Making Research Count for Patients: A Continual Pursuit

Cancer Progress Report 2013: Contents

In this section you will learn:

  • Mobilizing a patient's own immune system to treat cancer is yielding remarkable and durable responses, making immunotherapy an exciting area of cancer research.
  • From Sept. 1, 2012, to July 31, 2013, the FDA approved 11 new drugs for treating cancers, eight of which are molecularly targeted drugs.
  • During the same period of time, the FDA approved new uses for three previously approved anticancer drugs, one of which is a nanodrug.
  • In addition, three new technologies that improve cancer detection or guide treatment were approved by the FDA.
  • Cancer genomics research has led to clinical sequencing of tumors, which is beginning to guide cancer diagnosis and treatment.

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

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

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

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

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

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

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

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

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

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

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Releasing the Brakes on the Immune System

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

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

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

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

One PD1-targeted therapy, nivolumab, has produced several responses persisting more than two years in a number of non-small cell lung cancer patients, advanced melanoma patients, and renal cell carcinoma patients (110, 112, 113). As a result of these encouraging data, the FDA granted nivolumab fast track designation for these cancers. The FDA has also designated lambrolizumab, a second therapeutic antibody that targets PD1, as a breakthrough therapy for advanced melanoma, after it was reported to benefit patients (114) (see sidebar on FDA Designations​).

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

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

Boosting the Killing Power of the Immune System

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

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

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

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

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

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

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

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

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Flagging Cancer Cells for the Immune System

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

The first therapeutic antibody the FDA approved for the treatment of cancer, rituximab (Rituxan), works in part by directing the immune system to cancer cells. Since its approval for certain forms of non-Hodgkin lymphoma in 1997, the FDA has also approved rituximab for the treatment of chronic lymphocytic leukemia. Perhaps more importantly, although an anticancer therapeutic, rituximab has also been approved by the FDA for the treatment of several autoimmune disorders — rheumatoid arthritis, granulomatosis with polyangiitis (also known as Wegener’s granulomatosis), and microscopic polyangiitis. Thus, rituximab is one of many examples of how investments made in cancer research have been magnified many times over for the benefit of the broader medical community (see sidebar on Cancer Research At Work Against Other Diseases​).  

​When used to treat cancer, rituximab functions by attaching to cancer cells that have the protein CD20 on their surface. Upon attaching to CD20, rituximab does several things that lead to the destruction of the cancer cells (126). One of these is that it attracts immune cells, including NK cells (see sidebar on Key Players in the Immune System​), which then destroy the cancer cells. A second is that it triggers within the cancer cells a series of events that cause the cells to die. 

Even though rituximab has significantly increased survival for some cancer patients, a substantial number have disease that fails to respond to the initial treatment or eventually becomes resistant to it (126). Thus, many researchers have been working to develop more effective CD20-targeted therapeutic antibodies. Basic immunology research provided much insight, including a detailed molecular understanding of how rituximab attracts immune cells and instructs them to destroy the cancer cells (127). This knowledge led bioengineers to create the next generation of CD20-targeted antibodies with enhanced ability to recruit immune cells and direct them to attack the cancer cells (126). 

Obinutuzumab is the most promising of the new CD20-targeted antibodies. Compared with rituximab, obinutuzumab is better at recruiting and instructing immune cells to kill cancer cells and is better at directly killing the cancer cells themselves (128). Early-stage clinical trials have indicated that obinutuzumab may provide an effective new treatment option for patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia that has failed to respond to prior therapies or has relapsed after initially responding to earlier treatments (129, 130). 

The results of these studies were so promising that the FDA granted obinutuzumab breakthrough therapy designation (see sidebar on FDA Designations). Larger trials are underway, with initial results indicating that obinutuzumab significantly delays disease progression for patients with previously untreated chronic lymphocytic leukemia and suggesting that it might be more effective than rituximab (131). The final results of these trials are eagerly awaited.

