​Transforming Lives Through Research

Cancer Progress Report 2014: Contents

In this section you will learn:

  • From Aug. 1, 2013, to July 31, 2014, the FDA approved six new therapeutics for treating certain types of cancer.
  • Research is being performed to help cancer survivors meet the numerous challenges they face.
  • Five of the new anticancer therapeutics are molecularly targeted, and one of these is also an immunotherapeutic.
  • Cancer genomics research is a foundation for novel clinical trials designed to accelerate the pace at which new therapeutics are approved for patient care.
  • During the same period, the FDA authorized new uses for five previously approved anticancer therapeutics, two imaging agents, and one screening test.

Research has the power to transform and save lives.

Yesterday’s discoveries are being actively translated into tomorrow’s breakthroughs, thanks to the dedicated efforts of researchers from across the entire biomedical research community, as well as patients and their health care providers. As a result, our journey toward the conquest of cancer continues to advance at an ever-increasing pace.

Biomedical Research

The cycle of biomedical research is fed by observations with the potential to have an impact on the practice of medicine. These observations emanate from laboratory research, population research, clinical practice, and clinical research including clinical trials (see Figure 8), and are made by investigators working across the spectrum of research, from basic to population science (see sidebar on Who We Are).

Ultimately, the observations lead to questions, or hypotheses, that are tested in experiments, the results of which add to or change current clinical practice, or feed back into the cycle for another iteration of testing. Importantly, because the cycle is iterative, it is constantly building on prior knowledge.

Figure 8 depicts the continuum of biomedical research. The cycle can be divided into several discrete stages of research, and a brief description of each follows.


In the discovery phase of research, hypotheses generated from observations with medical relevance, are tested in experiments performed using models, ranging from single cells to whole animals, that mimic healthy and disease conditions (see sidebar on Research Models). In clinical research, these models are derived from patients. Cancer research uses models that mimic specific aspects of cancer or types of cancer—for example, increased cell growth or pancreatic cancer, respectively.

Therapeutic Development

The majority of research and therapeutic development performed today is “target based,” meaning that it focuses on traits unique to a disease that were uncovered during the discovery research process (see sidebar on Therapeutic Development). Once these targets are identified, they are then validated, meaning that the relationship of the trait to the disease state is confirmed, and then panels of potential therapeutics are tested to determine if they are capable of hitting and altering the target. A group of potential therapeutics that are capable of modifying the target, also known as “hits,” are then further studied to identify the most promising, which is referred to as the lead therapeutic. Lead therapeutics then go through an optimization process that aims to enhance potency and other factors while reducing toxicity. During preclinical testing, a lead therapeutic is rigorously assessed in animal models to identify any potential toxicity and further study potency prior to testing in humans.

Back to top

Clinical Trials

Before a medical product can be used routinely in patient care, it must be rigorously tested in clinical trials, which provide each patient with the best care available (see cancer survivor Jack Whelan). As highlighted by Carlos L. Arteaga, MD, perhaps one of the most significant advances taking place in clinical care in recent years is the fact that clinical trials are no longer seen as a last option, but rather can be incorporated as part of regular care after discussions between physician and patient.

Clinical trials are used to evaluate the safety and efficacy of a potential medical product before it can be approved by the FDA and used more broadly as part of standard care. All clinical trials are reviewed and approved by the FDA and institutional review boards before they can begin and are monitored throughout their duration. There are several types of cancer clinical trials, including treatment trials, prevention trials, screening trials, and supportive or palliative care trials, each designed to answer different research questions. In general, they add an investigational intervention to the standard of patient care. The following discussion focuses on treatment trials, which are used to evaluate potential new anticancer therapeutics.

Until recently, treatment clinical trials have been typically done in three successive phases, each with an increasing number of patients (see sidebar on Phases of Clinical Trials). One of the many advances in clinical research has been the advent of new ways of conducting and regulating clinical trials, which can eliminate the need for large, long multiphase trials (see below).

Conventionally, many adult clinical trials are conducted after patients have received prior treatments, like surgery, radiation, or other therapeutics, which have already been tested in prior clinical trials. In some cases, a clinical trial may be designed to test a presurgery treatment, which is referred to as a neoadjuvant treatment. Recently, such a trial was the basis upon which the FDA approved a new use for a previously approved breast cancer therapeutic called pertuzumab (Perjeta) (see New Path to Approving Breast Cancer Therapeutics).

For more than a decade, the process of therapeutic development has been steadily moving toward the production of therapeutics that precisely target the molecules disrupted as a consequence of cancer-specific genetic mutations. Unfortunately, it is estimated to cost more than $1 billion and take more than a decade to develop a targeted therapeutic and bring it to market (68). Thus, numerous efforts have been made to streamline clinical research. Some of these efforts are aimed at matching the right drugs to the right patients, whereas others focus on reducing the number of patients that need to be enrolled in a particular trial. Yet others are designed to reduce the time needed for the trial to continue before a clear result can be achieved—for example, by using alternative or surrogate endpoints (see sidebar on Alternative (Surrogate) Clinical Trial Endpoints) and expedited review strategies (see sidebar on FDA’s Expedited Review Strategies).

Two examples of clinical trials aimed at matching the correct therapy with the correct patient subset are BATTLE-2 and the I SPY-2 TRIAL (I SPY-2). In each of these unique clinical trials, a patient’s tumor is examined for unique signatures called biomarkers. The biomarker signatures are used to simultaneously test and match multiple investigational therapies to individual patients, thus maximizing the number of patients likely to benefit. These trials have numerous efficiencies, but the major efficiency is enabling a phase III trial that is smaller than is traditionally needed because, in an adaptive trial, only patients most likely to respond are included in the study.

