​​​​​​​​​​​​​​Transforming Lives through Precision Medicine

Cancer Progress Report 2015: Contents

In this section you will learn:

  • From Aug. 1, 2014, to July 31, 2015, the FDA approved nine new therapeutics for treating certain types of cancer, one new cancer prevention vaccine, and one new cancer-screening test.
  • During the same period, the FDA authorized new uses for six previously approved anticancer therapeutics and one imaging agent.
  • Pairing the increased understanding of cancer biology with information about each patient’s own cancer is increasing the precision with which radiotherapy and traditional chemotherapy are used.
  • Clinical trials that aim to match the right therapeutics with the right patients earlier are based on cancer genomics research, and are becoming more common.
  • Identifying ways to help cancer survivors meet the numerous challenges they face after their initial diagnosis is an area of intensive research.

The dedicated efforts of individuals working throughout the cycle of biomedical research (see Figure 14) have led to extraordinary advances across the continuum of clinical care that are transforming and saving lives in the United States and worldwide.


Biomedical research is an iterative cycle, constantly building on prior knowledge, with one discovery influencing the next (see Figure 14). In recent years, the cycle has become increasing efficient as the pace of discoveries has increased, and various sectors within the biomedical research enterprise have become further integrated, leading to one seamless ecosystem (see sidebar on Biomedical Research: What It Is and Who Performs It). As a result of these changes, the pace at which patient lives are transformed through precision medicine has accelerated and will continue to do so for the foreseeable future (see What Progress Does the Future Hold?).

In short, the biomedical research cycle is set in motion when discoveries with the potential to affect the practice of medicine are made by researchers in numerous areas of biomedical research, including laboratory research, population research, clinical research, and clinical practice. Ultimately, the discoveries lead to questions, or hypotheses, that are tested by researchers performing experiments in a wide range of models that mimic what happens in healthy and disease conditions (see sidebar on Research Models​). The results from these experiments can lead to the identification of a potential therapeutic target or preventive intervention, or they can feed backward in the cycle by providing new discoveries that lead to more hypotheses.

After identification of a potential therapeutic target, it takes several years of hard work before a candidate therapeutic is developed and ready for testing in clinical trials (see sidebar on Therapeutic Development). During this time, candidate therapeutics are rigorously tested to identify any potential toxicity and to ensure that they have the maximum chance of success in clinical testing.

Clinical trials are a central part of the biomedical research cycle. Before most potential new diagnostic, preventive, or therapeutic products can be approved by the FDA and used as part of patient care, their safety and efficacy must be rigorously tested through clinical trials (see sidebar on What Is the FDA?​). 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.

Treatment trials evaluating potential new anticancer therapeutics predominantly add an investigational intervention to the current standard of care. These types of clinical trial have traditionally been done in three successive phases, each with an increasing number of patients (see sidebar on Phases of Clinical Trials). Recently, the Tufts Center for the Study of Drug Development estimated that it costs pharmaceutical companies more than $2.5 billion to develop and gain approval for a new therapeutic, a process often lasting longer than a decade (90), although others have noted that not all costs associated with the discovery and development of new therapeutics are borne by industry (91). In the past five years, immense efforts have been made to address these issues by identifying new ways of conducting and regulating clinical trials that can eliminate the need for large, long, multiphase clinical trials (see Special Feature on Five Years of Progress, and below).

Briefly, many efforts to streamline the development of new anticancer therapeutics are powered by our increasing knowledge of cancer biology, in particular, cancer genomics. This knowledge has led researchers to focus on the production of therapeutics that precisely target the molecules disrupted as a result of cancer-specific genetic mutations. This, in turn, has led to novel clinical trial designs that aim to match the right therapeutics with the right patients earlier, to reduce the number of patients that need to be enrolled in clinical trials before it is determined whether or not the therapeutic being evaluated is safe and effective, and to decrease the length of time it takes for a new anticancer therapeutic to be tested and made available to patients.

One example of these new clinical trials is the phase II/III Lung Master Protocol (Lung-MAP) trial, which was launched in June 2014 (92). In this trial, patients with advanced squamous cell carcinoma of the lung are screened for more than 200 genetic alterations using DNA sequencing technologies and then assigned to the segment of the trial testing an investigational therapeutic that best suits their genomic profile. A second example is the NCI-MATCH (NCI-Molecular Analysis for Therapy Choice) trial, which opened for patient enrollment in August 2015 (93). Tumors from patients enrolled in NCI-MATCH will be analyzed for more than 4,000 different genetic alterations. Patients whose tumors, regardless of origin, harbor mutations that match any of the anticancer therapeutics being evaluated in the trial go on to be assessed for other trial eligibility criteria.

This new era of clinical trials offers the promise to accelerate the pace at which new anticancer therapeutics are tested in the clinic and reduce the number of patients that need to be enrolled in clinical trials, both of which may drive down costs. Therefore, the outcomes of these trials are eagerly anticipated by investigators and patient advocates throughout the biomedical research community.

Other major efforts to reduce the time needed for a clinical trial to continue before a clear result is achieved have been spearheaded by the FDA. For example, the FDA has developed four evidence-based strategies to expedite the evaluation of therapeutics for life-threatening diseases such as cancer (see sidebar on FDA’s Expedited Review Strategies​). An increasing number of anticancer therapeutics is being approved by the FDA using the most recently introduced of these review strategies, breakthrough therapy designation. A key part of this review strategy is that the FDA engages with those developing the investigational therapeutic early in the clinical trials process and provides continued guidance throughout the review period.

