A little less than three years ago, former President Barack Obama called on then Vice President Joseph Biden to lead the new National Cancer Moonshot Initiative that would increase efforts aimed at the prevention, diagnosis, and treatment of cancer. The goal set forth was to achieve a decade’s worth of progress in five years.1
“For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all,” President Obama said in his 2016 State of the Union Address.
The initiative’s first step was establishing a Cancer Moonshot Task Force that united 20 federal departments, agencies, and White House offices under the leadership of Vice President Biden. This Task Force identified five strategic goals critical to the overall mission of the Moonshot: catalyze new scientific breakthroughs, unleash the power of data, accelerate bringing new therapies to patients, strengthen prevention and diagnosis, and improve patient access and care.
The Task Force also consulted with external experts, including the presidentially appointed National Cancer Advisory Board (NCAB). A Blue Ribbon Panel of scientific experts was created to advise the NCAB. The panel has since released a report identifying 10 transformative research recommendations in support of the Moonshot’s goals (see SIDEBAR 1).2
The objectives are clear, but halfway through the Cancer Moonshot timeline, how far has the mission come? ASH Clinical News asked several experts in precision medicine about the successes and challenges to bringing precision medicine to all patients living with cancer.
Identifying the Enemy
Precision medicine has been a cornerstone of the Cancer Moonshot initiative since its inception. In 2016, the National Institutes of Health (NIH) made a $215-million investment in the Precision Medicine Initiative to accelerate biomedical research and provide clinicians with new tools to select therapies that can be used in a more individualized approach for patients. Oncology was selected as the initial focus for this initiative.3
However, precision medicine is nothing new for oncology, according to Charles G. Mullighan, MBBS (Hons.), MSc, MD, co-leader of the hematologic malignancies program at St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Precision medicine is more than matching a drug to a mutation; it is tailoring the treatment to an individual. That is something hematologist/oncologists have been doing for a long time,” said Dr. Mullighan, who also is chair of the ASH Committee on Scientific Affairs and co-chair of ASH’s Task Force on Precision Medicine.
Equipped with more precise tools for understanding and treating disease, clinicians can predict which patients will be susceptible to certain disease and which patients are more likely respond to specific treatments. “Within the past decade – with greater access to large-scale tumor sequencing and the identification of potentially actionable genetic changes – the idea of precision medicine has become much more fashionable,” Dr. Mullighan added.
Fashionable, yes, but maybe not accessible. The reality is that precision medicine is not yet considered part of the routine care of most patients with cancer, explained Louis M. Staudt, MD, PhD, director of the Center for Cancer Genomics at the National Cancer Institute (NCI).
That is because cancer is “an incredibly complex set of diseases that are essentially the result of a ‘Darwinian evolution’ of individual malignant cells within a patient that occurs typically over decades,” he said.
“The challenge in bringing precision medicine to every patient is to truly understand which genetic changes in cancer are important drivers of the malignant process and which are nonfunctional passenger mutations,” Dr. Staudt said. “In the future, I can envision and hope for a time when we can not only sequence a patient’s tumor but also point to evidence that shows which mutations are important to pay attention to and which will respond to a particular drug.”
But, in most cases, the science is not there yet, Dr. Staudt said.
Precision Medicine Progress
In some cases, though, a focus on understanding the genomic landscape of a disease has improved the diagnosis and treatment of certain blood cancers in recent years, Dr. Mullighan said.
In the pediatric arena, clinicians now have a better grasp of the drivers that classify subtypes of acute lymphocytic leukemia (ALL), which have helped them better select treatments. He offered the following example: About 10 percent of patients with childhood ALL have Philadelphia chromosome–like disease. About 10 percent of these cases will have ABL-class fusions that respond to ABL1 tyrosine kinase inhibitors, and another 30 percent will have mutations that activate the JAK-STAT pathway that may respond to JAK inhibitors.4
“Precision medicine is more than matching a drug to a mutation; it is tailoring the treatment to an individual.”