One of the major advances provided by the use of genomics in clinical research is the ability to use novel clinical trial designs to assign the correct therapy to the correct patient earlier and to improve organ-based classifications of cancers by including a description of the underlying genomic alterations. Such trials can take the form of basket or umbrella trials (see Figure 9). Basket trials aim to test one drug or one particular genetic mutation across multiple organs. Umbrella trials seek to test a drug or drugs across multiple genetic mutations within a particular type of cancer. For example, both I SPY-2 and BATTLE-2 are umbrella trials in breast and lung cancer, respectively.

Two ambitious umbrella trials are just getting underway and are possible only because of advances in DNA sequencing technology. The first of these, the Lung-MAP study, is a phase II/III trial that aims to test for multiple types of mutations in hundreds of genes prior to assigning patients with squamous cell lung carcinoma to one of five investigational drugs, including an immunotherapy (see Treatment With Immunotherapeutics). The NCI-MATCH trial is another phase II umbrella trial using advanced DNA sequencing technology to identify multiple types of mutations in hundreds of genes prior to assigning patients to one of numerous investigational therapeutics.

In addition, physician-scientists like Nikhil Wagle, MD, are using genomics to help understand why some individuals, referred to as rare responders, have exceptionally good responses to a treatment received as part of a clinical trial, whereas the majority of individuals do not gain benefit from the therapy.

Genomics is also being used to identify new patients who might benefit from previously approved molecularly targeted therapeutics. This is now possible because researchers are increasingly discovering that different types of cancer are driven by similar genetic abnormalities. Thus, molecularly targeted therapeutics that were first developed and FDA approved for the treatment of one type of cancer can now be repurposed as treatments for patients with a different type of cancer driven by similar genetic abnormalities. Approaches like these have the potential to benefit many patients.

For example, after genomics research established that about 5 percent of cases of the most common form of lung cancer, non–small cell lung cancer (NSCLC), are driven by genetic mutations that lead to altered expression and activity of the signaling protein ALK, researchers set out to develop ALK-targeted therapeutics. In August 2011, the FDA approved one such therapeutic, crizotinib (Xalkori), for the treatment of patients with ALK-positive NSCLC. After it was found that between 10 and 15 percent of childhood anaplastic large cell lymphomas (ALCLs) are also driven by ALK (69), researchers began testing crizotinib as a treatment for pediatric patients with ALCL. Early results from these trials have been very promising (70), with several patients, such as Zachery (Zach) Witt, having complete responses.

As discussed earlier, these advances in clinical research are possible only because of the ability to perform high-density genetic analysis of the tumors from patients in a given study. In November 2013, the FDA cleared the first high-throughput (next-generation) genomic sequencer, the Illumina MiSeqDx instrument and companion Universal Kit reagents, for broad clinical use. Together, this machine and these reagents are capable of reading a patient’s entire genome and assisting in the identification of multiple types of genetic mutations.

Because of the sheer amount of data generated by genomic studies, advanced computation and “big data” science are needed to help make sense of the data, as well as define new relationships between the data elements (see Figure 10). The need to understand big data is great, not only in clinical research but also in all of biomedical research.

Without question, genomics and the use of big data are revolutionizing clinical research, and it is anticipated that the use of genomics will soon become part of the standard of care in oncology (see What Progress Does the Future Hold?).

Back to top

Progress Against Cancer Across the Clinical Care Continuum

The tools that we use routinely to prevent, detect, diagnose, and treat cancer were developed as a result of extraordinary medical, scientific, and technical advances fueled by cancer research. In fact, it takes many years of dedicated work by thousands of individuals across the biomedical research community to bring a new medical product from concept to FDA approval.

In the 12 months leading up to July 31, 2014, the FDA approved six new anticancer therapeutics. During this time, the FDA also approved a new use for a previously approved test for detecting the cancer-causing pathogen HPV; new uses for two imaging agents; and new uses for five previously approved anticancer therapeutics, including a nanodrug form of paclitaxel (Abraxane), a traditional chemotherapy used to treat a number of cancer types.

The nanodrug form of paclitaxel was approved by the FDA for the treatment of metastatic pancreatic cancer in September 2013. This FDA approval followed earlier approvals of this nanotherapeutic for the treatment of patients with breast or lung cancer. It was the result of clinical trials showing that the nanodrug form of paclitaxel transformed the lives of many patients, like Dr. Charles Haerter (who was featured in the AACR Cancer Progress Report 2013 (5)), diagnosed with one of the most deadly forms of cancer (75).

In the quest to prevent and cure cancer, these new tools are used alongside those already in the clinician’s armamentarium. Thus, most patients are treated with a combination of surgery, radiotherapy, chemotherapy, and immunotherapy. In June 2014, the FDA approved a new use for the radioactive diagnostic imaging agent technetium Tc 99m tilmanocept (Lymphoseek) that will benefit some patients with head and neck cancer who are undergoing surgery. The agent can now be used to help surgeons find the sentinel lymph node(s) in patients with head and neck cancer, limiting the need for further surgery in patients with cancer-free lymph nodes and potentially improving postsurgical treatment decisions.

The following discussion focuses on recent FDA approvals that are transforming lives by having an impact on clinical care across the spectrum of cancer prevention, detection, diagnosis, treatment, and continuing care. It also highlights some advances across the continuum of clinical care that are showing near-term promise.

Cancer Prevention, Detection, and Diagnosis

The most effective ways to reduce the burden of cancer are to prevent cancer from developing in the first place and, if cancer does develop, to detect it as early as possible. As research provides new insights into the factors that increase a person’s risk of developing cancer (see Figure 5) and the timing, sequence, and frequency of the genetic, molecular, and cellular changes that drive cancer initiation and development, we have been able to develop new ways to prevent cancer onset or to detect a cancer and intervene earlier in its progression. In some cases, strategies to detect a cancer also provide key information for diagnosis.