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Progress Across the Clinical Cancer Care Continuum

The dedicated efforts of individuals working throughout the biomedical research cycle power the development of the tools that are used routinely to prevent, detect, diagnose, and treat cancer. The number of tools in the physician’s armamentarium increases over time, because research is a continuous endeavor that constantly translates scientific discoveries to newly FDA-approved medical products.

In the 12 months leading up to July 31, 2015, the FDA approved one new cancer prevention vaccine, one new cancer screening test, and nine new anticancer therapeutics, including four immunotherapeutics (see Table 1). During this period, the FDA also approved new uses for one imaging agent and six previously approved anticancer therapeutics, including the molecularly targeted chemotherapeutic ibrutinib (Imbruvica).

The January 2015, FDA approval of ibrutinib for Waldenström macroglobulinemia was the first-ever FDA approval of a treatment for this rare and incurable type of non-Hodgkin lymphoma. It followed earlier approvals of ibrutinib for chronic lymphocytic leukemia and mantle cell lymphoma, which were highlighted in the AACR Cancer Progress Report 2014 (1). The approval of ibrutinib for Waldenström macroglobulinemia was based on the results of a clinical trial showing that the agent transformed the lives of many patients (94), like Shelley Lehrman (who was featured in the AACR Cancer Progress Report 2014, Ref. 1).

As new tools become available to physicians, they are used alongside many that have been the mainstay of patient care for years. Thus, most patients with cancer are treated with a combination of surgery, radiotherapy, chemotherapy (including both traditional chemotherapeutics and molecularly targeted chemotherapeutics), ​and immunotherapy (see Appendix Tables 1 and 3​).

The following discussion focuses on recent FDA approvals of preventive, diagnostic, and therapeutic products that are transforming lives across the clinical care continuum. It also highlights some advances that are showing near-term promise for fueling change in cancer prevention, interception, detection, diagnosis, treatment, and ongoing care.

CancerPrevention, Detection, Interception, and Diagnosis

Cancer prevention and early detection and interception, are the most effective ways to reduce the immense worldwide burden of cancer. The development of new and better ways to prevent cancer onset or to detect a cancer and intercept it earlier in its progression, when there is a greater chance a patient can be successfully treated, have been spurred by research that led to the identification of many cancer risk factors (see Figure 8) and to the increasing knowledge of the causes, timing, sequence, and frequency of the genetic, molecular, and cellular changes that drive cancer initiation and development.

Preventing More HPV-related Cancers

Almost all cases of cervical cancer, as well as many cases of vulvar, vaginal, penile, anal, and oropharyngeal cancers, in the United States are caused by persistent infection, at the site at which the cancer arises, with certain strains of HPV (see Figure 12). The majority of these cancer cases are attributable to just two of the 12 strains of HPV that can cause cancer, HPV16 and HPV18 (82).

This knowledge led to the development and FDA approval of two vaccines that protect against infection with HPV16 and HPV18: Gardasil and Cervarix. Clinical trials showed that Gardasil and Cervarix are highly effective at preventing precancerous cervical abnormalities caused by HPV16 and HPV18, which are the tissue changes that precede invasive cervical cancer, and it was estimated that if all girls and women for whom vaccination is recommended were vaccinated, almost all cases of cervical cancer caused by HPV16 and HPV18 could be prevented (95).

In an effort to extend these successes to other cancer-causing strains of HPV, researchers developed a vaccine that protects not only against HPV16 and HPV18 but also against five other cancer-causing HPV subtypes—HPV31, 33, 45, 52, and 58. After it was shown in a clinical trial to be effective at preventing precancerous abnormalities that precede invasive cervical, vulvar, and vaginal cancers caused by HPV31, 33, 45, 52, and 58 (96), it was approved by the FDA in December 2014, for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV16, 18, 31, 33, 45, 52, and 58 (see sidebar on How Do the Three FDA-approved HPV Vaccines Differ?​).

The potential for Gardasil 9 to reduce the global burden of cancer is immense. For example, it is estimated that 90 percent of invasive cervical cancer cases worldwide could be prevented if all girls and women for whom vaccination is recommended are vaccinated (97). The potential for HPV vaccines to prevent a significant number of cases of oropharyngeal cancer is of great interest because more than 60 percent of these cancers in the United States are related to HPV infections, and the incidence of these cancers is increasing (82, 98). However, research is needed to confirm that HPV vaccination can indeed prevent people like Robert (Bob) Margolis (who was featured in the AACR Cancer Progress Report 2014, Ref. 1) from developing HPV-related oropharyngeal cancer.

Increasing Options for Colorectal Cancer Screening

In the United States, colorectal cancer screening has helped dramatically reduce colorectal cancer incidence and mortality through the identification and subsequent removal of precancerous colorectal abnormalities and the detection of early-stage cancers, which are more easily treated compared with advanced-stage disease (see Screening for Early Detection and Interception). However, 1 in 3 people for whom colorectal cancer screening is recommended are not up to date with their screening (88) (see sidebar on USPSTF Cancer-screening Recommendations for Average-risk Adults​​), and colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related death (6).

Fear of the colorectal cancer screening test is one reason that U.S. men and women give for not getting screened (88). There is a noninvasive colorectal cancer screening option recommended by the USPSTF, fecal occult blood testing, which tests stool samples for blood that is present in such small amounts it cannot be seen. Although these tests can reduce colorectal cancer deaths by about 30 percent (99), they miss almost one-third of cancers and more than two-thirds of precancerous abnormalities (100).