—Charles G. Mullighan,
MBBS (Hons.), MSc, MD
Increased use of sequencing also has revealed a large number of inherited polymorphisms and mutations that are associated with drug response, resistance, and toxicity and the risk of leukemic transformation. He noted, though, that these discoveries are a culmination of a decade’s worth of work, not just on research done since the Moonshot launched.
“At St. Jude, we sequence all patients with this diagnosis now,” Dr. Mullighan said. “We don’t wait until they relapse.”
The U.S. Food and Drug Administration (FDA) also has approved targeted therapies for acute myeloid leukemia (AML), noted Lucy Godley, MD, PhD, professor in the department of medicine, section of hematology/oncology at The University of Chicago.
For her day-to-day practice, the biggest precision medicine success story is the approval of midostaurin. The FLT3 inhibitor, in combination with chemotherapy, is indicated for the treatment of patients with newly diagnosed, FLT3-positive AML – approximately one-third of the adult AML population, generally considered to be a poor-risk mutation.5
“I now consider midostaurin standard therapy,” Dr. Godley said. She added that investigators are looking into whether midostaurin can be given more broadly, “because evidence has suggested that other leukemias could have FLT3 activated by other mechanisms.”
She also applauded the approvals of the IDH inhibitors ivosidenib and enasidenib, which are indicated for adult patients with relapsed or refractory IDH1- or IDH2-mutated AML. The FDA based its approval of ivosidenib on results from a single-arm study of 174 adults in which approximately 33 percent experienced complete response or complete response with partial hematologic recovery.6 Enasidenib was approved based on results from a single-arm study of 199 patients, in which 23 percent had complete remission or complete remission with partial hematologic recovery.7 Both drugs are approved with a companion diagnostic.
“In leukemia, it is common to have point mutations of IDH1 or IDH2 genes,” Dr. Godley explained. “There are many older people who have AML who wouldn’t be candidates for induction chemotherapy because of age or comorbidities who are now able to be treated with a pill. That is pretty remarkable.”
Precision medicine also has enabled researchers to identify powerfully prognostic mutations in myelodysplastic syndromes (MDS), according to Benjamin L. Ebert, MD, PhD, chair of medical oncology at Dana-Farber Cancer Institute in Boston.
“Given that MDS is a heterogenous disease and patient prognosis varies widely, these mutations are useful in helping to predict prognosis,” Dr. Ebert said.
In a recent New England Journal of Medicine paper, for example, researchers found that patients with MDS who harbored at least one persistent disease-associated mutation 30 days after undergoing allogeneic hematopoietic cell transplantation had higher rates of progressive disease and lower rates of progression-free survival at one year, compared with patients who had mutation clearance.8 “Knowing this information may provide an opportunity for earlier intervention to delay or prevent progression and also may [help] identify patients who can be recommended for more aggressive monitoring,” study coauthor Meagan Jacoby, MD, PhD, from the Washington University School of Medicine in St. Louis, told ASH Clinical News.9
Missing in Actionable
Precision medicine efforts have made next-generation sequencing easier, faster, and cheaper to perform – exponentially increasing the amount of information clinicians have about a disease’s genomic landscape. But not all mutations are created equal. In MDS, Dr. Ebert said, many of the primary drivers of the disease discovered to date are not able to be treated with drugs.
This isn’t a problem unique to MDS, he noted. The many hundreds or thousands of variations detected using whole-genome, whole-exome, or targeted sequencing can be beneficial, neutral, disease-associated, or of unknown consequence to the patient.
Dr. Godley discussed testing for AML as an example. Many physicians sending panels to in-house or commercial laboratories may be testing for a wide variety of AML-related genes, including p53, ASXL1, PHF6, DNMT3A, TET2, and more.
“There is an entire core of molecular genes that are prognostically significant for AML,” Dr. Godley explained. “If you surveyed all treating physician members of the American Society of Hematology, I think you would find that people are sending out a wide range of gene panels, and they are all interpreting the results very differently.”