HPV Holds New Keys to Cancer Prevention

Almost all cases of cervical cancer are attributable to persistent cervical infection with certain strains of HPV (42) (see Figure 7). Over time, this knowledge enabled two approaches for cervical cancer prevention and early detection: the development of vaccines that prevent infection with some cancer-causing strains of HPV and the development of a clinical test for detecting cancer-causing HPV strains (see Figure 11). Several recent advances could accelerate the pace of progress against cervical cancer, which affects more than 500,000 women each year worldwide (6) (see sidebar on Recent Advances in Cervical Cancer Prevention and Early Detection). Given that a substantial proportion of vulvar, vaginal, penile, and anal cancers, as well as some head and neck cancers—like the stage IV throat cancer that Robert (Bob) Margolis was diagnosed with in 2007—are also caused by HPV, these advances may have broader implications for reducing the global burden of cancer.

The two HPV vaccines currently approved by the FDA protect against infection with just two cancer-causing strains of HPV, HPV16 and HPV18. Although these are the two most common cervical cancer-causing HPV strains (44), researchers have been working to develop vaccines that protect against a greater number of the cancer-causing HPV strains. Recent results indicate that one vaccine that protects against seven cancer-causing HPV strains (HPV16, -18, -31, -33, -45, -52, and -58) can prevent precancerous cervical abnormalities caused by these strains (76).

The proportion of cervical cancer cases caused by individual HPV strains varies in different regions of the world and among different segments of a given population. For example, HPV16 and HPV18 account for more cases in Europe, North America, and Australia compared with Africa, Asia, and South/Central America (79), and for more cases among non-Hispanic white women in the United States compared with black and Hispanic women (80). Thus, the HPV vaccine that protects against nine cancer-causing HPV strains may particularly benefit women from racial and ethnic minorities and those living in less developed nations. It may also reduce the burden of other HPV-related cancers, which are frequently attributable to cancer-causing strains other than HPV16 and HPV18 (44).

In the United States, it is recommended that individuals receive three doses of either of the FDA-approved HPV vaccines to best ensure that they are protected against infection with HPV16 and HPV18. However, recent research has shown that two doses of vaccine can generate HPV16- and HPV18-targeted immune responses comparable to those generated by three doses (77, 78). On the basis of these results, the European Commission decided to approve the marketing of a two-dose Gardasil schedule in April 2014 (81). If long-term studies confirm that two vaccine doses provide protection against cervical cancer, it could mean that individuals who failed to complete the three-dose course would benefit from the vaccine doses they received. Moreover, a two-dose vaccine schedule could potentially reduce costs and increase compliance, which would lead to broader protection of the population.

Testing for HPV, together with the standard Pap test, was first recommended as an alternative to the Pap test alone for cervical cancer screening 10 years ago (82). It was recently reported that an HPV test called the cobas HPV test, which detects all currently identified carcinogenic HPV strains, identified women at high risk for cervical cancer more effectively than the Pap test alone (83). As a result, the FDA approved the use of the cobas HPV test as a stand-alone option for cervical cancer screening for women age 25 and older in April 2014. This provides women with a less burdensome screening option and could potentially reduce health care costs.

High-risk, High-reward Prevention

The hormone estrogen fuels the growth and survival of about 70 percent of breast cancers. It does this by attaching to specific proteins called hormone receptors in and on the breast cancer cells. This knowledge led to the development of antiestrogen therapeutics more than three decades ago, and these medicines are the mainstay of treatment for patients diagnosed with hormone receptor–positive breast cancer.

Two antiestrogen therapeutics, tamoxifen (Nolvadex) and raloxifene (Evista), are approved by the FDA for the prevention of breast cancer in women at high risk for developing the disease. However, their use in this setting is not widespread, in part, because tamoxifen increases the risk for endometrial cancer, and both therapeutics may increase risk for blood clots and stroke.

In December 2013, results of a large-scale clinical trial showed that another antiestrogen therapeutic, anastrozole (Arimidex), more than halved breast cancer development among postmenopausal women at high risk for developing the disease, with very few side effects (84). Thus, anastrozole may, in the future, provide a new cancer prevention option for women at high risk for breast cancer, such as those at high risk for inherited forms of the disease (see sidebar on How Do I Know If I Am at High Risk for Developing an Inherited Cancer?).

A Clearer Picture of Breast Cancer

Most women who receive a breast cancer diagnosis after a mammogram are referred for further testing to assess more precisely the size of the breast tumor and to determine whether the cancer has invaded local tissue or spread to other parts of the body. The results of these tests are important for providing the patient with an accurate diagnosis, which is crucial for deciding on the best course of treatment.

For some women, one of these follow-up tests is magnetic resonance imaging (MRI) of the breasts to establish the extent of the tumor within the breasts. MRI of the breasts can also be used to evaluate abnormalities seen by mammogram that were insufficiently clear for physicians to determine whether the patient has breast cancer or how large the tumor is.

In some cases, patients undergoing an MRI of the breasts are injected with a liquid called a contrast agent to help visualize abnormalities more clearly. In June 2014, the FDA approved a new contrast agent to use with MRI to assess the presence and extent of cancer within the breasts. This decision was made after the results of two large clinical trials showed that the new contrast agent, gadobutrol (Gadavist), significantly improved the ability of MRI to clearly visualize cancer in the breast.