In an effort to design a more effective stool-based colorectal cancer screening test, researchers exploited our growing knowledge of the genetic basis of cancer and developed a stool-based test that detects the presence of red blood cells and certain genetic mutations linked to colorectal cancer. In a large clinical trial, the new test, Cologuard, was significantly better at detecting colorectal cancers and precancerous colorectal abnormalities than a standard stool test for blood (100), and the test was approved by the FDA in August 2014. The hope of researchers in the field is that Cologuard will help increase the number of people who get screened for colorectal cancer, although further research is needed to determine whether or not this will be the case.

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Treatment With Surgery, Radiotherapy, and Traditional Chemotherapy

The advent of the era of precision medicine is transforming lives by changing the standard of cancer care from a one-size-fits-all approach to one in which greater understanding of the patient and his or her tumor dictates the best therapeutic strategy. For those patients for whom a molecularly targeted therapeutic is appropriate, the greater precision of these agents tends to make them more effective and less toxic than the treatments that have been the mainstay of cancer care for decades.

Although tremendous progress has been made, not all patients with cancer can be treated with molecularly targeted therapeutics. There are many reasons for this, including a need for more insight into the biology of many types of cancer. Moreover, in some cases, we know the underlying cause of the disease but so far have been unable to develop safe and effective therapeutics targeting the causative molecules.

Thus, surgery, radiotherapy, and traditional chemotherapy are the best treatment options for many patients with cancer, as they were for Congresswoman Rosa DeLauro, 29 years ago. In fact, these therapeutic modalities form the foundation of treatment for almost all patients, including those for whom molecularly targeted therapeutics and other novel agents are appropriate. Moreover, the more we know about individual patients and their individual cancers, the better we are able to tailor their treatment to be as effective and innocuous as possible. For example, surgery alone may be the best treatment option for some patients, as it was for Congressman Tom Marino​​.

Improving Diagnosis With Radiology

For many patients with cancer, surgery is an early step in their treatment. In some patients with solid tumors, the surgeon removes not only the initial tumor, but also lymph nodes in the surrounding area because these are the sites to which the tumor is most likely to first sp​read. The presence or absence of cancer cells in these nodes helps determine the extent to which the initial tumor has spread locally. This information helps establish a patient’s precise diagnosis, which is central to developing the most appropriate treatment plan for the patient.

To allow surgeons to see the lymph nodes clearly, patients are injected with a radioactive substance, a blue dye, or both prior to surgery, and then the surgeon uses a device that detects radioactivity and/or looks for lymph nodes that are stained with the blue dye during surgery. In October 2014, the FDA approved a new u​se for the radioactive diagnostic imaging agent technetium Tc 99m tilmanocept (Lymphoseek) that allows it to be used to find lymph nodes during surgery for any solid tumor where this procedure is a routine part of surgery.

Waysto Use Radiotherapy and Traditional Chemotherapy More Precisely

Radiotherapy and traditional chemotherapy are mainstays of cancer care (see sidebar on Using Radiation in Cancer Care​). However, both forms of treatment can have long-term adverse effects on patients. Thus, researchers are looking to pair our increasing understanding of cancer biology with knowledge of the traits of each patient’s own cancer to increase the precision with which radiotherapy and traditional chemotherapy are used, in order to tailor each patient’s treatment to be only as aggressive as is necessary for it to be effective.

Researchers recently identified one potential way to tailor treatment with radiotherapy for women who have had breast-conserving surgery after an early-stage invasive breast cancer diagnosis (101). For this group of patients, prior research had shown that radiotherapy to the breast after breast-conserving surgery could lower the risk of local breast cancer recurrence in the 10 years after diagnosis from 35 percent to 19 percent (102). However, recent research shows that breast radiotherapy does not reduce the risk for local breast cancer recurrence for some of these women, specifically those who have the luminal A molecular subtype of breast cancer and are considered clinically to have a low risk for recurrence because they are older than 60 and have a grade 1 or 2 tumor that is 2 cm or smaller (101). Although these results need confirming in further studies, they show promise for a future in which breast radiotherapy can be used more precisely, such that some patients are spared the time and potential toxicity of the treatment (103).

As we learn more about the biology of cancer and the way in which the traditional platinum-based chemotherapeutics carboplatin, cisplatin, and oxaliplatin exert their anticancer effects, we are beginning to understand that it may be possible to increase the precision with which these agents are used. Given that we know that platinum-based chemotherapeutics damage DNA, and that this damage ultimately kills cells if it is not repaired through an appropriate DNA damage repair pathway, it has been postulated that cancers carrying mutations in DNA damage repair pathway genes, such as BRCA1 and BRCA2, will be particularly sensitive to these agents (104). This has been found to be the case in a number of small studies of patients with BRCA-mutant ovarian or pancreatic cancer (105, 106). However, further studies are needed to extend these observations to larger numbers of patients, as well as a wider array of DNA damage repair pathway gene mutations and cancer types, before treatment with platinum-based chemotherapeutics is tailored in this way.

These examples of how we may be able to increase the precision with which we use radiotherapy and traditional chemotherapy to achieve maximal patient benefit with minimal harm are just two approaches among many that are being studied as we look to better tailor treatments to individual patients’ needs.

