebar). This occurs when the presence or absence of other genetic mutations, within either the patient’s genome or the tumor’s genome, modifies the response to therapy. These factors may alter how a patient metabolizes the drug or how effectively a drug hits its target.
Tumor heterogeneity also explains why simultaneously targeting multiple targets within a cancer cell should increase the likelihood of completely eliminating a tumor and simultaneously preventing drug resistance. For example, it is now commonplace to treat a variety of cancers by using a combination of traditional cytotoxic chemotherapies with varying mechanisms, as well as combinations of more traditional drugs with newer molecularly based drugs.
It is now clear that testing for multiple biomarkers will be necessary to predict innate resistance or the development of acquired resistance and therefore response to therapy. The development and use of biomarker signatures will increase the efficacy of an increasingly precise form of therapy. In the near future, biomarker signatures will be used to identify the most appropriate combination of molecularly based drugs for a given patient or patient population. This can only occur if there is further biomarker development and the regulatory path is cleared for combinations of molecularly based therapeutics.
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Molecularly Informed Clinical Trials
The first impact that biomarkers have had on cancer research was in drug development. Now biomarkers are revolutionizing the design of clinical trials required for their approval.
A drug that shows promise in laboratory studies is further developed by testing it in clinical trials; these trials are done with patients to determine definitively whether a treatment is safe and effective in humans. The FDA examines these clinical trial data to determine whether the drug meets the standards for approval.
Clinical trials are currently completed sequentially in a series, referred to as Phase I, II, and III clinical trials. Phase I trials are the first studies done in humans and are primarily intended to determine safety. Phase II trials continue to test safety and begin to evaluate how well a drug works to treat a specific type of cancer. If a drug, or new combination of drugs, fulfills the aims of these initial studies, then a Phase III clinical trial is initiated to compare the new therapy to the standard of care. Phase III studies involve large numbers of patients who are typically randomized to receive the standard of care or the new experimental treatment.
Historically, it takes many years for cancer clinical trials to determine the efficacy of a particular treatment based on defined endpoints, such as disease-free survival or overall survival. Because of this delay in obtaining the results, researchers are actively using advanced imaging techniques to monitor tumor size and number as surrogates for overall and disease-free survival for many tumor types. Surrogate endpoints can decrease the duration of the study, as well as reduce the overall time and cost of bringing new drugs to patients.
Researchers are also actively trying to identify biomarkers that will predict whether a patient is likely to respond to a given treatment. Tumor microarrays have already been shown to predict which breast cancer patients require chemotherapy from those who are unlikely to benefit from its use. Increasingly, clinical trials are measuring biomarkers in tumor tissue and blood collected at the time of surgery to provide a more detailed analysis of trial results and to identify individuals who may best benefit from a particular therapy.
The further evolution of this concept is seen in 2 Phase II proof-of-concept trials, I SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) and BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination).
In the I SPY 2 trial, experimental therapies are given prior to surgery, and response is determined by a series of MRI images that track tumor size. Patients are genetically screened for a number of biomarkers, and the researchers use that information to generate a common biomarker “signature” for patients who respond to a particular therapy. As the trial progresses, the experience of patients that have completed the trial is used to change the course of the trial while it is still active, rather than waiting until it has completely ended.
The BATTLE trial aims to stratify advanced stage non-small cell lung cancer patients genetically and determine outcomes in real time. This trial randomly assigns non-small cell lung cancer patients to a targeted therapy and then follows patient response as a function of their genotype. Early results from this trial suggest that this approach will be successful at linking biomarker signatures to drug response.
Importantly, because of their design, adaptive trials can reduce the number of patients that must be enrolled in order to achieve statistical significance. A large Phase III study may typically need to enroll 3,000 or more patients to obtain enough data to receive FDA approval, whereas only 300 patients may be required in an adaptive trial. Utilizing fewer patients per trial is increasingly important because not every targeted therapy will work for every patient. We will continue to witness these advances as modern clinical trial designs are adapted to incorporate biomarkers. Validated biomarkers have the potential to transform cancer research and dramatically improve patient care; however, in order for these advances to continue at a rapid pace, the challenge of patient enrollment in clinical trials must be addressed. Inadequate patient accrual is a major obstacle to all clinical trials and, in particular, to continued success in the development and approval of molecularly based drugs. Unfortunately, fewer than 5% of adults diagnosed with cancer participate in a clinical trial, despite the fact that clinical trials are an opportunity to receive the latest and most innovative treatments for their disease.