Back to top

Treatment With Molecularly Targeted Therapeutics

Research is continually expanding our understanding of cancer biology. This knowledge is allowing us to treat cancer by targeting specific molecules involved in different stages of the cancer process. As a result, the standard of cancer care is changing from a one-size-fits-all approach to one in which the molecular makeup of the patient and his or her tumor dictates the best therapeutic strategy. This approach, variously called personalized cancer medicine, molecularly based medicine, precision medicine, or tailored therapy, is already transforming lives and will undoubtedly benefit many more patients in the future.

As a result of the greater precision of molecularly targeted therapeutics, they are more effective and tend to be 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 also improving their quality of life.

Molecularly Targeting Blood Cancers

Cancers that begin in blood-forming tissues, such as the bone marrow, or in cells of the immune system are called hematologic cancers or blood cancers. Three very recent FDA decisions have provided new treatment options for some patients with two types of hematologic cancer, chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) (see sidebar on Recent Advances Against Blood Cancers).

CLL is the most common type of leukemia diagnosed among U.S. adults age 20 or older, with 15,720 new cases projected to be diagnosed in 2014 (1). In the majority of cases, CLL arises in immune cells called B cells, or B lymphocytes, that have a protein called CD20 on their surface.

Given that CD20 is found only on B cells, both normal and CLL B cells, therapeutic antibodies that target CD20 were developed for the treatment of CLL. Two such therapeutic antibodies, ofatumumab (Arzerra) and rituximab (Rituxan), were approved by the FDA in October 2009 and February 2010, respectively. Although these two agents, when used in combination with traditional chemotherapies, significantly increase survival for many patients (85), a substantial number of patients have disease that does not respond to initial treatment or eventually becomes resistant to it (85, 86). As a result, researchers began working to develop more effective CD20-targeted therapeutic antibodies.

After attaching to CD20 on the surface of CLL cells, one of the ways in which rituximab and ofatumumab exert antileukemic effects is by flagging the CLL cells for destruction by immune cells. As a result, these agents can be considered molecularly targeted therapeutics and immunotherapeutics (see sidebar on How Immunotherapeutics Work ).

After basic immunology research uncovered a detailed molecular understanding of how rituximab attracts immune cells and instructs them to destroy the cells to which it is attached (87), bioengineers were able to create a new generation of CD20-targeted antibodies with enhanced ability to recruit immune cells and direct them to attack cancer cells (86).

One of the new generation of CD20-targeted antibodies, obinutuzumab (Gazyva), was approved by the FDA for the treatment of CLL in November 2013. This decision was made after early results from a large clinical trial showed that most patients with CLL lived significantly longer without their disease worsening when obinutuzmab was added to their traditional chemotherapy treatment, chlorambucil (88). Subsequent results from this clinical trial have shown that the addition of obinutuzumab to chlorambucil also provided an overall survival advantage compared with chlorambucil alone (89).

The FDA approval of obinutuzumab for the treatment of CLL was not only an important decision for patients with CLL, like David Rampe, but it was also a groundbreaking moment for regulatory science. This is because the use of obinutuzumab for the treatment of CLL was the first time a therapeutic was approved by the FDA after having been designated a “breakthrough therapy” (see sidebar on FDA’s Expedited Review Strategies).

The FDA recently approved a second therapeutic with breakthrough therapy designation for the treatment of CLL. Ibrutinib (Imbruvica) is a therapeutic that targets Bruton agammaglobulinemia tyrosine kinase (BTK), which is a protein that is one component of a signaling pathway that promotes the survival and expansion of CLL B cells. Ibrutinib was designated a breakthrough therapy for CLL in April 2013 and approved by the FDA for this use just 10 months later, after early stage clinical trials showed that the majority of patients with CLL responded to the therapeutic for an extended period (90).

Additional large-scale, randomized clinical trials are needed to confirm that the dramatic responses seen in patients with CLL who are being treated with ibrutinib translate into extended survival. These studies are underway. In fact, data from one of these trials showed that when compared with ofatumumab, ibrutinib significantly lengthened the time to disease progression and overall survival for patients with CLL (91).

After receiving breakthrough therapy designation for the treatment of MCL, a form of non-Hodgkin lymphoma, in February 2013, ibrutinib was approved by the FDA for this use just nine months later. Similar to CLL, MCL arises in B cells that are particularly dependent on the BTK signaling pathway for survival and expansion. Blocking BTK with ibrutinib effectively shrank tumors in the majority of patients with MCL (92). MCL patients have a particularly poor outlook, and it is hoped that longer follow-up of these patients will reveal that ibrutinib not only dramatically shrinks MCL tumors but also extends survival.

Ibrutinib is also being tested in clinical trials as a treatment for a number of other types of blood cancer originating in B cells that depend on BTK: diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, and Waldenström macroglobulinemia. In the case of Waldenström macroglobulinemia, ibrutinib has been designated a breakthrough therapy by the FDA because it has shown tremendous benefit to patients with this rare disease, such as Shelley Lehrman. Determining if treatments for a certain cancer might benefit patients with other types of cancer improves patient care and increases the return on prior investments in cancer research.

Idelalisib (Zydelig) is another molecularly targeted therapeutic that had breakthrough therapy designation for the treatment of CLL and some forms of non-Hodgkin lymphoma. Idelalisib targets phosphatidylinositol 3-kinase (PI3K) delta, a component of a second signaling pathway that promotes survival and expansion of the B cells affected in these diseases. Early clinical trial results were extremely promising (93, 94), and in July 2014, the FDA approved idelalisib for the treatment of CLL and two forms of non-Hodgkin lymphoma: follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma.

Back to top

Two Approaches to Address Treatment Resistance

Despite the major advances we have made in treating cancer, some cells in a tumor are not completely eliminated by the therapies we currently use, and over time, a disease may continue to progress. This is referred to as treatment resistance.