TreatmentWith Molecularly Targeted Therapeutics

Research is powering the field of precision medicine in many ways, including by increasing our understanding of the molecules involved in cancer initiation and development. Therapeutics directed to these molecules target cancer more precisely than traditional chemotherapeutics and, therefore, tend to be more effective and less toxic. As a result, molecularly targeted therapeutics—a mainstay of precision medicine—are not only saving the lives of countless cancer patients but also allowing these patients to have a higher quality of life than many who came before them.

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Molecularly Targeting Ovarian Cancer

Ovarian cancer is one of the cancer types for which we have made little progress in recent years. In fact, the five-year relative survival rate for women with ovarian cancer has not changed significantly in the past 25 years: it was 40.4 percent in 1990 and it is estimated to be 45.6 percent today (23).

Traditional platinum-based chemotherapeutics are part of the treatment for most women with ovarian cancer. These agents work by damaging DNA, and it is thought that they may be effective for patients with ovarian cancer because many ovarian cancers have mutations in DNA damage repair pathway genes, such as BRCA1 and BRCA2, and cannot efficiently repair the DNA damage caused by the platinum-based chemotherapeutics (104) (see Ways to Use Radiotherapy and Traditional Chemotherapy More Precisely​).

Unfortunately, the majority of ovarian cancers that initially respond to platinum-based chemotherapeutics eventually progress and are said to have become treatment resistant (see sidebar on The Challenge of Treatment Resistance​​).

In December 2014, the FDA made two decisions that provided a new treatment option for a group of patients with t​reatment-resistant ovarian cancer. Specifically, the agency approved the molecularly targeted therapeutic olaparib (Lynparza) for women with advanced ovarian cancer who have been previously treated with three or more chemotherapy regimens and who have inherited a defective BRCA1 or BRCA2 gene, as determined by an FDA-approved test, or companion diagnostic (see sidebar on Companion Diagnostics​). At the same time, the FDA approved a test to identify the patients for whom olaparib is approved, the BRACAnalysis CDx.

Olaparib is the first in a new class of agents that target poly ADP-ribose polymerase (PARP) proteins, which have a key role in one of the many pathways that cells use to repair damaged DNA (see Figure 15​). Therefore, blocking PARP proteins with olaparib reduces the ability of a cell to repair damaged DNA.

BRCA1 and BRCA2 have a role in a second DNA repair pathway, and many BRCA1 and BRCA2 gene mutations disable this pathway. Thus, the rationale for testing olaparib as a potential treatment for women with advanced ovarian cancer who have inherited a BRCA1 or BRCA2 gene mutation is that having two DNA repair pathways out of action may mean that the ovarian cancer cells are unable to repair DNA damage that accumulates as they multiply (see Developing Cancer), and that the accumulating damage will ultimately cause the cancer cells to die (see Figure 15).

In fact, blocking PARP with olaparib led to tumor shrinkage or disappearance in a significant number of women with advanced ovarian cancer who had an inherited BRCA1 or BRCA2 gene mutation (107). It is hoped that future studies will reveal that olaparib also extends survival for women with advanced ovarian cancer who inherit a BRCA1 or BRCA2 gene mutation, like Patty Klein.

Keeping Breast Cancer Cells at Bay

Despite major advances made in treating breast cancer, the disease remains the second-leading cause of cancer-related death for women in the United States (6). One recent FDA decision has the potential to power even more progress against breast cancer because it has provided a new treatment option for certain patients with the disease.

The majority of breast cancers are positive for proteins called hormone receptors. The growth of these breast cancers is fueled by hormones, which attach in a lock-and-key fashion to the hormone receptors on individual breast cancer cells, stimulating the cells to multiply and survive. This knowledge led to the development of therapeutics like tamoxifen, which blocks the hormone estrogen from attaching to its receptor, and letrozole, which lowers the level of estrogen in the body. Therapeutics like these have been used extremely successfully for decades to treat patients with hormone receptor-positive breast cancer. However, they have limited clinical benefit if disease progresses.

In February 2015, the FDA approved the molecularly targeted therapeutic palbociclib (Ibrance) for use in combination with letrozole for treating postmenopausal women with estrogen receptor–positive, HER-2–negative, advanced breast cancer.

Palbociclib is the first in a new class of agents that block cell multiplication by inhibiting the function of two proteins that play a role in driving this natural process—cyclin-dependent kinase 4 (CDK4) and CDK6 (see Figure 16​​). Its FDA approval was based on early-stage clinical trial results showing that adding palbociclib to letrozole significantly increased the time to disease progression among postmenopausal women with estrogen receptor–positive, HER-2–negative, advanced breast cancer (108), and it is hoped that longer follow-up of these patients, as well as an additional large-scale study that is already underway, will show that this combination of therapeutics also extends survival.

With recent early results from a phase III clinical trial showing that adding palbociclib to another estrogen receptor–targeted therapeutic, fulvestrant, also increases the time to disease progression among postmenopausal women with hormone receptor–positive, HER-2–negative, advanced breast cancer (109), there will undoubtedly be many more women like Janet Klein​ who will benefit from palbociclib in the future.

Thwarting the Most Common Form of Skin Cancer

Basal cell carcinoma is the most commonly diagnosed cancer among people of European ancestry (110, 111). Most patients are cured with topical therapy, surgery, radiotherapy, or a combination of these treatments. However, in a small fraction of patients, the disease progresses and becomes extremely challenging to treat.