As part of its Precision Medicine Initiative, the American Society of Hematology (ASH) is working to enhance genomic profiling of all hematologic disease and has appointed dedicated task forces and working groups to clarify how genomic information can be used in the treatment of blood disorders. The Somatic Working Group, for one, is exploring ways to improve and educate physicians about the clinical application of molecular data. Read more about ASH’s efforts in this area in SIDEBAR 2.
“Interpretation of these results is complicated, and I don’t think people have a true understanding of how complicated it is,” she added. “For example, there is an underappreciation of how common germline mutations in AML are. Whether a mutation is somatic or germline is a question that many physicians are likely not even thinking about.”
Clonal hematopoiesis further complicates the issue, Dr. Godley said. “If I see a patient with a p53 mutation in the peripheral blood, I can give three possible explanations: That patient could have MDS, clonal hematopoiesis, or Li-Fraumeni syndrome, which involves an inherited mutation.”
Clinicians need more knowledge about what genes should be included on a panel, she noted, providing the example of a family practitioner from Michigan who sent samples to a large commercial lab to test for inherited thrombocytopenia. He didn’t know that the commercial panel he selected didn’t include some of the most common genes associated with the condition.
“If the average clinician thinks a panel is comprehensive when it isn’t – or assumes that these large companies perform their due diligence when they do not – that is a huge problem,” she said.
Unleash the Data!
The lack of knowledge surrounding next-generation sequencing interpretation is not surprising given the explosion of genomic information and the prevalence of electronic health records. Combined, these two developments have produced an unprecedented amount of health data. The Moonshot initiative seeks to maximize access to these data through efforts like the NCI’s Genomic Data Commons (GDC).
“The challenge in bringing precision medicine to every patient is to truly understand which genetic changes in cancer are important drivers of the malignant process.”
—Louis M. Staudt, MD, PhD
The GDC is a single, scalable repository for cancer genomics data, patient information, pathologic and radiologic images, and relevant preclinical data. Researchers can submit their data, followed by a pre-processing period in which submitters can “clean up” data before they are processed and validated by the GDC team. After processing is completed, the data are made publicly available and accessible through GDC tools.
“These are big data – almost too big to wrap your head around,” Dr. Staudt told ASH Clinical News. “We are in the realm of multiple petabytes of data for cancer genomics. That’s Amazon- or Google-size data.”
At present, the GDC contains data from several of the world’s largest cancer genomics databases, such as he Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments.
“We also have opened the doors to any comprehensive genomic profiling in cancer for which we think the sharing of data would benefit the community,” Dr. Staudt said.
For example, in September the NIH announced it had made 574 diffuse large B-cell lymphoma (DLBCL) biopsy samples available in the GDC Data Portal. The data originated from a study published in the New England Journal of Medicine that uncovered four prominent genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics.10In the future, the NCI plans to capitalize on the success of the GDC by building comparable data systems to share data generated by proteomics, radiologic imaging, histologic imaging, and more, Dr. Staudt said. As part of its precision-medicine efforts, the NIH also launched the All of Us Research Program, an initiative seeking to build a national research cohort of more than 1 million people. The database will include information about participants’ lifestyle, biology, and environment “to inform thousands of studies, covering a wide variety of health conditions.”
“We want this program to reflect the rich diversity of our country,” said Eric Dishman, director of the All of Us Research Program. “Working with participants across the country, we hope to contribute to medical breakthroughs that may lead to more tailored disease prevention and treatment solutions in the future.”11
Greater accessibility and sharing of data is extremely important in theory, Dr. Godley said, but she is worried about reality, including the ability to properly obtain informed consent from patients.
“In the big picture, yes, we want to share data, but, when we get into the details about who ‘owns’ a patient’s data and how we can protect confidentiality, things get complicated,” she cautioned. “I would argue that nothing is more identifying than your DNA sequence. As soon as someone has sequenced a certain number of highly polymorphic regions, the patient has been identified.”