Resistance to treatment occurs in two ways: acquired resistance, which develops during the course of a given treatment, and innate resistance, which is present even before a certain treatment begins. There are many molecular reasons for treatment resistance, making it one of the greatest challenges that we face today when caring for patients with cancer (see sidebar on The Challenge of Treatment Resistance).

Two FDA decisions in the first four months of 2014 have helped address the problem of treatment resistance for a group of patients with lung cancer and for some patients with melanoma.

In April 2014, the FDA approved a molecularly targeted therapeutic called ceritinib (Zykadia) for patients with NSCLC that has become resistant to another molecularly targeted therapy, crizotinib.

Both crizotinib and ceritinib block the function of a signaling protein called ALK, which drives about 5 percent of cases of NSCLC. Although crizotinib benefits many patients with NSCLC driven by ALK, not all patients respond (95). Moreover, the majority of patients who initially respond eventually relapse because their cancer has become resistant to crizotinib (95).

NSCLC resistance to crizotinib occurs through a variety of molecular mechanisms, including the emergence of new mutations in ALK (96) (see sidebar on The Challenge of Treatment Resistance ). Recent research has shown that ceritinib is able to block many of the unique forms of ALK that result from these new mutations (97). In this way, ceritinib benefits many patients, like James (Rocky) Lagno, with crizotinib-resistant NSCLC driven by ALK (98).

In January 2014, the FDA approved the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) for the treatment of certain forms of melanoma, the most aggressive form of skin cancer. This is the first time that two molecularly targeted therapeutics have been approved by the FDA as a combination treatment for the same disease. It is expected that combinations of molecularly targeted therapeutics will become an integral part of treatment in the near future as our understanding of cancer biology increases (see What Progress Does the Future Hold?).

About 50 percent of melanomas are driven by an abnormal protein called BRAF V600E (99). This knowledge led to the development and subsequent FDA approval of two BRAF V600E–targeted drugs, vemurafenib (Zelboraf) and dabrafenib (Tafinlar). Because of their specificity, these drugs are FDA approved only for the treatment of patients with metastatic melanoma who have the BRAF V600E protein, as determined by specific tests or companion diagnostics (see sidebar on Companion Diagnostics). However, recent results from a large clinical trial indicate that vemurafenib may also benefit patients with metastatic melanoma driven by a second abnormal BRAF protein, BRAF V600K (100).

Trametinib blocks the activity of two proteins, MEK1 and MEK2, that function in the same signaling network as abnormal BRAF proteins. Trametinib is FDA approved for the treatment of metastatic melanoma driven by either BRAF V600E or BRAF V600K. As with vemurafenib and dabrafenib, patients must test positive for one of these mutations before beginning treatment with trametinib.

Although vemurafenib, dabrafenib, and trametinib benefit many patients with melanoma driven by abnormal BRAF proteins, some patients never respond to these therapeutics, whereas the majority of those who initially respond relapse within approximately one year of starting treatment owing to treatment resistance (99, 101, 102). Because dabrafenib and trametinib block different components of the same signaling network, it was thought that together they might eliminate the emergence of resistance (103). In fact, clinical trial results show that the combination almost doubles the length of time before metastatic melanoma becomes resistant to treatment and progresses (103).

Above and Beyond for Patients With Peripheral T-cell Lymphoma

The drugs crizotinib, ceritinib, dabrafenib, and trametinib, discussed above, target the aberrant proteins driving some forms of lung cancer and melanoma that result from specific genetic mutations. However, research, has shown that changes in the chemical tags on the DNA itself, or on the proteins around which the DNA is wrapped, as well as mutations within the proteins that read, write, and/or erase these tags, can also lead to cancer. Collectively, these tags are referred to as the epigenome, and it functions to control how the various genes are read (see sidebar on Genetic and Epigenetic Control of Cell Function). Importantly, the epigenome is dynamic and can be changed by cells as needed. It can also be altered by drugs that target its readers, writers, and erasers. In fact, the FDA has already approved four drugs that target two such types of epigenome-modifying proteins. This expanding class of drugs is emerging as an exciting new avenue of attack on cancer, particularly because early indications are that some of the cancer-induced changes to the epigenome may be reversible.

Among the many chemical tags included in the epigenome is a class of tag called acetyl groups. These tags can be added or removed from the histones around which the DNA is wrapped by proteins called histone acetylases or deacetylases, respectively. In July 2014, the FDA approved belinostat (Beleodaq), which targets multiple types of histone deacetylases, for the treatment of patients with peripheral T-cell lymphoma who had become resistant to or had relapsed on prior therapies. This decision was based on clinical trials results showing that belinostat was effective in more than 25 percent of patients, many of whom had received numerous prior therapies. It therefore offers a new treatment option for the 7,000 to 10,000 individuals anticipated to be diagnosed with peripheral T-cell lymphoma in 2014, most of whom will become resistant to their initial therapy.

Back to top

New Option for Blocking Blood Supply to Tumors

Research has shown that many solid tumors are dependent on the growth of new blood and lymphatic vessels to grow and survive. It has also led to the identification of many molecules that control these processes, as well as the development of anticancer therapies that specifically block these molecules. In fact, in the past 10 years, the FDA has approved 10 such therapeutics, which are called angiogenesis inhibitors (see Figure 12).

The newest member of this growing class of therapeutics is ramucirumab (Cyramza). It was approved by the FDA for the treatment of metastatic gastric (stomach) cancer and cancer of the part of the esophagus that connects to the stomach (gastroesophageal junction adenocarcinoma) in April 2014. Patients with metastatic gastric cancer have a very poor outlook; just 4 percent survive five years (7). With such a clear need for new treatment options, the fact that ramucirumab extended overall survival for patients with metastatic gastric cancer in phase III clinical trials (104, 105) provides patients with new hope.

