Making Research Count for Patients

Cancer Progress Report 2012: Contents

Cancer research over the past four-plus decades 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. These advances have helped save millions of lives in the U.S. and worldwide.

This past progress has set us on our current path to a more complete understanding of cancer biology, which is moving cancer research in exciting new directions. Continued discovery is yielding further insights into the complexity of cancer, which exists at every level, from populations to individuals to specific cancers and to the very genes that drive these cancers. This unprecedented knowledge is beginning to transform the current standard of care, providing new hope for patients.

Uncovering the mysteries of cancer and translating them into breakthrough therapies for patient benefit requires the collaboration of researchers and physicians from various disciplines. In the past 12 months alone (September 2011 through the end of August 2012), the FDA approved eight new drugs for cancer treatment, bringing to fruition the hard work of many thousands of individuals over many years. Also during this same period, the FDA approved additional uses for three existing drugs, increasing markedly the number of patients benefiting from them.

In the following discussion which focuses on these recent FDA approvals and also provides insight into other therapies that are showing near-term promise, it is important to note that these recently developed therapies are predominantly used in conjunction with the traditional triad of cancer patient care—surgery, radiotherapy and chemotherapy. Although not highlighted in this report, substantial progress has been made in these important areas of cancer medicine. Determining the optimal combination of treatment approaches is an area of intensive investigation.

A New Day for Our Current Knowledge

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 cancer development. As a result, we now have the ability in some cases to identify the molecular drivers of an individual patient’s tumor and use that information to select cancer therapies precisely targeted to the cancer-causing molecular deficiency. These therapies are more effective and less toxic than the treatments that have been the mainstay of patient care for decades, meaning that they are saving the lives of countless cancer patients as well as improving their quality of life.

Despite the tremendous progress in patient care that has been achieved through the development and use of molecularly targeted drugs, at this time not all cancer patients are able to benefit to the same extent. In some individuals, a drug predicted to destroy the tumor fails to have any effect, and for others, the tumor responds initially but then starts to grow again. Other patients may have a tumor for which the specific underlying molecular defect has yet to be defined. Still other patients may have defined mutations that are not matched with a precisely targeted therapy. Leveraging our current knowledge has proven fruitful, both in enabling cancer researchers to address these challenges and in further advancing quality patient care.

A New Day for Old Targets

Variability in patient responses to new target drugs is a major challenge in cancer treatment. While some patients’ tumors will respond, some will not respond at all, and still others will initially respond and stabilize or begin to grow again. To meet this challenge, we need to understand what causes the variability and use this information to design combination therapies or new therapies to overcome these causes. This is an active area of research and it is beginning to bear fruit. In many cases, diligent analysis of the drug and its molecular target is critical, and it is enabling the design of more efficacious drugs that target the same molecule as the original therapies.

Two New Ways to Hit a Breast Cancer Target

An estimated 226,870 new cases of breast cancer will be diagnosed in 2012 (3). In approximately one out of every five cases, the cancer overexpresses HER2 protein (73). These cancers tend to be aggressive and have a poor patient outlook. Decades of fundamental research led to the clinical development and FDA approval of the therapeutic antibody trastuzumab (Herceptin), which exerts its anticancer effects after attaching to HER2 on the surface of the breast cancer cells. It revolutionized treatment for women with HER2-positive breast cancer, prolonging survival in those with metastatic disease by 24% (74) and reducing the risk of recurrence after surgery in those with early-stage disease by up to 24% (75). Unfortunately, some patients with advanced HER2-positive breast cancer fail to respond, and in most of those who do respond initially, the disease ultimately progresses. A second FDA-approved HER2-targeted therapy, lapatinib (Tykerb), provides some benefit in these situations (76, 77), but new therapies for this subtype of breast cancer are urgently needed.

Rigorous scientific assessment of the reasons why trastuzumab fails to eliminate all HER2-postive breast cancer cells in most patients led to the development of pertuzumab (Perjeta), which the FDA approved in June 2012 as part of a combination therapy for the treatment of metastatic HER2-positive breast cancer. The FDA-approved combination includes trastuzumab and pertuzumab because together, they are thought to provide a far more comprehensive blockade of HER2 function, and thus greater anticancer activity than either does alone. In patients with advanced HER2-positive breast cancer, this dual targeting of a single molecule (HER2) significantly prolongs the time to disease progression by almost 50% (73). 

An exciting new approach to treating women with HER2-positive breast cancer is currently in the early stages of clinical testing. The drug being studied, called T-DM1, is an antibody-drug conjugate, and its development is the culmination of many years of dedicated collaboration among researchers from many different disciplines. Antibody-drug conjugates are a new type of targeted therapy that uses an antibody component to deliver cytotoxic chemotherapy drugs more precisely to just those cancer cells that express the antibody target. This precision reduces the side effects of the chemotherapy agent compared with systemic delivery. In the case of T-DM1, a small amount of the chemotherapy drug DM1 is attached to trastuzumab, which delivers the DM1 directly to HER2-positive cancer cells. Early results from clinical trials of T-DM1, suggest that the drug significantly reduces the risk of cancer progression or death in many women who, like Kathryn Becker, have metastatic HER2-positive breast cancer (78). Additional time to follow the patients on these trials is needed to make a definitive conclusion as to the efficacy of this approach.