The immunotherapies highlighted in this Special Feature on Immunotherapy underscore how decades of research in numerous disciplines are paying dividends for many cancer survivors, like Andrew Messinger and Maddie Major. Pursued for years by literally hundreds, perhaps thousands, across the biomedical research enterprise, the dream of immunotherapy is 110 years old. However, we are now much closer to realizing the dream as immunotherapies are delivering robust and lasting responses for some patients with several different forms of cancer. 

Molecularly Targeted Therapies

Research is continually expanding our understanding of cancer biology, making it increasingly possible to link specific defects in the molecular machinery of cells to cancer development. This knowledge is directly enabling the development of medicines that precisely target these alterations and block their ill effects. As a result, the standard of care is transforming from a one-size-fits-all approach to one in which the molecular makeup of the patient and of the tumor dictate the best therapeutic strategy. This approach is variously called personalized cancer medicine, molecularly based medicine, precision medicine, or tailored therapy. 

The number of molecularly targeted therapies approved by the FDA is increasing, and is expected to continue to grow as our knowledge of cancer biology expands. Because of the greater precision of many of the newest cancer medicines, they are more effective and less toxic than the treatments that have been the mainstay of patient care for decades. Thus, these new medicines are not only saving the lives of countless cancer patients, but are also improving their quality of life.

A Direct Hit: Targeting Chemotherapy to Breast Cancer

It is anticipated that in 2013, more than 45,000 individuals in the United States will be diagnosed with breast cancer that overexpresses the protein HER2 (1, 132). HER2-positive breast cancer tends to be aggressive, and the outcome for patients is typically poor. Decades of research led to the development and FDA approval of three HER2-targeted therapies that have revolutionized the treatment of this disease: trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta). These drugs significantly prolong survival for patients with metastatic disease when given together with standard chemotherapies (133-135). Unfortunately, some patients fail to respond to treatment, and in most of those who do respond initially, the disease ultimately progresses. As a result, new therapies for this subtype of breast cancer are urgently needed and being actively researched.

An exciting new treatment for patients with metastatic HER2-positive breast cancer, like Kim Alexander, was approved by the FDA in February 2013. The drug, ado-trastuzumab emtansine (Kadcyla), which was referred to as T-DM1 during clinical development, is an antibody-drug conjugate. Antibody-drug conjugates are a new type of targeted anticancer therapy, which use an antibody to deliver an attached drug directly to those cancer cells that display the antibody’s target on their surfaces. This precision reduces the side effects of the drugs compared with traditional chemotherapy that is delivered systemically. In the case of T-DM1, the chemotherapy DM1 is attached to the antibody trastuzumab using a stable linker. The HER2-targeting properties of trastuzumab allow T-DM1 to be delivered directly to HER2-positive cells. The result is a significant improvement in survival for many patients (132). 

​The development of antibody-drug conjugates is an intensively studied area of cancer research that is showing great promise for near-term patient benefit. In the United States alone, approximately 80 clinical trials are either ongoing or actively recruiting patients to test antibody-drug conjugates as a treatment for several cancers. Leveraging our current knowledge of conventional chemotherapies and of the precision targeting of anticancer antibodies to develop new antibody-drug conjugates not only improves patient care by reducing side effects, but it also increases the return on prior investments in cancer research. 

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Blocking Tumor Sustenance

Research has shown that many solid tumors are very dependent on the growth of new blood and lymphatic vessels to grow and survive. Thus, targeting these key components of the tumor microenvironment provides an ideal avenue for therapy. 

Since February 2004, the FDA has approved nine drugs that work in similar ways to impede the growth of the new blood and lymphatic vessel networks that enable cancer cells to thrive. These drugs mainly function by stopping members of a family of growth-promoting proteins called VEGFs from activating the molecules they attach to, VEGF receptors, which are mostly found on blood and lymphatic vessel walls. 

These therapies have had the biggest impact for patients with the most common type of kidney cancer in adults, renal cell carcinoma. However, they also greatly benefit those with the most aggressive form of liver cancer, as well as patients with some forms of pancreatic cancer; some gastrointestinal stromal tumors and soft-tissue sarcomas; and some colorectal, lung, and thyroid cancers. 