Ramucirumab is also being tested in numerous clinical trials as a potential treatment for other types of cancer. Recent results from one of these trials showed that ramucirumab significantly prolonged survival for some patients with the most deadly form of lung cancer, NSCLC (106). If these data result in an FDA approval, this will provide more patients with new treatment options and increase the return on prior investments in cancer research.

New Path to Approving Breast Cancer Therapeutics

Breast cancer is the second leading cause of cancer-related death for women in the United States (1). Studies have shown that intervening early and aggressively can improve survival for breast cancer patients who have a high risk of recurrence. Therefore, the FDA outlined a new path for regulatory approval of breast cancer therapeutics in May 2012 (107) (see sidebar on New FDA Approach to Breast Cancer Therapeutics).

In September 2013, pertuzumab (Perjeta) became the first therapeutic approved under this new regulatory path.

Pertuzumab is a therapeutic antibody that targets the HER2 protein. About one in every five of the 235,030 cases of breast cancer anticipated to be diagnosed in the United States in 2014 will overexpress HER2 (1, 109).

The FDA decision allows pertuzumab to be used as part of a presurgery course of treatment for certain patients with HER2-positive, early stage breast cancer. The decision was based on clinical trial results showing that women who received pertuzumab in addition to trastuzumab and the traditional chemotherapy docetaxel before breast cancer surgery were significantly more likely to have no residual invasive cancer detected in breast tissue and lymph nodes removed during surgery compared with women who received only trastuzumab and docetaxel (110).

It is important to note that these data are preliminary and that we do not know for certain whether the pertuzumab-containing presurgery treatment will improve patients’ long-term outcomes, including survival. To determine this, a large-scale clinical trial is ongoing and the results are expected in 2016.

Treatment With Immunotherapeutics

A new approach to cancer treatment that has begun to transform the lives of patients is immunotherapy.

Cancer immunotherapy refers to treatments that can unleash the power of a patient’s immune system to fight cancer the way it fights pathogens. Not all cancer immunotherapies work in the same way (see sidebar on How Immunotherapeutics Work). As our scientific understanding of the immune system and how it interacts with cancer cells increases, we can expect to see novel immunotherapies and new ways to use those that we already have.

Given that some patients have remarkable and durable responses following immunotherapy, this form of cancer treatment holds incredible promise for the future, potentially even cures for some patients. The progress is very recent, and most experimental cancer immunotherapies, which are the focus of the following discussion, are still in clinical development and have, therefore, not yet been approved by the FDA.

Releasing the Brakes on the Immune System

Cells called T cells are key players in the immune system that can naturally destroy cancer cells. However, tumors can prevent T cells from carrying out this function. For example, some tumors have high levels of proteins that can put the brakes on T cells, stopping them from attacking the cancer cells. The finding that these tumor proteins trigger T cells’ brakes by attaching to complementary proteins, called immune checkpoint proteins, on the surface of T cells, led researchers to look for ways to disrupt these interactions.

Ipilimumab (Yervoy) is the only checkpoint inhibitor currently approved by the FDA; it targets the checkpoint protein CTLA4 and was approved for the treatment of metastatic melanoma in March 2011. This FDA approval, which followed almost 25 years of basic, translational, and clinical research (see Figure 13), has transformed the lives of many patients with metastatic melanoma, including Andrew Messingerr (who was featured in the AACR Cancer Progress Report 2013 (5)).

In some patients with metastatic melanoma, ipilimumab has yielded dramatic and durable responses (111). These spectacular responses paved the way for clinical trials, many of which are still ongoing, testing whether ipilimumab might also be effective against other forms of cancer. They also motivated researchers to rapidly develop therapeutics that target a second checkpoint protein, called PD-1, as well as therapeutics that target the protein on tumor cells that attaches to PD-1, PD-L1.

As a result of promising early results in a small clinical trial (112), the FDA granted one therapeutic antibody that targets PD-1, pembrolizumab (previously called both MK-3475 and lambrolizumab), breakthrough therapy designation for the treatment of metastatic melanoma. More recent data extend the initial results, with the majority of patients, like Richard Murphy, still gaining benefit from pembrolizumab more than one year after starting treatment (113). Large-scale clinical trials are currently ongoing to confirm these results.

Beyond melanoma, pembrolizumab is also being tested in clinical trials as a potential treatment for more than 30 other types of cancer. Results are not yet available for the majority of these. However, early results show that the immunotherapeutic benefits some patients with NSCLC and, potentially, some with head and neck cancer (114, 115), although these results are preliminary.

A second therapeutic antibody targeting PD-1, nivolumab, is also being tested in clinical trials as a potential treatment for numerous cancer types. Recent preliminary results show that nivolumab benefits some patients with advanced melanoma; it has been reported that more than 40 percent of patients are still gaining benefit from this therapeutic more than three years after starting treatment (116). Early results indicate that it may also benefit patients with NSCLC (117, 118), Hodgkin lymphoma, and renal cell carcinoma (119), which is the most common form of kidney cancer.

Recent promising early results from a small clinical trial showed that a therapeutic that targets PD-L1, MPDL3280A, could benefit patients with bladder cancer (120). As a result, the FDA granted MPDL3280A breakthrough designation for the treatment of bladder cancer.

Unfortunately, not all patients have dramatic responses following treatment with ipilimumab or a PD1-targeted therapeutic. To help increase the number of patients who may benefit from these therapeutics, researchers are assessing combinations of immunotherapies that target different checkpoint proteins and combinations of immunotherapies that work in different ways, as well as combining immunotherapies with other types of anticancer treatments, including molecularly targeted therapeutics.