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What to do When One of the Most Effective Molecularly Targeted Drugs Doesn’t Work

Imatinib (Gleevec) was the first molecularly targeted chemical developed for cancer treatment. Its discovery was the result of a series of groundbreaking scientific findings. First, chronic myelogenous leukemia (CML) was linked to an abnormal chromosome in tumor cells, called the Philadelphia chromosome; subsequently, researchers found that two genes, BCR and ABL, were fused to create both the odd chromosome and a mutated protein that fueled this cancer type. Because imatinib effectively blocks the activity of the BCR-ABL fusion protein, its 2001 FDA approval changed the lives of CML patients. Five-year survival rates increased from just 31% to more than 90% (3, 79). Unfortunately, a small fraction of patients fail to respond to imatinib. Other patients initially respond, but eventually stop. In these cases, when the disease returns, or relapses, the leukemia is said to have acquired resistance to imatinib (see Sidebar on Drug Resistance). 

Fundamental research determined that those patients who either fail to respond or ultimately relapse have leukemias that harbor mutations in imatinib’s target, the BCR-ABL fusion protein, that prevent the drug from blocking BCR-ABL activity. Researchers have identified ways to circumvent most of these mutations, and two second-generation drugs, dasatinib (Sprycel) and nilotinib (Tasigna), were developed and FDA approved. However, both fail to block one particular mutation, and that remains a significant clinical problem. Fortunately, recent advances have led to the development of an investigational drug, ponatinib, which is active against this mutation. Ponatinib is showing tremendous promise in phase II clinical trials, where robust anti-leukemic activity has been reported in patients with CML that is resistant or intolerant to currently available treatments.

Refining Drug Potency and Specificity

The striking success of drugs such as imatinib is very encouraging in that they precisely target the cancer-driving molecular aberrations that are intrinsic to cancer cells. However, recent clinical experience has revealed that for many cancers, in particular those affecting large organs such the liver and kidneys, targeting cancer cells alone is not sufficient to completely treat a patient’s cancer. In the case of the most common type of kidney cancer in adults, which is renal cell carcinoma, research has identified that these cancers are particularly dependent on the growth of new blood and lymphatic vessels to grow and thrive. Thus, they are the perfect targets for therapeutic intervention.

Over the past decade, the FDA has approved seven drugs that work in similar ways to impede the growth and stability of the emerging blood and lymphatic vessel networks. These drugs target a family of growth molecules and their receptors, called VEGF, which are found mostly on blood and lymphatic vessel walls. These therapies have significantly improved outcomes in patients with metastatic renal cell carcinoma, a particularly insidious stage of the disease that is resistant to conventional chemo- and radiotherapy, and which has a five-year survival rate of less than 10% (80). Of the antiangiogenesis drugs that block the VEGF receptors, their ability to suspend new vessel growth differs, due in part to varying efficiency in VEGF blockade as well as their effects on several related molecules. Drugs with greater potency and specificity for the VEGF receptors are being developed; for example, the FDA approved a new drug in this class, axitinib (Inlyta), for the treatment of renal cell carcinoma in January 2012 (81). Furthermore, in August 2012, the FDA approved the newest member of this growing family, ziv-aflibercept (Zaltrap), for the treatment of metastatic colorectal cancer.

Drugs that block the VEGF receptors, disrupting the blood and lymphatic vessel networks that grow to support a cancer’s growth, are not just used to combat renal cell carcinoma; they are also FDA approved for the treatment of the most aggressive form of liver cancer, some forms of pancreatic cancer, and some lung and colorectal cancers. An emerging new drug in this class of therapies is regorafenib, which potently targets the TIE2 receptor in addition to the VEGF receptors. This agent has the potential to increase its effectiveness as a therapy, since TIE2 is also believed to play an important role in blood and lymphatic vessel stability and growth. Regorafenib is currently being tested in clinical trials as a treatment for several advanced stage cancers. Particularly promising are the preliminary results of a large study examining its utility as a treatment for patients with metastatic colorectal cancer (82). With a five-year survival rate of only 12% with this disease, there is a huge need for new treatment options (3). See the female metastatic colorectal cancer patient’s story.

Improving Patient Quality of Life by Reducing Side Effects

The FDA approved bortezomib (Velcade) for the treatment of multiple myeloma in 2003 and for the treatment of one of the rarest but fastest growing forms of non-Hodgkin's lymphoma, mantle cell lymphoma, in 2006. The drug is highly effective in patients with multiple myeloma, with its use almost doubling the five-year survival rate. Many patients, like Congressman M. Robert Carr, have achieved a durable complete response to the treatment (83).