One new therapeutic option in this growing class of drugs is cabozantinib (Cometriq), which was approved by the FDA for the treatment of metastatic thyroid cancer in November 2012 (136). In addition, in September 2012, the FDA approved regorafenib (Stivarga) for the treatment of metastatic colorectal cancer, after it was shown to significantly prolong patient survival (137). In light of the results of a large trial that showed that regorafenib increased by more than fourfold the time before disease progressed for patients with advanced gastrointestinal stromal tumors, the FDA approved regorafenib for the treatment of this disease in February 2013 (138). 

The nine FDA-approved drugs that block VEGFs or the function of VEGF receptors are currently being tested in numerous clinical trials as treatments for several additional forms of cancer. One promising clinical trial is examining the utility of pazopanib (Votrient) as a treatment for patients with advanced ovarian cancer (139). Also encouraging are the initial results of a large trial testing sorafenib (Nexavar) as a treatment for certain patients with thyroid cancer (140). Determining if treatments for certain cancers might benefit other groups of patients not only improves patient care, but it also has the added bonus of increasing the return on prior investments in cancer research. 

In February 2013, the FDA approved Pomalidomide (Pomalyst) for the treatment of multiple myeloma. Pomalidomide is a member of a family of drugs called immunomodulatory drugs. These drugs fight multiple myeloma by modulating aspects of the immune system and by reducing the production of VEGFs, which leads to disruption of new blood and lymphatic vessel networks (141). Importantly, pomalidomide benefits patients with multiple myeloma that has progressed after treatment with earlier generation immunomodulatory drugs (142).

Lessons Learned From CML

Imatinib (Gleevec) was the first molecularly targeted chemical approved by the FDA for the treatment of a cancer, CML. Its development was the result of a series of groundbreaking scientific discoveries (see Figure 14). Imatinib blocks the activity of an aberrant protein called BCR-ABL, which fuels most cases of CML. Five-year survival rates for CML increased from just 31 percent to around 90 percent following the 2001 FDA approval of imatinib (1, 143). Unfortunately, a small fraction of patients never respond to imatinib, while other patients initially respond, but eventually their leukemia returns, or relapses, having acquired resistance to the drug (see sidebar on Drug Resistance​).

Researchers have determined that imatinib-resistant leukemias harbor unique forms of BCR-ABL that cannot be blocked by the drug. Two second-generation drugs, dasatinib (Sprycel) and nilotinib (Tasigna), that are able to block most of these distinctive BCR-ABL proteins, were developed and approved by the FDA in 2006 and 2007, respectively. However, all three drugs fail to block one particular form of BCR-ABL, called T315I, which remains a significant challenge.

Three FDA decisions in the last four months of 2012 should help address this serious clinical issue and has increased the number of treatment options for patients with imatinib-resistant CML. The first was the September 2012 FDA approval of bosutinib (Bosulif). Like imatinib, dasatinib, and nilotinib, bosutinib blocks the activity of BRC-ABL but fails to block the T315I BCR-ABL mutant. Its use as a treatment for CML was approved by the FDA after it was shown to have anti-leukemic activity in patients with CML resistant to one or more of imatinib, dasatinib, and nilotinib (144). The second was the October 2012 FDA approval of omacetaxine mepesuccinate (Synribo). Understanding how omacetaxine mepesuccinate works is an area of active investigation; currently, it seems that it does not directly block BCR-ABL activity but rather reduces levels of BCR-ABL protein. Perhaps as a result of its unique mode of action, early clinical studies indicate that omacetaxine mepesuccinate has clinical benefit in patients with CML harboring the T315I BCR-ABL mutant (145). 

The third decision is the December 2012 FDA approval of ponatinib (Iclusig), a drug that is transforming the lives of patients like Hans Loland, who has CML harboring the T315I BCR-ABL mutant. The development of ponatinib culminated in a clinical trial that showed that ponatinib benefited patients with CML resistant to multiple other BCR-ABL–blocking drugs (146). Most dramatically, it was effective for nearly all patients with CML harboring the T315I BCR-ABL mutant. Although it is too soon to tell how long ponatinib will control disease, early signs are very promising.