Those details tend to get glossed over in discussions of data sharing and data repositories, she said, because people do not want to grapple with these difficult issues.
Rethinking Clinical Trials
Under the umbrella of the Moonshot, regulators and researchers also are looking for ways to design innovative clinical trials and promote the review of products to bring targeted drugs to patients more efficiently – and to keep pace with genomic discoveries.
Signed into law in December 2016, the 21st Century Cures Act was designed help accelerate medical product development and more quickly and efficiently bring new innovations to patients.12 This legislation included the new Regenerative Medicine Advanced Therapy (RMAT) designation, which is available for drugs intended to treat, modify, reverse, or cure a serious life-threatening disease or condition or for drugs with preliminary evidence showing that they address an unmet medical need for those conditions. More than 20 products have received RMAT designation, including treatments for sickle cell disease and lymphoma.13
The Cures Act also created the FDA’s Oncology Center of Excellence, which leverages the combined skills of regulatory scientists and reviewers to expedite the development of oncology and hematology products. The center takes an integrated approach to the clinical evaluation of drugs, biologics, and devices for the treatment of cancer.
Since the Moonshot Initiative launched, the RACE for Children Act (Title V of the FDA Reauthorization Act) has become law. It requires companies developing cancer drugs to also develop candidates for children if the molecular target of the drugs under development is relevant to a pediatric cancer.14 “From the pediatric perspective this was a major advance,” Dr. Mullighan said.
To get more drugs to the regulatory process, experts guiding the Moonshot also are looking to incorporate genomic data into clinical trials.
Traditionally, clinical trials have studied an investigational drug in patients with distinct histologic disease subtypes: estrogen receptor–positive breast cancer, muscle-invasive bladder cancer, AML, etc. “We looked at a tumor under a microscope and gave a histologic diagnosis, and that was how patients were enrolled into trials,” Dr. Godley said.
Now, more clinical trialists are attempting to define patients’ diseases molecularly and match patients with a relevant targeted treatment under investigation. This would mean, for example, that patients with BRCA1 mutations may be enrolled in a trial regardless of the histologic subtype of their disease.
Dr. Godley acknowledged that this approach has its pros and cons, including that patients may still have to be subdivided based on disease type. “With BRCA1 mutations, for example, there are different pathways of DNA repair that are more or less active in different tissue types,” she explained. “So, PARP inhibitors may be effective in breast or ovarian tumors, but less effective in leukemia or pancreatic disease because that DNA repair pathway is not as important in that tissue.”
Changing clinical trials will be a huge challenge for the field and will require close evaluation, Dr. Godley noted. “In the end, we may have the same problem that we had with the old way, because we just decided to classify tumors in a different way. Hopefully, we are not just exchanging one problem for another.”
The Long Arm of Precision Medicine
As more knowledge is gained about the use of precision medicine in cancer and hematologic malignancies, there is hope that its application will spread to benign hematologic conditions as well.
“Precision medicine should be as important for nonmalignant disease as it is for malignant disease,” said Rodrigo T. Calado, MD, PhD, associate professor of hematology at the University of São Paulo’s Ribeirão Preto Medical School in Brazil. The heterogenous clinical presentation of sickle cell anemia makes it a prime candidate for precision medicine strategies, he added. “Precision medicine could be beneficial to identify patients who would benefit from more intense approaches like bone marrow transplant or gene therapy or who would benefit from mild therapies like hydroxyurea.”
One relatively recent application of precision medicine in classic hematology is the use of genomics to identify patients with inherited or acquired aplastic anemia, Dr. Calado said. The clinical presentation of these patients may be the same, but genomic information is required to confirm a diagnosis of acquired vs. inherited disease.