Bortezomib is a unique drug that blocks the breakdown of proteins, leading to the disruption of multiple pathways that are necessary for tumor cell proliferation. Its mode of action is not as precise as that of drugs that target cancer-driving molecular defects intrinsic to cancer cells, and as a result it has significant side effects. One side effect that considerably diminishes the quality of life of many patients is a condition called peripheral neuropathy, which causes numbness, loss of sensation and pain in the hands and feet. 

Two FDA decisions in 2012 should help reduce this serious adverse side effect and will increase the number of treatment options available to patients with multiple myeloma. The first is the July 2012 FDA approval of carfilzomib (Kyprolis) as a new treatment for multiple myeloma. Like bortezomib, carfilzomib prevents the breakdown of proteins, but its blocking effects are more sustained and it can be administered on a schedule that is effective but significantly reduces peripheral neuropathy (84). The second is the January 2012 FDA approval of a change to the way that bortezomib can be given to patients. Clinical trial results indicated that administering bortezomib under the skin, rather than into the veins, did not diminish treatment effectiveness, but dramatically reduced suffering related to severe peripheral neuropathy (85).

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A New Day for Existing Drugs

After performing arduous clinical trials that lead to FDA approval for a drug, researchers and clinicians continue their endeavors, seeking to maximize the number of patients who can benefit. Determining if treatments for certain cancers might benefit other groups of patients and if a drug’s side effects can be mitigated to make it tolerable to more people not only improves patient care, but it also increases the return on prior investments in cancer research. In the first eight months of 2012, the FDA expanded the use of three previously approved cancer treatments—pazopanib (Votrient), everolimus (Afinitor) and, as noted above, bortezomib—increasing their true clinical worth.

The FDA approved pazopanib for the treatment of metastatic renal cell carcinoma in October 2009. It targets the VEGF receptor family, disrupting the growth and stability of the emerging blood and lymphatic vessel networks that support the cancer’s growth. A recent large-scale clinical trial showed that pazopanib more than doubles the time to disease progression in patients with certain metastatic soft-tissue sarcomas (86), a group of cancers that it is estimated will be newly diagnosed in more than 11,000 Americans in 2012 (3). In light of this, in April 2012, the FDA approved the drug as a treatment for advanced soft tissue sarcoma, providing new hope for patients who have seen little change in their treatment options for decades.

Everolimus targets the key molecule, mTOR, in the mTOR signaling pathway, which senses energy levels, controls tumor cell viability and drives cell growth. As a result of various genetic mutations, this pathway is overactive in several types of cancer, and over the past few years the FDA has approved everolimus for the treatment of metastatic renal cell carcinoma, certain pancreatic cancers called neuroendocrine tumors, and noncancerous brain tumors in patients with an incurable inherited disease called tuberous sclerosis. Between 25,000 and 40,000 Americans have tuberous sclerosis, which causes noncancerous tumors to grow in the brain and many other vital organs (87). A recent clinical study indicated that everolimus reduces the burden of noncancerous brain tumors in patients with tuberous sclerosis and also dramatically shrinks their noncancerous kidney tumors, data that led to the April 2012 FDA approval of everolimus for this condition (88). In July 2012, the FDA approved everolimus for the treatment of women with hormone receptor–positive advanced breast cancer (see below) after a large-scale trial showed it significantly prolonged time to disease progression or death (89).

Increasing the number of cancer types for which a drug is approved as a treatment is not a trivial advance. It is one that is significant for the many patients, their families and their loved ones who have benefitted from this progress. Numerous studies are underway to pair other proven cancer treatments with new patient populations, and these are expected to uncover new ways to enhance and expand both the clinical value of our knowledge and the return on prior investments in cancer research.

A New Day for Anti-hormone Therapy

Hormones like estrogen, progesterone, testosterone and their derivatives influence the growth of certain subtypes of breast cancer and most cancers of the male and female reproductive organs. These hormones attach to specific proteins called receptors, in a lock-and-key fashion, which stimulate cancer growth and survival. This knowledge has provided insight into risk factors and treatments for some of these hormone-fueled cancers.

In breast cancer, for example, understanding that estrogen drives the approximately 70% of breast cancers that express the estrogen receptor led to the clinical development of anti-estrogen therapies. These drugs work in one of two ways. Some drugs, like tamoxifen, attach to the estrogen receptors inside cancer cells, blocking estrogen from attaching to the receptors. Other therapies, like aromatase inhibitors, lower the level of estrogen in the body so that the cancer cells cannot get the estrogen they need to grow. Anti-estrogen therapies have been extremely successful, as indicated by the fact that in women with early-stage estrogen receptor-positive breast cancer, tamoxifen treatment reduces the risk of disease recurrence by almost 50% and the chance of mortality by 30% (90).