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Two Drugs: One Cancer-driving Pathway

In 2011, the FDA revolutionized the treatment of metastatic melanoma, the most aggressive form of skin cancer, when it approved vemurafenib (Zelboraf). This drug blocks an abnormal form of the signaling protein BRAF, called BRAF V600E, which fuels about 45 percent of melanomas (147). Thus, the FDA approved the use of vemurafenib only for patients who have metastatic melanoma shown to be driven by BRAF V600E as identified using a special test, a companion diagnostic, called the cobas 4800 BRAF V600 Mutation Test (see sidebar on Companion Diagnostics​).

Further advances against metastatic melanoma were made in May 2013, when the FDA approved two new drugs, dabrafenib (Tafinlar) and trametinib (Mekinist) (148, 149). Like vemurafenib, dabrafenib specifically blocks the activity of BRAF V600E, and the FDA approved its use only for patients with metastatic melanoma shown to be driven by BRAF V600E as identified by the cobas 4800 BRAF V600 Mutation Test or the newly FDA-approved THxID BRAF test. 

In contrast to vemurafenib and dabrafenib, trametinib blocks the activity of two proteins called MEK1 and MEK2, which function in the same signaling network as BRAF V600E (see Figure 15). As the MEK proteins come after BRAF V600E in the pathway, trametinib is effective against the estimated 5 percent of metastatic melanomas fueled by other abnormal BRAF proteins, most prominently BRAF V600K, which are detected by the THxID BRAF assay but not the cobas 4800 BRAF V600 Mutation Test (149). 

Despite the positive clinical responses achieved with vemurafenib, dabrafenib, and trametinib, most patients relapse within one year of starting treatment (147-149). Based on these data and other preclinical research, it was thought that because dabrafenib and trametinib block different components of the same cancer-driving signaling network, a combination of the two drugs may be more effective for metastatic melanoma patients compared with either drug alone. Early clinical trials suggest this hypothesis may be true because the combination of drugs is nearly doubling the length of time before the disease progresses (150). Based on promising clinical results, an application for the use of this combination of drugs for the treatment of metastatic melanoma was filed for FDA review in July 2013. This approach provides a window into the near-term future of molecularly targeted therapy: rational combination of treatments grounded in our understanding of cancer biology (see On The Horizons). 

Helping Some Lung Cancer Patients Breathe Easier 

Lung cancer is the leading cause of cancer-related deaths among men and women in the United States, with 159,480 Americans predicted to die from the disease in 2013 (1). Non-small cell lung carcinoma accounts for about 85 percent of lung cancer cases. About 10 percent of non-small cell lung carcinomas are a result of mutations in the EGFR gene. In order to help direct EGFR-targeted therapies to these patients, the FDA approved a companion diagnostic (the cobas EGFR Mutation Test) to detect the two most common EGFR mutations found in non-small cell lung carcinomas, in May 2013.

The development and approval of this companion diagnostic greatly facilitated the May 2013, FDA approval of the EGFR-targeted therapy erlotinib (Tarceva) as the first treatment for patients with metastatic non-small cell lung carcinoma driven by either of the mutations detected by the diagnostic — EGFR exon 19 deletions or an EGFR exon 21 L858R substitution. Prior to the approval of the companion diagnostic, oncologists could only use erlotinib to treat patients with metastatic non-small cell lung carcinoma after they had received at least one other therapy. Thus, the companion diagnostic is helping a substantial number of patients with non-small cell lung carcinoma save time in their quest to find the best drug to treat their cancer. 

In July 2013, the FDA approved a new EGFR-targeted therapy, afatinib (Gilotrif), for the treatment of patients with non-small cell lung carcinomas with EGFR exon 19 deletions or an EGFR exon 21 L858R substitution. Patients with these mutations can be identified using the cobas EGFR Mutation Test or the therascreen EGFR RGQ PCR Kit, which was FDA approved at the same time as afatinib. The ability of these companion diagnostics to hone in on those patients most likely to benefit from afatinib (151) provides an example of the importance of developing new anticancer drugs alongside companion diagnostics to ensure that they reach the patients who need them as quickly as possible.