To this end, recent remarkable results showed that 75 percent of patients with metastatic melanoma treated with a combination of ipilimumab and nivolumab were still benefiting two years after the start of treatment (121). In a second small clinical trial, early results showed that a combination of ipilimumab and an oncolytic virotherapy called talimogene laherparepvec benefited more patients with metastatic melanoma than either immunotherapeutic alone (122).

Back to top

Enhancing the Killing Power of the Immune System

Another approach to cancer immunotherapy is to boost the ability of T cells to eliminate cancer cells. To return to the analogy of the car, this approach is like stepping on the accelerator, and it can be achieved in a number of ways, including the administration of adoptive T-cell therapy, a soluble molecule called a cytokine that can enhance T-cell function, or a therapeutic cancer vaccine.

Adoptive T-cell therapies are complex medical procedures built upon our accumulating knowledge of the biology of cancer and the biology of the immune system. In these procedures, T cells are harvested from a patient, expanded in number and/or genetically modified in the laboratory, and then returned to the patient, where they attack and potentially eliminate the cancer cells. No FDA-approved adoptive T-cell therapies are yet available. Several approaches, however, are currently being tested for a number of types of cancer, one of which, called CTL019, recently received breakthrough therapy designation from the FDA for the treatment of ALL (see sidebar on Types of Adoptive T-Cell Therapies).

CAR T–cell therapy has been particularly successful for adults with CLL and for adults and children with ALL (123-125). In fact, a recent study indicates that 86 percent of pediatric patients with ALL experienced complete remissions, and one patient remains in remission 20 months after initiating treatment (126). Although this therapy is promising, some children eventually relapse.

Researchers are currently working to develop CAR T cells that will target other types of cancer, including acute myeloid leukemia, multiple myeloma, and some solid tumors, but the research is in the very early stages (127, 128). As research continues to increase our understanding of why CAR T–cell therapy does not work for all patients, new and more effective CAR T–cell therapies are likely to emerge in the future (128).

Tumor-infiltrating lymphocyte therapy (TIL therapy) is an experimental approach primarily used to treat patients with metastatic melanoma. Since its development 12 years ago (129), it is estimated that durable responses occur in about one in every five patients with metastatic melanoma and that many of these individuals, like Roslyn Meyer (who was featured in the Cancer Progress Report 2011), have ongoing responses (130).

Until recently, TIL therapy has largely been limited to the treatment of melanoma. However, new reports indicate that it may be causing tumor regression for one patient with bile duct cancer and complete, ongoing responses for two patients with cervical cancer (131, 132). Thus, TIL therapy may one day benefit patients with a wide range of cancer types.

The majority of patients treated with TIL therapy also receive high doses of the cytokine IL-2 to give the transferred T cells a boost, and it is the IL-2 that causes the most severe adverse effects of the treatment. Researchers are investigating a number of ways to overcome this problem, including engineering less toxic forms of IL-2 (133). This is important because even though IL-2 was approved by the FDA to treat metastatic melanoma and renal cell carcinoma in 1998, it is not used very often because of its toxic, even lethal, side effects. When it is used, however, recent results show that high-dose IL-2 can lead to durable responses (134, 135).

Therapeutic cancer vaccines enhance the killing power of the immune system by training the patient’s T cells, while they are inside the patient’s body, to recognize and destroy the patient’s cancer cells. The development of these immunotherapeutics is an intensively studied area of cancer research. In fact, in the United States alone, several hundred ongoing clinical trials are testing therapeutic cancer vaccines.

One therapeutic cancer vaccine being tested as a treatment for the most aggressive form of brain cancer, glioblastoma multiforme (GBM), in a large-scale clinical trial, after showing promise in early stage clinical trials, is DCVax-L (136). DCVax-L is a cell-based vaccine whereby each patient receives a customized treatment that uses dendritic cells from his or her own body to boost cancer-fighting T cells. As a result of the immense potential of this immunotherapeutic, in March 2014, the Paul Ehrlich Institute—the German equivalent of the FDA—approved the use of DCVax-L for the treatment of patients with GBM and less aggressive forms of the disease through an early access program.

Living With or Beyond Cancer

As a result of advances in cancer research, more people are surviving longer and leading fuller lives after a cancer diagnosis than ever before. In fact, the number of U.S. residents living with, through, or beyond cancer is estimated to have risen to almost 14.5 million, compared with just 3 million in 1971 (2, 3). This 14.5 million includes an estimated 379,112 individuals who, like Jameisha (Meisha) Brown, received their cancer diagnosis as a child or adolescent (ages 0–19) (1). These individuals are considered cancer survivors, although it is important to note that not all people who have received a cancer diagnosis identify with this term.

Three distinct phases are associated with cancer survivorship: the time from diagnosis to the end of initial treatment, the transition from treatment to extended survival, and long-term survival. Recent and promising progress realized for individuals in the first group was discussed in the previous two sections of the report (see Molecularly Targeted Therapeutics, and Treatment With Immunotherapeutics). Here, the discussion focuses on advances made for those in the latter two groups, as well as the numerous challenges they face.

Each distinct phase of cancer survivorship is accompanied by a unique set of challenges (see sidebar on Life After Initial Cancer Treatment Ends). Moreover, the issues facing each survivor vary, depending on many factors, including gender, age at diagnosis, type of cancer diagnosed, general health at diagnosis, and type of treatment received. Importantly, it is not just cancer survivors who are affected after a cancer diagnosis but also their caregivers, and this population is growing proportionally with the number of cancer survivors. Caregivers are at risk for poor health outcomes, and this is often compounded by the fact that a subset of caregivers are already cancer survivors themselves.