The most exciting recent advances in understanding hormone-driven cancers have been made in the area of prostate cancer, the most commonly diagnosed cancer in the U.S. (3). It is estimated that there will be more than 240,000 new cases of the disease in 2012, and that more than 28,000 American men will succumb to it. Most prostate cancers, almost two out of every three, are diagnosed in men aged 65 or older, with African American men bearing a disproportionate burden of the disease (4). The knowledge that prostate cancer can be powered by hormones called androgens, like testosterone, provided the rationale for developing anti-hormone therapies called androgen- deprivation therapies. These therapies for prostate cancer work in similar ways to the anti-estrogen therapies used to treat breast cancer: They lower androgen levels or stop them from attaching to androgen receptors.

Androgen-deprivation therapies are most commonly used to treat advanced prostate cancer. Most individuals with this diagnosis respond very well to these treatments, and their cancers shrink or grow more slowly. Unfortunately, in most cases, the prostate cancers eventually stop responding to androgen-deprivation therapies and a more aggressive disease called castration-resistant prostate cancer arises, which has a very poor prognosis and urgently requires new treatment options.

While the most frequently used androgen-deprivation therapies reduce androgen levels, they do not eliminate these hormones completely. Basic research led a better understanding of how the body manufactures and responds to androgens, which revealed a way to more completely block androgen production. This, in turn, led to the development of a groundbreaking new anti-androgen therapy, abiraterone (Zytiga), which the FDA approved in April 2011 for the treatment of metastatic castration-resistant prostate cancer. In a large-scale clinical trial, abiraterone significantly prolonged survival (91) and provided new hope to patients like Antoni Smith. Ongoing clinical studies are examining whether abiraterone might provide a more effective treatment than the current standard of care for prostate cancer patients with less advanced disease. The results of one of these studies indicate that the presurgical use of abiraterone in patients with localized high-risk disease shows promise (92).

On August 31, 2012, the FDA approved a new androgen-deprivation therapy, enzalutamide (Xtandi, formerly called MDV3100). Enzalutamide attaches to androgen receptors and blocks their attachment to androgens. It is more effective than current drugs and has fewer side effects (93). The results of a recent large-scale clinical trial examining enzalutamide as a treatment for metastatic castration-resistant prostate cancer indicate that it significantly prolongs survival (94). These exciting findings are good news for patients who desperately need new treatment choices. Continuing research is assessing the potential of enzalutamide as a treatment for earlier stage prostate cancer.

Clinical research to further optimize the treatment schedule must be undertaken soon if patients are to gain the maximum benefit from recent progress in anti-hormone therapy. For example, the ideal sequence to administer these new drugs, when during the course of the disease to give them and the best combination of these and other treatments has yet to be determined. Moreover, despite the tremendous advances, some metastatic castration-resistant prostate cancer patients, like S. Ward “Trip” Casscells, M.D., never respond to either abiraterone or to enzalutamide, and most individuals who do respond only do so temporarily. Additional new therapies are required for these patients, and further research efforts are essential if we are to meet this unmet medical need.

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A New Day for Targeted Therapy

Our dramatically increasing knowledge of cancer biology at the molecular level is beginning to transform the standard of care from a one-size-fits-all approach to personalized cancer medicine, also called molecularly based medicine, precision medicine or tailored therapy. With this type of medicine, the molecular makeup of the patient and of the tumor dictate the best therapeutic strategy. The overall goal is to increase survival and quality of life for most cancers.

The majority of the drugs recently approved by the FDA for cancer treatment are designed to precisely block the malfunctions that drive cancer growth. Many have been discussed above, as they specifically target molecules for which earlier drugs have provided tremendous patient benefit, but two—vismodegib (Erivedge) and ruxolitinib (Jakafi)—are unique because they oppose the function of cancer-driving molecules not previously targeted for therapy.

The development of vismodegib and ruxolitinib were the result of many research successes. These advances built upon a powerful knowledge base about cancer and represent a clear-cut example of the significant returns that are made on investments in such research.

Vismodegib is the first drug approved for the treatment of advanced basal cell carcinoma. Basal cell carcinoma is the most commonly diagnosed cancer in the U.S., estimated to affect about 2 million Americans annually (95). It is almost always curable with surgery; however, for the small fraction of patients in whom the cancer progresses to an advanced stage, there was no effective therapy until the FDA approved vismodegib in January 2012. Vismodegib is also the first drug that blocks a signaling network called the Hedgehog pathway, which fundamental research has determined is overactive in almost all basal cell carcinomas because of several different genetic mutations. With clinical trials showing that it dramatically shrinks tumors in most patients (96), like Donna Johnson, vismodegib is a welcome new treatment option for a condition for which there was a clear unmet need. Continuing clinical studies are assessing whether vismodegib might benefit patients with other types of cancers that have defects in the Hedgehog pathway, including pancreatic and lung cancers, amplifying the clinical value of the drug.