Low patient participation in clinical trials, particularly in underserved and minority populations and geriatric patients, is a major hurdle that must be addressed. There are many reasons why patients do not participate in clinical trials: fear of side effects, lack of awareness, lack of physician awareness or encouragement, bothersome trial requirements, ineligibility, language or cultural barriers, age, and race (see
Aging and Cancer and
Cancer Disparities Sidebars).
Overall, today’s advances in cancer treatment have given us a window into the future of cancer care, and these discoveries are only the beginning. Personalized cancer medicine is still in its early stages of development. As fundamental science continues to provide more molecular information about the biology of cancer, we will witness the further development of unimaginable advances in molecular therapeutics and diagnostic tools, all of which will facilitate the needed precision when choosing the best treatment for an individual patient’s cancer.
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Molecularly Based Prevention
Our increasing understanding of the unique biological processes of cancer cells has enhanced methods to assign tumors to specific subtypes, enhanced and expanded the process of cancer drug development, and improved patient care. It has also begun to provide a molecular profile of a patient’s risk of developing cancer that can be used to tailor their individual prevention program.
For example, it is now known that women who have inherited a mutation in one or both of the two tumor suppressor genes, BRCA1 and BRCA2 (BReast Cancer Associated genes 1 and 2), have a 50 to 85% risk of developing breast cancer over their lifetimes, as well as a markedly increased risk of ovarian cancer (meet three-time inherited cancer survivor
Zora Brown). Men who inherit these mutations are also at increased risk of developing breast cancer, and have an increased risk of an aggressive form of prostate cancer. Inherited BRCA mutations are only responsible for about 5 to 10% of all breast and ovarian cancer cases that occur. Currently, however, other genes have been discovered that can be inherited in a mutated form, which confers a marked increase in the risk of developing certain cancers. Unlike these inherited mutations, the vast majority of breast and other cancers are caused by acquired, or somatic, mutations that accumulate during one’s lifetime.
Although currently there is no way to correct these inherited cancer gene mutations, the knowledge that individuals are in a high-risk category can induce them to modify their behaviors to reduce risk from other factors, intensify their screening or early detection strategies or, under certain circumstances, consider the option of preventive removal of the organs that are at greatest risk for cancer.
In addition to behavior modification, increased screening, and preventive surgery, research has given us a new prevention tool, called chemoprevention. Our ability to associate detailed information, including molecular information, about the patient and tumor, with an increase in cancer risk has given rise to the field of chemoprevention, which aims to treat at-risk individuals with a targeted drug to reduce their risk.
One example, although not molecularly based, is in non-small cell lung carcinoma where the cytotoxic chemotherapeutic pemetrexed (Alimta) is an effective maintenance therapy only for those patients that have the non-squamous cell form of lung cancer. Identifying the molecular details about this patient population can only further enhance the precision of this chemopreventive strategy.
In breast cancer, however, the molecular understanding that the hormone, estrogen, drives at least 65% of breast cancers has provided an excellent chemopreventive tool. Two FDA-approved drugs that block the effect of estrogen on its receptor, tamoxifen (Novadex) and raloxifene (Evista), reduce the chance of developing breast cancer by about 50%, or by 38% in women at increased risk, respectively. Further the protective effect can last for years.
Likewise, the non-steroidal anti-inflammatory drug, celecoxib (Celebrex), is FDA-approved to prevent and reduce the formation of colorectal polyps in patients with a high-risk genetic condition, called familial adenomatous polyposis (FAP); studies have shown a dose-dependent approximate reduction in the occurrence of polyps between 30 and 50%.
Similarly, finasteride (Proscar), a synthetic anti-androgen agent, has been shown to reduce prostate cancer by 25% in men, aged 55 and older. These are remarkably powerful effects, but we must work even more diligently to identify agents that can effectively prevent the initiation of cancers and that do not themselves have significant side effects. Current preventive agents are effective, but are not widely embraced by physicians and the general public for individuals who have no apparent disease. Using better patient stratification, and incorporating more molecular data about high-risk populations, will ensure the future success of chemoprevention.
Chemoprevention is an important area of research and future opportunity; as such, it has not been overlooked by federal funding agencies. There are approximately 150 chemoprevention clinical trials underway to identify strategies that can be used to reduce cancer incidence in high-risk populations. Continued investment in biomarkers and targeted therapies will result in better matching of high-risk patients to chemopreventive agents in ways that will ultimately tip the risk-benefit scale in favor of these new interventions.
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Progress Report 2011 Contents