Closing RANK on a Rare Bone Tumor

In June 2013, the FDA approved a new use for the therapeutic antibody denosumab (Xgeva). It can now be used to treat giant cell tumor of bone, an uncommon disease for which treatment options had barely changed in the past three decades. Giant cell tumor of bone rarely metastasizes and is most commonly treated with surgery (152). Although this cures some patients, it causes substantial morbidity, and in many cases tumors recur. Moreover, some patients have tumors that cannot be removed with surgery, and denosumab has been shown to provide substantial benefit in these cases (153). 

Advances in our understanding of normal bone biology were central to the clinical development of denosumab, which targets the protein RANKL on the surface of certain bone cells. Normally, RANKL activates these cells causing a reduction in bone density and strength. Thus, blocking RANKL with denosumab strengthens bones. As such, it was first developed and FDA approved for the treatment of postmenopausal women with osteoporosis who were at high risk for fractured bones; it was subsequently approved by the FDA for the prevention of fractures caused by cancer metastases to the bone. Thus, the FDA approval of denosumab for giant cell tumor of bone not only benefits patients with this cancer, but it also increases the return on prior investments in cancer research.

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Technology Advances for Patient Benefit

Technologies ranging from the earliest microscopes to our most advanced whole-genome sequencing machines have enabled us to achieve our current comprehensive understanding of the biology of cancer. They are also increasingly being exploited for the benefit of patients. Here, we discuss some of the recent technological advances that are being harnessed to detect, diagnose, and treat many forms of cancer. These advances are but a glimpse of what is to come; there are many innovative technologies under development that are poised to revolutionize cancer medicine in the near future.

Nanotechnology: Tiny Technologies Make a Big Impact

Nanotechnology refers to the manufacturing of objects with dimensions one million times smaller than a millimeter (the smallest width of a human hair is just fifty times smaller than a millimeter). Nanomedicine is the application of nanotechnology to the research and practice of medicine. Nanodrugs comprise an anticancer agent and a nanosized carrier that is designed in such a way that it selectively delivers the drug to the cancer and protects the drug from being destroyed by the body’s defenses during transport. As a result, nanodrugs allow the delivery of higher levels of anticancer agents to cancer cells than traditional systemic delivery methods, increasing effectiveness while reducing toxic side effects. 

The conventional chemotherapy paclitaxel (Taxol) is used to treat some breast, ovarian, and lung cancers, specifically the most common form of lung cancer — non-small cell lung cancer. A nanodrug form of paclitaxel (Abraxane) has been approved by the FDA to treat certain patients with breast cancer since January 2005. In October 2012, the FDA approved nanoparticle paclitaxel for the treatment of advanced non-small cell lung cancer after a large clinical trial comparing nanoparticle paclitaxel with conventional paclitaxel as a treatment for advanced non-small cell lung cancer showed that the nanodrug benefited more patients (154).

The highly encouraging results of a recently concluded large clinical trial indicated that nanoparticle paclitaxel also significantly prolonged survival for patients with metastatic pancreatic cancer (155). Pancreatic cancer is one of the most deadly forms of cancer; most patients die within 12 months of diagnosis, and just 6 percent survive five years (1). With such a clear need for new treatment options, the breakthrough achieved with nanoparticle paclitaxel is providing new hope for patients like Dr. Charles Haerter

Mapping Cancer’s Escape Route

For many patients with cancer, the first step in their treatment is to have their tumor surgically removed. In some patients, most commonly patients with breast cancer or melanoma, the surgeon also removes the lymph node or nodes to which the cancer is most likely to first spread to from the initial tumor. These lymph nodes are called sentinel lymph nodes. The presence or absence of cancer cells in these nodes helps determine the extent of the disease and provides information that is central to the development of the rest of the patient’s treatment plan. 