A similarly powerful example of drug development in the era of personalized cancer medicine began less than 10 years ago, when researchers discovered genetic mutations leading to excessive activity of a certain signaling network in most patients with myelofibrosis, a type of chronic leukemia for which there was no specific treatment. This discovery propelled researchers across disciplines to collaborate on the development of the first ever drug to precisely target this altered signaling network, called the JAK2 signaling network. The result of these endeavors was ruxolitinib (Jakafi), which the FDA approved for the treatment of myelofibrosis in November 2011, after several clinical studies showed that it significantly reduced symptoms, dramatically improving patient quality of life (97). Ongoing clinical studies are examining whether ruxolitinib might provide a viable treatment option for patients with other types of cancers with JAK2 signaling defects, including pancreatic cancer and certain subtypes of breast cancer.

The extraordinary progress that has been made in recent years toward developing drugs that precisely target the molecular defects driving cancers has already made a real difference in the lives of a growing number of cancer patients, the more than 13 million cancer survivors in the U.S., and their families and loved ones. Despite these advances, diseases like pancreatic and liver cancers still represent major killers, and they have no effective molecularly targeted therapies. In the case of pancreatic cancer, fewer than one in 16 patients are living five years after diagnosis (3). Jill Ward, who is about to celebrate her fifth year of survivorship, is a rarity. Much more work needs to be done if the outlook for those diagnosed with this disease is to improve. For some time, researchers have known the identity of a predominant cancer-driving molecular defect, but they have been unable to successfully develop drugs that precisely target it. They are actively looking for ways around this obstacle. One approach that basic research suggests might have promise is combining two molecularly targeted drugs that are specific for different signaling network components (98), and this idea is currently in the early stages of being tested in clinical studies.

Combinations of molecularly targeted drugs are also being investigated as potential new approaches to treating cancers other than pancreatic cancer. For example, a drug that blocks the mutated B-RAF protein, which is the molecular defect found to drive more than 50% of melanoma cases, has revolutionized the treatment of this deadly disease (99); however, these cancers eventually acquire resistance to the drug and they progress (see Sidebar on Drug Resistance). Melanoma research has identified several molecular pathways that bypass the inhibition of mutated B-RAF, and recently initiated clinical studies are assessing whether adding a second drug that precisely targets one of these resistance signaling networks will further prolong survival in patients who have experienced progression. The results are eagerly awaited.

A New Day for Immunotherapy

Over the past four-plus decades, cancer researchers have accumulated a tremendous understanding of the complexity of cancer. It is now evident that while the genetic alterations in cancer cells have a profound effect on the development of cancer, cancer cells can also modify their surroundings, often called the tumor microenvironment, enhancing the growth and spread of the cancer. 

A key component of the tumor microenvironment is the immune system. Research has determined that in some cases, the immune system completely eliminates a cancer before it becomes clinically apparent. This fact is central to the idea that it might be possible to develop therapies that train a patient’s immune system to destroy a cancer. Putting this into clinical practice, however, has proven extremely challenging. Recent scientific advances have revealed one of the reasons for this phenomenon, i.e., that tumors have developed many sophisticated ways to block their own destruction by the immune system. Progress in our understanding of the approaches that tumors use to escape elimination is finally converging with advances in our basic understanding of the immune system to yield multiple new strategies that have the potential to revolutionize cancer treatment.

Cancer treatment that alters the immune system is called immunotherapy. Not all immunotherapies operate in the same way, however, and the ongoing discovery of the many intricacies of the immune system is continuing to open new pathways to the development of novel treatment strategies. Among the immunotherapy approaches currently saving patient lives are some that seek to boost the natural cancer-fighting ability of the immune system by taking its brakes off, some that enhance the killing power of the patient’s own immune cells and others that flag cancer cells for destruction by the immune system. The first approach—using therapies that boost the immune system by taking its brakes off—is now leading the field of immunotherapy, producing remarkable and durable responses in cancers that are not amenable to standard treatments. However, other approaches are starting to gain traction as well after many challenging years of development.

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Targeting the Immune System to Release Its Brakes

It is well established that immune cells called T- cells are naturally capable of destroying cancer cells and that this ability can be suppressed by the tumor. One explanation for this was provided by the discovery that T cells in the tissues surrounding a tumor express high levels of molecules that tell T cells to slow down and to stop acting aggressively. This finding led researchers to seek ways to counteract these molecules, which are often called immune checkpoint proteins.

The most well-understood immune checkpoint protein is called CTLA-4, and a therapeutic antibody, ipilimumab (Yervoy), which targets CTLA-4, was approved by the FDA in March 2011 for the treatment of metastatic melanoma. Ipilimumab releases the brakes on T cells and significantly prolongs survival (100). Some patients, like Andrew Messinger (who was featured in the AACR Cancer Progress Report 2011), are still gaining benefit from it more than three years after starting therapy (101). Ongoing clinical studies are examining whether ipilimumab might be effective against other cancers. Early results in patients with advanced lung cancer are encouraging, but need verification in larger numbers of patients (102).