The discovery two decades ago that genetic mutations leading to overactivation of a signaling pathway, called the Hedgehog pathway, fuel the growth of nearly all basal cell carcinomas led researchers to develop therapeutics that target the Hedgehog pathway (110). The first of these molecularly targeted therapeutics, vismodegib (Erivedge), was approved by the FDA for the treatment of locally advanced or metastatic basal cell carcinoma in January 2012 (84).

A July 2015, decision by the FDA to approve a new Hedgehog pathway–targeted therapeutic called sonidegib (Odomzo) provides a new treatment option for patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation. The decision was based on early results from an ongoing clinical trial showing that more than half of the patients who received sonidegib have had their tumors shrink dramatically (112). It is hoped that with more time, sonidegib will also prove to increase survival for patients with this devastating disease.

Blocking the Blood Supply to Tumors

Research has shown that many solid tumors need to establish their own blood and lymphatic vessel network to grow and survive. It has also led to the identification of many molecules that control the growth of the new blood and lymphatic vessels within a tumor. This combined knowledge has guided the development of 11 anticancer therapeutics that specifically block these many molecules (see Figure 17). These therapeutics are sometimes referred to as antiangiogenic agents.

Bevacizumab (Avastin) was the first of this growing class of anticancer therapeutics; it was approved by the FDA for the treatment of metastatic colorectal cancer in 2004. Since then, bevacizumab has been approved for the treatment of a variety of other types of cancer, with the most recent suite of approvals coming 10 years after the first (see Appendix Table 1​). Specifically, the use of bevacizumab in combination with certain traditional chemotherapeutics was approved for the treatment of persistent, recurrent, or metastatic cervical cancer in August 2014, and for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in November 2014. The fact that adding bevacizumab to treatment with traditional chemotherapeutics provided clinical benefit in phase III clinical trials (113, 114), offers new hope for patients with these diseases.

The newest member of the class is lenvatinib (Lenvima). In February 2015, lenvatinib was approved by the FDA for treating certain patients with thyroid cancer—those with locally recurrent or metastatic differentiated thyroid cancer that has progressed despite radioactive iodine therapy. Differentiated thyroid cancers will account for about 56,205 thyroid cancers newly diagnosed in the United States in 2015. Although many patients with this type of cancer are treated successfully, the 10-year survival rate for those with disease that is refractory to radioactive iodine therapy is just 10 percent from when metastases are detected (115). With results of a phase III clinical trial showing that lenvatinib was effective for almost 65 percent of patients (115), this molecularly targeted therapeutic will undoubtedly transform the lives of many patients with metastatic differentiated thyroid cancer, like Lori Cuffari​, in the future.

The FDA recently also approved two new uses for another antiangiogenic agent, ramucirumab (Cyramza). In December 2014, it was approved for some patients with the most deadly form of lung cancer, NSCLC, after it was shown to extend overall survival for patients with metastatic disease in a phase III clinical trial (116). Then, in April 2015, it was approved for use in combination with a suite of traditional chemotherapeutics referred to as FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) to treat patients with metastatic colorectal cancer. This approval was based on the results of a phase III clinical trial showing that adding ramucirumab to FOLFIRI extended overall survival (117). With ramucircumab having previously been approved for treating metastatic gastric (stomach) cancer and gastroesophageal junction adenocarcinoma, these new approvals both expand the number of patients who may benefit from ramucirumab and increase the return on prior investments in biomedical research.

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Targeting ​​the Epigenome

Research has shown that cancer cells have numerous genetic mutations and also pr​ofound abnormalities in the patterns of chemical marks, called epigenetic marks, on DNA and histones that control gene accessibility (see Cancer Development: Influences Inside the Cell​). It has also led to understanding that epigenetic alterations and genetic mutations often work together to promote cancer development. Moreover, after learning that the epigenome is dynamic and naturally changes over time, researchers began investigating whether therapeutics that target the proteins that naturally read, write, and erase epigenetic marks could reverse cancer-associated epigenetic abnormalities and provide clinical benefit.

In fact, there are now six FDA-approved anticancer therapeutics that work by targeting proteins that read, write, or erase epigenetic marks (see sidebar on Editing the Epigenome​). Most recently, in February 2015, the FDA approved panobinostat (Farydak) for the treatment of patients with multiple myeloma who have relapsed despite prior treatment with at least two standard therapeutics, including bortezomib and an immunomodulatory agent. The decision was based on the fact that panobinostat increased the average time before disease progressed for patients enrolled in a phase III clinical trial (118).

Treatment With Immunotherapeutics

Since the first AACR Cancer Progress Report was published in 2011, immunotherapy has emerged as one of the most exciting new approaches to cancer treatment that has ever entered the clinic. This is because the number of patients who have benefited from these revolutionary anticancer treatments rose dramatically during this period. As a result of the remarkable patient responses, the number of immunotherapeutics approved by the FDA has also risen, with four being approved in the past year alone, from Aug. 1, 2014 to July 31, 2015.

Cancer immunotherapy refers to agents that can unleash the power of a patient’s immune system to fight cancer the way it fights pathogens. Not all immunotherapeutics work in the same way (see sidebar on How Immunotherapeutics Work).

Given that our scientific understanding of the immune system and how it interacts with cancer cells is rapidly increasing, we can expect to soon see novel immunotherapeutics as well as new ways to use those that we already have. With many current immunotherapeutics yielding remarkable and durable responses for some patients, and new agents and treatment strategies on the horizon, immunotherapy holds extraordinary promise for the future—potentially even cures for some patients.