To identify the sentinel lymph nodes, patients are injected with a radioactive substance, a blue dye, or both. The surgeon then uses a device that detects radioactivity to find the sentinel node(s) and/or looks for lymph nodes that are stained with the blue dye. In March 2013, the FDA approved a new agent for locating lymph nodes in patients with breast cancer or melanoma who are undergoing surgery to remove sentinel lymph nodes. The agent, technetium Tc 99m tilmanocept (Lymphoseek), is a radioactive diagnostic imaging agent that was shown in two clinical trials to locate more sentinel lymph nodes in more patients compared with vital blue dye (156, 157). Further, technetium Tc 99m tilmanocept identified more sentinel lymph nodes that were subsequently shown by routine pathology to contain cancer cells. As a result, its use should improve post-surgery treatment decisions for patients who have breast cancer or melanoma. 

Clear Images with Lower Radiation Doses 

Exposure to ionizing radiation is linked to the development of cancer (158). In the United States, the main source of ionizing radiation is a natural source: Radon gas. However, people are also exposed to ionizing radiation from man-made sources, predominantly medical equipment, treatments, and diagnostic agents. 

A growing concern is the dramatic rise in the number of CT scans being performed for screening and diagnostic purposes (159). It has been estimated that the number of CT scans performed each year in the United States rose from three million in 1980 to 85 million by 2011 (160, 161). In 2011, approximately 11 percent of these CT scans were performed on children. Experts believe that children are particularly vulnerable to the effects of ionizing radiation, and a recent report projected that for every 4 million pediatric CT scans performed, almost 5,000 cancers will develop (162). However, the researchers also calculated that substantially reducing the top 25 percent of radiation doses would likely prevent almost half of those cancer diagnoses.

One approach to limit radiation exposure from CT scans is to develop new machines that use lower doses of ionizing radiation. In September 2012, the FDA approved one such machine, the Aquilion One Vision CT scanner that provides high-quality images using lower radiation doses than previous generation CT scanners (163). As technology continues to advance, progress in this area is expected to continue. When combined with educational programs to reduce the number of these procedures and to reduce radiation doses to only what is medically necessary, further decreases in cancer risk should be seen. 

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Seeing the Wood Through the Trees: Improving Breast Cancer Detection

The rapid pace of technological innovation over the past few decades has been translated into a vast array of tools that have transformed the way that we detect and diagnose cancer. This arsenal of tools includes the machines that have enabled the United States to establish a population-based mammography screening program. Although early detection of breast cancer through regular mammography screening of women older than 40 has been credited with reducing the mortality rate for breast cancer (1), researchers have known for a long time that the greater the density of a woman’s breasts, the less likely a cancer will be visible on a screening mammogram (164, 165). Moreover, women with extremely dense breasts have a more than fourfold increased risk of breast cancer (164). 

Ultrasound imaging can detect small tumors in dense breasts; however, hand-held ultrasound devices are not a routine part of population-based screening programs. The FDA’s September 2012 decision to approve the use of the somo-v Automated Breast Ultrasound System (ABUS) in combination with a standard mammography for women with dense breast tissue should help to address this problem. The new device can automatically scan the entire breast in about one minute to produce several images for review. When tested in a clinical trial, the use of the somo-v ABUS in conjunction with standard mammography increased breast cancer detection in women with dense breasts, as compared to mammography alone (165). 

The approval of the somo-v ABUS provides hope for more effective early breast cancer detection for the estimated 40 percent of women undergoing mammography screening who have dense breasts. However, as with all screening approaches, including standard mammography screening, there is the possibility that its use will lead to overdiagnosis and subsequent overtreatment (see Prevention and Early Detection of Primary Tumors). Research to investigate this issue is vital to ensure that the public has confidence in this and other new screening approaches under development. 

Genomic Medicine

As mentioned earlier in this report, one of the greatest advances in cancer research was the discovery that cancer can be caused by permanent changes, or mutations, in the genetic material in a normal cell (see Figure 6). Knowing that cancer arises because these mutations lead to protein abnormalities that disrupt normal cell behaviors has enabled researchers to develop anticancer drugs that target the abnormal proteins and/or the disrupted cell behaviors. These molecularly targeted drugs are providing patients with some forms of cancer with less toxic and more effective treatment options, thereby realizing the promise of precision medicine.