The development of ipilimumab highlights the power of continued investment in research: CTLA-4 was first identified in 1987, but it took almost 25 years of scientific endeavor before it became an FDA-approved therapeutic target. In addition, the tremendous success of this novel therapeutic antibody has inspired the ongoing development of therapies directed toward other immune checkpoint proteins, including one called programmed death-1, or PD1 (see Sidebar on Immune Checkpoint Therapeutics). The effects of a therapeutic antibody that targets PD1, as well as one that targets the protein to which PD1 attaches, called PDL1, are currently being assessed in clinical trials. The early results are very promising (103, 104) and indicate that ipilimumab has blazed the way for a family of similar effective therapies.

Targeting the Immune System to Boost Its Killing Power

Another recent development in immunotherapy for cancer treatment is using strategies to enhance the ability of a patient’s own immune cells to eliminate cancer cells. This can be done in several ways, including giving a patient a vaccine to program their own immune system to recognize and destroy their cancer or by growing the patient’s immune cells in the laboratory and reprogramming them to recognize and destroy their cancer. The latter are treatments collectively called adoptive immunotherapies.

Sipuluecel-T (Provenge) is the only FDA-approved therapeutic cancer vaccine. It is used to treat metastatic castration-resistant prostate cancer, after it was shown to prolong patient survival (105). It is a cell-based immunotherapy, wherein each treatment is customized for the patient and helps direct their immune system to destroy their cancer cells. While only an early success, it provides hope that other effective cancer treatment vaccines can be developed. As such, this is an intensively studied area of cancer research. In the U.S. alone, more than 300 clinical trials testing cancer vaccines are actively recruiting patients.

Adoptive immunotherapies are complex medical procedures that are built upon our accumulating knowledge of the biology of the immune system, in particular, T cells. The first step is to harvest a defined population of T cells from the patient. T cells that target the patient’s cancer are then selected from the harvested population or generated by genetic engineering, grown in very large numbers and then returned to the patient’s body, where they fight the cancer.

There are no FDA-approved adoptive immunotherapies, but at the NCI, one procedure using T cells harvested from a patient’s own surgically removed tumors has been used to treat metastatic melanoma for more than 20 years (106). During this period, the treatment protocol has been refined many times, as scientific and technological advances have facilitated improvements, and about 20% of patients, including Roselyn Meyer (who was featured in the AACR Cancer Progress Report 2011), now achieve long-term remission (107). Despite these successes, the NCI adoptive immunotherapy treatment is not yet considered standard of care; it remains an area of active research and is only available to patients enrolled in clinical trials.

The effectiveness of numerous other adoptive immunotherapies is currently being assessed in various clinical trials for several types of cancer. Very early clinical studies of an adoptive immunotherapy for the treatment of chronic lymphocytic leukemia recently showed that the strategy has tremendous promise (see Sidebar on Adoptive Immunotherapy for Chronic Lymphocytic Leukemia) (108), but more patients need to be treated to confirm this. Additional new adoptive immunotherapies with enhanced ability to yield patient benefit are likely to emerge in the near future as our understanding of T cells and how they combat cancer increases.

Directing the Immune System to Cancer Cells

Therapeutic antibodies have been saving the lives of cancer patients since 1997, when the FDA approved rituximab (Rituxan) for the treatment of certain forms of non-Hodgkin’s lymphoma. More than a dozen therapeutic antibodies have been approved by the FDA for use against several cancers, and many more are in clinical trials.

A therapeutic antibody is a protein that attaches to a defined molecule on the surface of a cell. These agents can exert anticancer effects in several different ways. For example, they can block cancer-driving signaling networks initiated by the specific molecule to which they attach, and they can work by attaching to cancer cells expressing their target, flagging them for destruction by the immune system. Therapeutic antibodies that flag cells for the immune system are a form of molecularly targeted immunotherapy, and they include an experimental medicine, called Ch14.18, that is showing promise as a treatment for high-risk neuroblastoma. 

Immunotherapy with Ch14.18, in combination with two factors that also boost the killing power of the immune system, has been shown in clinical trials to increase dramatically—by 20 percentage points—the chance that a child with high-risk neuroblastoma will be cancer free two years later (109). Although this treatment strategy is not FDA approved, it is at the forefront of care for a group of patients who have a tremendous need for new treatment options; fewer than one in every two children diagnosed with high-risk neuroblastoma live five years (110).

Despite the tremendous success of the Ch14.18 combination immunotherapy, which is enabling some children, like Brooke Mulford, to live disease free, the treatment is associated with significant toxicities. They can be so severe that some children cannot complete the treatment course, while those who do, suffer lasting negative side effects. Ongoing basic and clinical research is seeking ways to mitigate these severe side effects as well as to identify those children most likely to benefit from treatment or those least likely to respond, so that the latter can be spared from futile and potentially noxious therapies.