Releasing the Brakes on the Immune System

Through research we have learned that immune cells called T cells are naturally capable of destroying cancer cells. We have also learned that some tumors evade destruction by T cells because they have high levels of proteins that can trigger the brakes on T cells, stopping them from attacking the cancer cells, and that these tumor proteins work by attaching to complementary proteins, called immune checkpoint proteins, on the surface of T cells.

This knowledge has led researchers to develop immunotherapeutics, which are called checkpoint inhibitors, that prevent tumor proteins from attaching to immune checkpoint proteins, thereby releasing the brakes on T cells. The first immune-checkpoint inhibitor to be developed was ipilimumab (Yervoy). It was approved by the FDA in 2011 for the treatment of metastatic melanoma after it was shown to be the first treatment ever to extend overall survival for patients with this deadly disease (119). Long-term follow-up of patients has shown that about one in every five patients treated with ipilimumab survives for more than three years and that the risk of death from melanoma for these patients is very low (120).
Motivated by the success of ipilimumab, which has saved the lives of many patients with metastatic melanoma, like Andrew Messinger (who was featured in the AACR Cancer Progress Report 2013, Ref. 28), and the need to provide new treatment options for patients who do not respond long-term to ipilimumab, researchers focused on targeting a second checkpoint protein, called PD-1, as well as one of the proteins that attaches to PD-1, PD-L1. As a result of three recent FDA decisions, two of these novel immunotherapeutics are now treatment options for some patients with melanoma, and one is a treatment option for some patients with lung cancer.

The first two decisions, both in the second half of 2014, were the approvals of the PD-1 checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) for the treatment of metastatic melanoma that has progressed despite treatment with ipilimumab. These approvals were the result of clinical trials showing that pembrolizumab and nivolumab benefited more than 25 percent of patients (121, 122). Subsequent studies showed that many patients with ipilimumab-refractory metastatic melanoma, like Richard Murphy (who was featured in the AACR Cancer Progress Report 2014, Ref. 1), continued to benefit from these immunotherapeutics more than one year after starting treatment (123, 124).

More recently, results from two phase III clinical trials—one comparing pembrolizumab with ipilimumab and one comparing nivolumab with ipilimumab—showed that pembrolizumab and nivolumab were both more effective than ipilimumab for patients with metastatic melanoma that had not been treated previously with a checkpoint inhibitor (125, 126). This suggests that pembrolizumab and nivolumab might soon be approved not just for patients whose metastatic melanoma has progressed after ipilimumab treatment but also for those who have not yet received ipilimumab, and the FDA recently granted this use of nivolumab priority review (see sidebar on FDA’s Expedited Review Strategies​).

The third FDA decision, in March 2015, was the approval of nivolumab for treating a certain group of patients with metastatic non-small cell lung cancer (NSCLC ) that has progressed despite treatment with a traditional platinum-based chemotherapeutic. Specifically, it was approved for those patients with the squamous cell type of NSCLC, which accounts for about 25 to 30 percent of all lung cancers diagnosed in the United States, after it was shown in a phase III clinical trial to extend overall survival for patients with this deadly disease (127).

Recently, nivolumab was shown to benefit not only patients with squamous NSCLC, but also those with the more common nonsquamous NSCLC like Donna Fernandez​ (128). Pembrolizumab and an immunotherapeutic that targets PD-L1—atezolizumab (previously known as MPDL3280A)—have also been shown to benefit patients with both types of NSCLC (129, 130), and the FDA has granted both of these agents breakthrough designation for the treatment of NSCLC. Thus, it is likely that we will hear more about targeting PD-1 and PD-L1 as a treatment for NSCLC in the very near future.

Beyond melanoma and NSCLC, pembrolizumab, nivolumab, and atezolizumab are being tested in clinical trials as a potential treatment for many other types of cancer. Results are available for only some of them. For example, clinical trial results show one or more of these PD-1/PD-L1–targeted immunotherapeutics benefit some patients with bladder cancer (131, 132), gastric (stomach) cancer (133), head and neck cancer (134), Hodgkin lymphoma (135), and renal cell carcinoma (136). Although many of the results are preliminary, results for nivolumab as a potential treatment for Hodgkin lymphoma and for atezolizumab as a potential treatment for bladder cancer are sufficiently promising that the FDA has granted them breakthrough therapy designations.

Despite the spectacular successes, treatment with ipilimumab and PD-1/PD-L1–targeted immunotherapeutics does not yield remarkable and long-term responses for all patients. In an effort to increase the number of patients who may benefit from these immunotherapeutics, researchers are testing combinations of checkpoint inhibitors and combinations of immunotherapeutics that work in different ways. In fact, treatment of metastatic melanoma with a combination of ipilimumab and nivolumab is currently under priority review at the FDA (see sidebar on FDA’s Expedited Review Strategies) after it was shown to benefit significantly more patients than ipilimumab alone (137).

In addition, recent research suggests that traditional chemotherapeutics and certain forms of radiotherapy may themselves be immunostimulatory. Therefore, researchers are investigating whether the utility of immune-checkpoint inhibitors can be expanded by combining members of this burgeoning class of immunotherapeutics with traditional chemotherapeutics and radiotherapy.

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Boostingthe Killing Power of the Immune System

Another approach to cancer immunotherapy is to enhance the ability of T cells to eliminate cancer cells. If we think of checkpoint inhibitors as releasing the brakes on the immune system, these immunotherapeutics step on the accelerator, and they work in several ways (see sidebar on How Immunotherapeutics Work​). These cancer treatments are showing great promise for improved patient care; however, all the breakthroughs discussed here are still in clinical development and have not yet been approved by the FDA.