Technological advances are making it possible to efficiently and cost-effectively read every unit, or base, of the DNA from a patient’s cancer, and to compare it to the sequence of their normal cells (see Figure 16). Widespread use of these new technologies has led to an explosion of genetic information about cancers of different types. One approach, known as whole-genome sequencing, compares the entirety of the DNA in a patient’s normal tissue with that from their tumor. Initiatives using these new “massively parallel” sequencing technologies have identified all of the genetic changes within hundreds of samples of many types of cancer (see sidebar on Large-Scale Genomic Initiatives). 

One message that is emerging from analysis of the genomic data is that there are about 140 genes that, when altered, can promote, or drive, the development of cancer (166). More significantly, these driver genes produce proteins that participate in perhaps only a dozen molecular networks (see Figure 17). The fact that the same driver genes and networks are disturbed in different cancers is changing the way that researchers view and, more importantly, how clinicians treat cancer. Increasingly, cancer is viewed as a group of genetic diseases, defined not only by where they originate — in the brain, breast, liver, lung, etc. — but also by the genetic alterations that are driving their formation. 

As cancers of different anatomical origins can be driven by similar genetic and molecular alterations, molecularly targeted drugs developed to treat cancer arising in one tissue can be repurposed as effective treatments for cancers with the same defect originating in a different tissue. For example, the HER2-targeted therapy trastuzumab was originally developed to treat patients with breast cancers that overexpress the HER2 protein due to the presence of extra copies of the HER2 gene and later shown to prolong survival for patients with stomach cancer harboring extra copies of the HER2 gene (167). 

Currently, however, our use of large-scale genomic data is limited to the research setting. Here, it is guiding the development of new cancer drugs, directing the repurposing of established molecularly targeted therapies, and aiding clinical researchers in assigning patients, like Carol Weinbrom​, to the most appropriate therapies and clinical trials. 

Recently, two independent large-scale genomic studies provided insight that could benefit some patients with breast cancer that tests negative for HER2 gene amplification (168, 169). These patients are considered ineligible for treatment with HER2-targeted therapies like trastuzumab. However, the large-scale genomic analyses found that some tumors that test negative for HER2 gene amplification harbor a mutation in the HER2 gene that causes their HER2 proteins to be overactive in the same way that HER2 gene amplification does, suggesting that they might be sensitive to HER2-targeted therapies. Thus, a clinical trial has been launched to evaluate whether the investigational HER2-targeted therapy neratinib is a good treatment option for patients with metastatic breast cancer harboring HER2 gene mutations but not amplifications. 

Such genomically informed clinical trials are likely to become more common in the future. It is hoped that such trials will not only accelerate the translation of scientific discoveries into new therapies, but will also increase the number of patients who benefit from new and existing molecularly targeted drugs. To accomplish this, several new collaborative, genomic-based approaches to anticancer drug development and clinical trials are being planned (see sidebar on Molecularly Informed Clinical Trials).

In addition to guiding clinical trial design, researchers are beginning to use large-scale genomic analysis to help understand why a small number of patients often respond in otherwise failed clinical trials. In many clinical trials testing anticancer drugs, not enough patients benefit from the drug to support its further development, although there are often exceptions: rare patients who gain enormous benefit from the drug under investigation. These patients are referred to as rare or exceptional responders. Genomic studies that focus on explaining why these patients responded while the majority of patients did not are sometimes referred to as “n-of-1” studies.

The promise of exceptional responder studies was highlighted recently when researchers performed large-scale genomic analysis on a tumor sample from an exceptional responder in a clinical trial testing the drug everolimus (Afinitor) as a treatment for metastatic bladder cancer (170). They identified a mutation in a gene called TSC1 that was of interest because a nonfunctional TSC1 protein would make cancer cells more dependent on the cellular pathway that everolimus shuts down. Further analysis revealed that TSC1 was mutated in several other patients in the clinical trial, including two patients who had minor responses to everolimus. This finding may resurrect everolimus as a potential treatment for bladder cancer, but only for patients with disease harboring mutations in the TSC1 gene. 

As we move further into the era of precision medicine, it is evident that large-scale genomic analyses will be an essential catalyst for further progress against cancer in both the research setting and the clinic.

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Cancer Progress Report 2013 Contents

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