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A New Day for Patient Stratification

The rapid pace of scientific and technological innovation over the past few decades has made it possible to link specific genetic mutations to distinct behaviors of individual cancers. As a result, we now have the ability to understand that two patients with what is described clinically as a single disease, say lung cancer, may actually have two completely different cancers at the molecular level. Thus, these patients may have two very distinct courses of disease over time, and will therefore require entirely different molecularly targeted drugs.

Our arsenal of precisely targeted cancer drugs is expanding each year. However, the effective therapeutic use of these drugs often requires a test, called a companion diagnostic, that can accurately match patients with the most appropriate therapies. Patients positively identified by the test can rapidly receive a treatment to which they are very likely to respond. Those patients identified as very unlikely to respond can be spared any adverse side effects of the therapy and immediately start an alternative treatment, saving them precious time in their race to find an effective therapy. Moreover, definitive stratification of patient populations can also provide substantial health care savings by avoiding the deployment of ineffective courses of cancer treatments and the treatment costs associated with their adverse effects.

Many molecularly targeted cancer drugs have been FDA approved without a companion diagnostic. In August 2011, however, the FDA approved a drug/test pair that is now benefiting a defined group of lung cancer patients. The drug, crizotinib (Xalkori), blocks the signaling molecule ALK. It was developed after fundamental research established that genetic aberrations that lead to altered ALK expression and activity drive some lung cancers. Crizotinib dramatically improves the survival of patients with ALK gene defects, like Monica Barlow (111). However, these individuals make up fewer than 7% of all patients diagnosed with the most common form of lung cancer, non-small-cell lung cancer. Without the companion diagnostic, this small population of patients would not be identified, making crizotinib clinically useless because the patient and financial costs would far outweigh the benefits.

The success of crizotinib and the importance of its companion diagnostic emphasize the value of having a way to identify those patients with a high likelihood of responding to a particular drug, and many molecularly targeted drugs for cancer treatment are now being developed side-by-side with a companion diagnostic. 

Additional clinical tests to divide patients with a given cancer into therapy groups based on the molecular characteristics of their individual cancers are urgently needed because not all patients with a given genetic defect will benefit from a drug targeting that alteration. For example, while genetic alterations that result in cancers driven by a specific cell surface protein called EGFR are found in 10% of non-small-cell lung cancers (112) and in almost 50% of glioblastomas (113), the most common and most aggressive brain tumors in adults, drugs that precisely target EGFR provide benefit only to the non-small-cell lung patients (112, 113). Many researchers are seeking to understand why this is and to establish ways to better predict whether or not a patient with an EGFR genetic alteration will respond to EGFR-targeted drugs. Early findings suggest that more specifically characterizing the type of genetic mutation that is responsible for the cancer might provide one way to more precisely forecast the drug response (112, 113).

Variability in initial responsiveness to a particular molecularly targeted therapy occurs between two types of cancer with apparently identical molecular underpinnings and also between two patients with the same cancer type and the same cancer-driving molecule. Therefore, it is now clear that tests that look for the presence or absence of a single molecular defect are insufficient to definitively predict a patient’s response to a drug. In some instances, this occurs because of other malfunctions in the molecular machinery of the cancer cells themselves. For example, clinical studies found that certain drugs that target EGFR can prolong the survival of patients with metastatic colorectal cancer, but only if the cancer cells express the normal form of the protein KRAS (114). Unfortunately, about four out of every 10 colorectal cancers have a mutated form of KRAS. So, since July 2009, the FDA has required the use of a KRAS test, one of which was just approved by the FDA in July 2012, prior to giving a patient an EGFR-targeted drug for the treatment of metastatic colorectal cancer. Thus, the use of two tests to characterize the molecular subtype of a patient’s individual cancer can help avoid unnecessary exposure to the side effects of potentially ineffective treatments.

For most cancers it is unlikely that two tests alone will be sufficient to predict a patient’s response to a molecularly targeted drug because it is highly unlikely that a second indicator of response will be present in as large a fraction of the patient population as mutated KRAS is in metastatic colorectal cancer patients. Identifying panels of response predictors, or biomarker signatures (see Sidebar on Pharmacogenomics), through the use of advanced genome sequencing technologies, is an area of intense research investigation, as these panels hold the promise of dramatically increasing the precision of cancer medicine.

While not based on wholesale genomic analysis, there are currently two multi-gene test panels used by clinicians to help them tailor their approach to treating women with certain forms of early-stage breast cancer. The tests, a 21-gene test called Oncotype DX and a 70-gene test called MammaPrint, estimate the likelihood of cancer recurrence at a distant site. Clinicians can use this information as they decide whether anti-hormone treatment alone is likely to be sufficient or whether a chemotherapeutic drug should also be used. Although clinicians already use both tests, they are undergoing further testing in clinical trials to help refine and expand their utility. It is envisaged that near-term progress in genomic medicine should yield additional clinically applicable gene signatures to guide therapeutic decision-making and tailoring of a patient’s treatment plan.