In one recent study, researchers used next-generation sequencing to look at the genomes of blood samples from more than 400 patients with acquired aplastic anemia. About one-third had stem cell clones that appeared with mutations in a few genes, such as DNMT3A and ASXL1. Patients with these mutations fared worse than those without mutations, and worse than patients with mutations in other genes such as BCOR and PIGA.15
Distinguishing between the two conditions provides important clinical decision-making information, he noted. “If a patient has inherited aplastic anemia, he or she can be treated with bone marrow transplantation or other hormones, while someone with acquired aplastic anemia could be treated with immunosuppressive therapy,” Dr. Calado said. “In the past, we would have had to wait until a patient didn’t respond to immunosuppression to identify a mutation that was the cause of non-response. Today, we can look at that before we treat.”
The Race to the Moon
With all these advances in precision medicine, is the Cancer Moonshot Initiative on its way to success? The experts who spoke with ASH Clinical News all agreed: Probably, but it’s still too early to tell.
“The pace of progress is definitely increasing rapidly, thanks in part to the technologies that we have available to study cancers,” Dr. Ebert said, “but I don’t think we can quantify how much progress has been made across this enormous number of fields just yet.”
To continue the forward march of progress and for more patients to benefit from precision medicine advances, there must be a continued investment in basic research through the Moonshot and other programs, Dr. Godley emphasized.
“The American public has access to the best drugs and the most sophisticated medicine because of an investment in basic scientific research by the NIH and other foundations over many decades,” she said. “But in recent years this investment has been eroding.”
Although the 2018 NIH budget was $37 billion, and the NIH reports that more than half of that goes to support basic research, recent increases came after a decade of nearly flat funding: In 2005, the NIH budget was $28.5 billion; it inched to $30 billion in 2015.16,17
“The drugs patients get today are based on decades of investment in basic research,” Dr. Godley said. “Progress in precision medicine won’t continue in five, 10, or 20 years if people don’t appreciate the connection between basic research and medical advances.” —By Leah Lawrence
- Cancer Moonshot. Report of the Cancer Moonshot Task Force. Accessed October 24, 2018.
- National Cancer Institute. Cancer Moonshot Blue Ribbon Panel. Accessed October 24, 2018.
- National Cancer Institute. NCI and the Precision Medicine Initiative®. Accessed October 24, 2018.
- Pui CH. Progress in the study of pediatric ALL. Clin Lymph Myel Leuk. 2017;17:S65-7.
- Novartis. Novartis receives FDA approval for Rydapt in newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and three types of systemic mastocytosis (SM). April 28, 2017. Accessed October 26, 2018.
- U.S. Food and Drug Administration. FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation. July 20, 2018. Accessed October 26, 2018.
- U.S. Food and Drug Administration. FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia. August 1, 2017. Accessed October 26, 2018.
- Duncavage EJ, Jacoby MA, Change GS, et al. Mutation clearance after transplantation for myelodysplastic syndrome. N Engl J Med. 2018;379:1028-41.
- ASH Clinical News. Post-transplant gene mutations predict risk for MDS progression. November 1, 2018. Accessed November 2, 2018.
- National Cancer Institute. Genetics and pathogenesis of diffuse large B-cell lymphoma. Accessed October 24, 2018.
- National Institutes of Health. NIH’s All of Us Research Program expands national network of medical centers. Accessed November 7, 2018.
- U.S. Food and Drug Administration. 21st Century Cures Act. Accessed November 2, 2018.
- Hildreth C. What is an RMAT designation and who had one? Bioinformant. June 19, 2018. Accessed October 24, 2018.
- Kids v Cancer. RACE for Children Act Becomes Law! August 29, 2017. Accessed October 26, 2018.
- Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35-47.
- National Institutes of Health. History of Congressional Appropriations, Fiscal years 2000-2018. Accessed October 28, 2018.
- National Institutes of Health. Extramural Nexus. NIH’s Commitment to Basic Science. March 25, 2016. Accessed October 28, 2018.