One way to boost the killing power of the immune system is through adoptive T-cell therapy. During this complex medical procedure, 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 (see sidebar on Types of Adoptive T-Cell Therapies​).

CAR T–cell therapy is a form of adoptive T-cell therapy that has been particularly successful for adults and children with acute lymphoblastic leukemia (ALL) that has progressed despite several other forms of treatment. In fact, recent reports indicate that about 90 percent of patients with relapsed ALL who receive CAR T–cell therapy experience complete remissions (138, 139). Even though only some have remained in remission long term, these results provide hope for a group of patients who have few treatment options, and the FDA has granted two CAR T–cell therapies, CTL019 and JCAR015, breakthrough therapy designation for the treatment of ALL.

Motivated by the success of CAR T–cell therapy as a treatment for ALL, researchers are working to develop CAR T cells that will target other types of cancer, including some types of non-Hodgkin lymphoma, multiple myeloma, and some solid tumors (140, 141). This research is in the very early stages, but there are promising signs that CAR T–cell therapies will emerge as a viable treatment option in the future for patients with a variety of cancer types.

Another way to boost the killing power of the immune system is with therapeutic cancer vaccines. These immunotherapeutics train a patient’s T cells, while they are inside the patient’s body, to recognize and destroy the patient’s cancer cells. One therapeutic cancer vaccine, sipuleucel-T (Provenge), has been available since 2011 for the treatment of some patients with prostate cancer, but there are many therapeutic cancer vaccines now being tested in clinical trials, although results are not currently available for most of these vaccines.

One clinical trial that has recently reported results found that a combination of two therapeutic cancer vaccines, CRS-207 and GVAX Pancreas, extended survival for patients with advanced pancreatic cancer (142), and this combination of immunotherapeutics has been granted breakthrough therapy designation by the FDA for the treatment of this deadly condition.

Directing the Immune System to Cancer Cells

An immune cell must find a cancer cell before it can destroy it. Many therapeutic antibodies that have been approved by the FDA for the treatment of various types of cancer (see Appendix Table 1​) work, at least in part, by helping immune cells find cancer cells. The most recent therapeutic antibody to be added to this group of immunotherapeutics is dinutuximab (Unituxin), which works by attaching to a protein, GD2, on neuroblastoma cells and flagging them for immune cells, which upon attaching to another part of dinutuximab are triggered to destroy the neuroblastoma cells.

Dinutuximab, which was previously called ch14.18, was approved by the FDA in March 2015 for treating children with high-risk neuroblastoma that has progressed after responding to prior treatments. The approval was based on clinical trial results showing that adding dinutuximab and two immune system-boosting agents—granulocyte-macrophage colony-stimulating factor and interleukin-2 (see sidebar on How Immunotherapeutics Work​)—to standard 13-cis-retinoic acid (RA) treatment significantly extended overall survival (143).

Children like Elizabeth Buell-Fleming​ have benefited from dinutuximab; however, treatment with this immunotherapeutic is associated with significant toxicities. These toxicities can be so severe that some children do not complete the course of treatment. Consequently, researchers are looking to identify ways to pinpoint more precisely those children most likely to benefit from dinutuximab, so that those unlikely to respond can be spared the potential adverse effects of this treatment.

Because of the effectiveness and promise of antibody-based immunotherapeutics, many researchers have been working to develop both new, as well as, improved versions of this important class of anticancer therapeutics.

One such therapeutic is the first of a new class of antibody-based immunotherapeutics called bispecific T cell–engager (BiTE) antibodies, blinatumomab (Blincyto), was approved by the FDA in December 2014 for treating certain patients with a type of ALL called B-cell ALL.

BiTE antibodies function as a connector, bringing T cells into close proximity with cancer cells, which are then eliminated by the T cells. Blinatumomab attaches to a molecule called CD3 on T cells and to CD19, a molecule found on the surface of most B-cell ALL cells. By attaching to these molecules on the different cells, blinatumomab brings the two cell types together, directing the T cells to home in on the B-cell ALL cells.

The approval of blinatumomab for treating adults who have precursor B-cell ALL that has progressed despite a prior form of treatment and that has a molecular profile characteristic of poor outcomes (it lacks the Philadelphia chromosome) was based on results from a clinical trial showing that the novel immunotherapeutic was effective in more than 30 percent of patients (145). Historically, precursor B-cell ALL that has progressed following initial treatment is extremely challenging to treat. In fact, even with intensive therapy, the median survival is between three and six months. Thus, the approval of blinatumomab provides patients like Sergio Ramirez​ with new treatment options and new hope.

Living With or Beyond Cancer

Research is powering advances in cancer detection, diagnosis, and treatment that are helping more and more people to survive longer and lead fuller lives after a cancer diagnosis. According to the latest estimates, almost 14.5 million U.S. residents with a history of cancer were alive on Jan. 1, 2014, compared with just 3 million in 1971, and this number is projected to rise to 19 million on Jan. 1, 2024 (3, 5). About 3 percent of these individuals, including Jay Steiner​, received their cancer diagnosis as a child or adolescent (ages 0–19) (144) (see sidebar on Surviving a Cancer Diagnosis as a Child or Adolescent​).