A New Day for Genomic Medicine

The explosion of genetic information and our ever-increasing understanding of how to apply it are providing patients with some forms of cancer less toxic and more effective treatment options, thereby realizing the promise of personalized medicine.

Many major advances are highlighted in this report, but gaps in our knowledge remain. For example, there are many forms of cancer, including liver and pancreatic cancers, for which we have insufficient genetic and/or technical knowledge to design effective molecularly targeted therapies. Even for those cancers for which there is a therapy that precisely targets an underlying cancer-driving molecular defect, not all patients’ cancers harbor the matching molecular malfunction, so not all patients will benefit from the drug. Breast cancer is a clear case in point. Women whose breast cancers have a genetic alteration that leads to overexpression of HER2 benefit from HER2-targeted therapies such as trastuzumab and pertuzumab, as well as women whose breast cancers express the estrogen and progesterone hormone receptors, benefit from anti-hormone therapies. The 10% to 15% of women, like Lori Redmer, whose breast cancers lack the expression of HER2, the estrogen receptor and progesterone receptor are said to have triple-negative breast cancer, and for them there is no molecularly targeted therapy currently available.

Recent innovations have propelled rapid technological advances that are making it possible to efficiently read every known component of the DNA from an individual’s cancer. Capitalizing on these advances is the goal of large-scale genomic enterprises such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). These and other similar initiatives aim to identify all of the genomic changes in many types of cancer, by comparing the DNA in a patient’s normal tissue with the tumor DNA, to discover the relevant genetic alterations that drive a given cancer. This information can then be used to improve our ability to diagnose, treat and prevent this devastating disease. In addition, it promises to provide new avenues of precision treatments for patients that currently have none. Moreover, near-term expansion of the use of DNA sequencing will help uncover the mutations specific to metastases, which are likely distinct from those in the original tumors from which the metastases arise. Such analyses have great potential to reveal new approaches to treating this deadly stage of the disease where our current efforts fall short.

To date, large-scale genomic analyses have been completed for just a few types of cancer, with research into many others underway. The clear message that is emerging from these studies is that while the genetic changes being uncovered vary widely, taken together they affect only a handful of signaling networks. Further, the same networks, albeit at different junctures, are affected in different cancers. This is changing the way researchers view cancers. They see them more as genetic diseases, defined not as much by where they originate—in the breast, brain, lung, liver, etc.—but by the genetic changes that are their Achilles’ heels. At this juncture the major challenge is to determine how to best use both our current therapies and the newly developed drugs in combination to effectively target the altered signaling networks identified by genomic analyses. Further, the goal is to make this strategy part of standard of care for the treatment and prevention of cancer.

Colorectal cancer is one of the cancers for which wholesale genomic analyses have been completed (115). Researchers examined all of the genes in pairs of normal and cancerous tissue of more than 200 patients with colorectal cancer. They found that most of the genetic alterations detected in a significant portion of the cancers affected just five signaling networks. Of note, one signaling network, called the WNT signaling pathway, was altered in nearly all of the cancers (93%), suggesting that drugs that block this pathway might benefit many patients with colorectal cancer. In addition, 5% of the cancers had extra copies of the HER2 gene, indicating that trastuzumab and pertuzumab might be effective therapies for individuals with these cancers since they successfully treat breast and stomach cancers that harbor additional HER2 genes. The data from this study highlight the potential that large-scale genomic technologies have for identifying new drug targets for individual cancer types, but much more work is needed if we are to deliver on this promise.

Currently, the greatest use of large-scale genomic analyses remains in the research setting, as highlighted by the work of Joyce O’Shaughnessy, M.D., where it can guide the development of new cancer drugs, direct the repurposing of established therapies to treat novel genetic aberrations and inform clinical research by assigning the most appropriate patients to the best clinical trials. To date, wholesale genomic analysis has been successfully used to guide the choice of therapy for a few patients in the research setting, highlighting the fact that the day when it becomes part of standard practice is close at hand. Clearly, these advances are an early step toward a future where most cancer treatment and prevention strategies are based on both a person’s genetic makeup and the genetic makeup of their specific cancer.

If this is to become a reality, the cost of deciphering a person’s genetic code and that of their particular cancer must drop even further than it has in the past decade The cost is estimated to have fallen about 100-fold since 2002, but it remains several thousand dollars per test for a robust data set (116), which is likely too high for routine clinical use. Additionally, new storage infrastructure, bioinformatics systems and telecommunications networks will be required to manage the massive amounts of information generated by the large-scale analyses. Further, the collection and interpretation of this information to inform cancer care will only be possible if we are able to support the cost of the required infrastructure, educate the current and future workforce to understand the meaning of the data generated, assemble multidisciplinary teams of researchers and physicians, and involve the patients themselves, their caregivers, and the community.  

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Cancer Progress Report 2012 Contents

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