Among the 1.6 million U.S. residents projected to receive a cancer diagnosis in 2014 are approximately 16,000 children and adolescents (1). Fortunately, the overall five-year survival rates for children and adolescents diagnosed with cancer are currently 83 and 85 percent, respectively, and survivors of cancer diagnosed by the age of 19 account for almost 3 percent of the U.S. cancer survivor population (3). However, as discussed by Congressman Michael McCaul, these individuals face particularly demanding challenges. In fact, a recent study found that 98 percent of adult survivors of childhood cancer had one or more chronic health conditions, and 68 percent have severe/disabling or life-threatening conditions (138).

Given that cancer survivors who received their diagnosis as a child or adolescent are at extremely high risk for long-term and late treatment-related side effects, the Children’s Oncology Group, an NCI-supported clinical trials group that cares for more than 90 percent of these individuals, developed guidelines for their long-term care (see sidebar on Guidelines for Long-term Follow-up of Survivors of Childhood, Adolescent, and Young Adult Cancers).

Individuals who receive a cancer diagnosis as a child, adolescent, or young adult are not the only group extremely vulnerable to treatment-related health issues. The elderly are also particularly susceptible to the toxic effects of many treatments for myriad reasons, including the presence of other health conditions normally associated with aging, such as poor heart function and type II diabetes. Fortunately, outcomes for the elderly have significantly improved advances in surgery, radiotherapy, and palliative care, along with the advent of the molecularly targeted therapeutics era. However, a need still exists for effective methods of predicting therapeutic toxicities in the elderly, and recent research has made inroads in developing some models that could help in this regard (139). Undoubtedly, continued research will only further advance our ability to effectively treat our most at-risk populations.

A major concern for all cancer survivors is the return of their cancer or the development of a new cancer. Just as a healthy approach to living can prevent the development of cancer, it can also help prevent a cancer recurrence (see Healthy Living Can Prevent Cancer From Developing, Progressing, or Recurring). For example, emerging evidence indicates that regular, intense aerobic exercise can reduce recurrence and mortality in early breast, prostate, and colorectal cancer survivors (140). However, adopting healthy approaches to living can be as difficult for cancer survivors as it is for otherwise healthy individuals. More research is necessary to understand how best to help modify behaviors to embrace healthy living approaches.

In addition to adopting healthy living approaches, some cancer patients receive treatment for a time after their initial therapy is complete to help decrease their risk for tumor recurrence and metastasis emergence, thereby increasing their chance of long-term survival. This approach is called adjuvant therapy, and it can be any form of anticancer therapeutic or radiotherapy.

Although the concept of adjuvant therapy is not new, it is becoming more common because many new anticancer therapeutics are better tolerated, although not completely without side effects. As a result, patients may be able to take them for longer periods. Whether a patient receives adjuvant therapy depends on a number of factors, including the stage of disease and other factors that may categorize a tumor as having a higher risk of recurrence. A clinician can prescribe adjuvant treatment for nearly any form of cancer; however, it is most commonly prescribed for high-risk forms of breast cancer, colorectal cancer, melanoma, and some gynecologic cancers.

Recent research has identified a potential new adjuvant therapy approach to decreasing tumor recurrence for patients with hormone receptor–positive breast cancer (141). Specifically, results from two large-scale clinical trials showed that inclusion of an antiestrogen therapeutic called exemestane, as part of a five-year course of adjuvant therapy, decreased cancer recurrence in premenopausal women with breast cancer fueled by estrogen (141).

Given that research has shown that about one in four cancer survivors has a decreased quality of life owing to physical problems and one in 10 owing to emotional problems (142), it is clear that much more research is needed to help the growing number of cancer survivors achieve a higher quality of life.

One issue that affects many women who survive cancer is infertility. Fortunately, a large-scale clinical trial recently reported promising results that may help preserve fertility for some of the 15 percent of premenopausal women diagnosed with breast cancer who have tumors that do not have hormone receptors or other molecules that can be targeted with precise therapeutics. The only therapeutics available to these patients are traditional chemotherapeutics, which frequently cause infertility by damaging the ovaries. In this clinical trial, women who were treated with a therapeutic called goserelin (Zoladex), which shuts down their ovaries, putting them into temporary menopause while they received chemotherapy, were almost twice as likely to have a normal pregnancy after their cancer treatment compared with women who did not receive goserelin (143).

These research advances provide new hope for premenopausal women who are cancer survivors. Unfortunately, these individuals form only a small proportion of the U.S. cancer survivor population and the advances address only some of the challenges faced by these patients. Further progress toward reducing the impact of cancer treatment on cancer survivors in the future will take a concerted effort from all stakeholders in the biomedical research community (see sidebar on The Biomedical Research Community).

To address this need, a number of professional societies and not-for-profit organizations have recently developed clinical-practice guidelines that are designed to improve the prevention and management of some of the health-related issues affecting cancer survivors, including fatigue, anxiety and depression, and sexual dysfunction (144-146). Advocacy organizations, such as the Women Survivor Alliance, cofounded by Karen Shayne and Judy Pearson, also have an integral role to play if we are to meet the needs of cancer survivors, their loved ones, and future men, women, and children navigating the cancer journey.

Top of page

Cancer Progress Report 2014 Contents

American Association for Cancer Research Foundation
The AACR Cancer Progress Report is published by the American Association for Cancer Research (AACR). The mission of the AACR is to prevent and cure cancer through research, education, communication, and collaboration.

Requests for permission to reuse or reprint any part of the Cancer Progress Report should be sent to permissions@aacr.org.

© 2018 AACR | 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106
215-440-9300 | aacr@aacr.org

The American Association for Cancer Research (AACR) is a 501(c)(3) registered nonprofit organization (23-6251648).
Other AACR Sites
AACR Website
AACR Foundation Website
Cancer Today Magazine
AACR Blog: Cancer Research Catalyst

Follow the AACR

Follow the AACR Foundation