Every cancer survivor has a unique experience and outlook, which can range from successful treatment and living cancer free for the remainder of his or her life to living continuously with cancer for the remainder of life. Therefore, not all people who receive a cancer diagnosis identify with the now commonly used term “cancer survivor.”

Cancer survivorship encompasses three distinct phases: the time from diagnosis to the end of initial treatment, the transition from treatment to extended survival, and long-term survival. Recent progress in treating cancer was discussed in the previous two sections of the report (see Treatment With Molecularly Targeted Therapeutics, and Treatment With Immunotherapeutics​). Here, the discussion focuses on recent advances that can help improve outcomes and quality of life for individuals in each distinct phase of cancer survivorship and highlights some of the challenges they continue to face.

Each phase of cancer survivorship can be challenging for different reasons (see sidebar on Life After a Cancer Diagnosis in the United States​). Moreover, the issues facing each cancer survivor are unique and depend 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. In fact, research has shown that caregivers are at risk for poor health outcomes, with one recent study finding that the health and well-being of cancer survivors can be affected by the mood and quality of life of their spouses, who are often the primary caregivers (148). As such, incorporating caregiver care into survivorship programs may improve outcomes and quality of life for cancer survivors.

​Molecularly Targeting a Side Effect of Advanced Cancer

One side effect of cancer experienced at some point during the course of their disease by up to 30 percent of individuals who receive a cancer diagnosis is hypercalcemia of malignancy (149). Hypercalcemia, or elevated levels of calcium in the blood, is particularly common among patients with advanced cancer and indicates a particularly poor outlook. If left untreated, hypercalcemia of malignancy leads to kidney failure, progressive mental impairment, coma, and ultimately death.

The discovery that hypercalcemia of malignancy is often caused by cancer-driven release of calcium from bone led researchers to test whether the condition could be treated using the therapeutic antibody denosumab (Xgeva), which targets a protein called RANKL on certain bone cells, ultimately causing a decrease in calcium release. After clinical trials showed that denosumab rapidly lowered blood calcium levels in more than half of patients and that the response lasted about 3.5 months (150), in December 2014 the FDA approved the molecularly targeted therapeutic for the treatment of hypercalcemia of malignancy that is not responding to standard treatments.

As a result of the effects of denosumab on bone, the molecularly targeted therapeutic had previously been approved for treating postmenopausal women with osteoporosis who are at high risk for fractured bones and individuals with giant cell tumor of bone, as well as for the prevention of factures caused by cancer metastases to the bone. Thus, the FDA approval of denosumab for the treatment of hypercalcemia of malignancy not only benefits patients with this lethal condition but also increases the return on prior investments in biomedical research.

Modifying Behaviors to Improve Outcomes

Major concerns for all cancer survivors who successfully complete their initial treatment include whether their cancers will return or cause their death and whether their cancers and/or cancer treatment will diminish their quality of life. Many factors related to lifestyle that increase a person’s risk of developing cancer can also increase risk of cancer recurrence, reduce survival time, and negatively affect quality of life for cancer survivors (see Figure 8​​). Thus, modifying behaviors to eliminate or avoid these risk factors can improve outcomes and quality of life for cancer survivors.

For example, research shows that quitting smoking can improve outcomes for cancer survivors: it reduces risk of death from cancer and it also reduces risk for developing a second cancer (36). Even in the face of this knowledge, a recent study found that 9 percent of cancer survivors continued to smoke (151). Therefore, enhanced provision of cessation assistance to all patients with cancer who use tobacco or who have recently quit, and further research to improve our understanding of how best to help individuals quit smoking is urgently needed (152).

Evidence is also beginning to emerge that obesity can increase risk of cancer recurrence among survivors of several types of cancer including breast, colorectal, prostate, and urothelial bladder cancers (153-156), whereas regular aerobic exercise can reduce recurrence and mortality in survivors of early breast, prostate, and colorectal cancers (157). More recently, results from a clinical trial show that breast cancer survivors who participated in a weight training program had increased muscle strength and experienced less deterioration of physical function (158, 159). This is important because deterioration of physical function and loss of muscle strength have been linked to increased risk for bone fractures and other health issues that limit quality of life.

Unfortunately, modifying behavior can be as difficult for cancer survivors as it is for otherwise healthy individuals, and more research is needed to understand how best to help cancer survivors improve their chances of good outcomes.

The Importance of Patient-reported Outcomes

As researchers are learning more about the biology of cancer and translating this knowledge into new and improved ways to prevent, detect, and treat cancer, it is becoming increasingly clear that the pace at which further advances are made will be accelerated by enhanced patient engagement throughout the continuum of research and care.

The phase of the biomedical research cycle where patient engagement is highest is clinical trials. In addition to direct measurements of patient status, a growing number of trials also include a patient-reported outcome endpoint. Patient-reported outcomes are reports of the status of a patient's health condition directly from the patient. Such reports are valuable not only to the treating physicians, but also to regulators and drug developers. The importance of this aspect of clinical trials is increasingly being recognized as integral to the success of a clinical trial, and in November 2011, the FDA approval of jakafi (Ruxolitinib) for the treatment of myelofibrosis was based in part on patient reports of the positive impact of the molecularly targeted therapeutic on their symptoms (160).

Improved implementation of patient-reported outcomes into all phases of care of cancer survivors is essential if we are to gain a more complete picture of the safety and efficacy of newly approved anticancer therapeutics (see Increasing Patient Participation in Precision Medicine Initiatives​).​

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