The 2016 Blue Ribbon Panel report described 10 transformative research recommendations for achieving the Moonshot’s goal of condensing a decade’s worth of progress into just five years. The recommendations include:
- Establish a network for direct patient involvement: Encourage patients to contribute their comprehensive tumor profile data to expand knowledge about what therapies work, in whom, and in which types of cancer.
- Create a translational science network devoted exclusively to immunotherapy: Establish a cancer immunotherapy network to discover why immunotherapy is effective in some patients but not in others.
- Develop ways to overcome cancer’s resistance to therapy: Identify therapeutic targets to overcome drug resistance through studies that determine the mechanisms that lead cancer cells becoming resistant to previously effective treatments.
- Build a national cancer data ecosystem: Create a national ecosystem for sharing and analyzing cancer data so that researchers, clinicians, and patients will be able to contribute data, which will facilitate efficient data analysis.
- Intensify research on the major drivers of childhood cancers: Improve our understanding of fusion oncoproteins in pediatric cancer and use new preclinical models to develop inhibitors that target them.
- Minimize cancer treatment’s debilitating side effects: Accelerate the development of guidelines for routine monitoring and management of patient-reported symptoms to minimize debilitating side effects of cancer and its treatment.
- Expand use of proven cancer prevention and early detection strategies: Reduce cancer risk and cancer health disparities through approaches in development, testing and broad adoption of proven prevention strategies.
- Mine past patient data to predict future patient outcomes: Predict response to standard treatments through retrospective analysis of patient specimens.
- Develop a 3D cancer atlas: Create dynamic 3D maps of human tumor evolution to document the genetic lesions and cellular interactions of each tumor as it evolves from a precancerous lesion to advanced cancer.
- Develop new cancer technologies: Develop new enabling cancer technologies to characterize tumors and test therapies.
Source: National Cancer Institute. Cancer Moonshot℠ Blue Ribbon Panel Report 2016. Accessed November 2, 2018.
As part of its efforts to advance hematology research, the American Society of Hematology (ASH) established the Task Force on Precision Medicine to lead efforts in increasing the understanding of germline and somatic mutations in hematologic disorders.1 A separate Task Force on Immunotherapy – a key focus of the Moonshot Initiative – was formed to address specific scientific and clinical issues related to this area of precision medicine.
“When discussing germline mutations, the first challenge is knowing what genes have variants that lead to hematologic disease,” explained Task Force Co-Chair Benjamin L. Ebert, MD, PhD, chair of medical oncology at Dana-Farber Cancer Institute. “The second challenge is, once you sequence those genes, determining which variants are pathogenic and which don’t have an impact on the likelihood of developing disease.”
The Task Force is approaching these challenges through the publication of a series of review articles designed to educate clinicians about the implications of sequencing studies and through the laborious task of annotating all variants that clinicians might find in these hematologic disorders as benign or pathologic, Dr. Ebert explained.
As part of that effort, ASH has partnered with the National Institutes of Health Clinical Genome Resource (ClinGen) to develop a broad and accessible compendium of genomic data aimed at improving the diagnosis of hematologic disorders. ASH is supporting two expert review panels to analyze the clinical significance of variants and mutations understood to be associated with myeloid malignancies and platelet disoders.2
The Task Force also is eager to expand research about somatic mutations. Certain hematologic diseases have been very well-studied in terms of finding pathogenic mutations, Dr. Ebert said. However, this research is far from complete.
“The Task Force is looking for opportunities to support research about under-studied disease states,” Dr. Ebert said. “We also want to aggregate all of the complex somatic data that have been collected and make these easily accessible by researchers and clinicians.”
- Mullighan CG. The ASH Agenda for Hematology Research: a roadmap for advancing scientific discovery and cures for hematologic diseases. Blood Advances. 2018;2:2430-2.
- American Society of Hematology. ASH announces partnership with the University of North Carolina, a ClinGen grantee, to curate genomic data for blood disease research. April 5, 2018. Accessed November 2, 2018.