VA RESEARCH: THE VA’S NATIONAL PRECISION ONCOLOGY PROGRAM

Building a System of Excellence for cutting-edge cancer care

By Craig Collins

Even among medical professionals, it can be difficult to appreciate the speed at which the field of oncology – the study and treatment of cancer – has transformed in the 21st century. Before 2003, when the international Human Genome Project completed identifying and mapping all of the genes in the human genome, oncologists mostly fought cancer with the three blunt instruments at their disposal: surgery, chemotherapy, and radiation.

With the ability to sequence the genes of humans and tumor cells, researchers began investigating ways to block or disrupt the disease pathways of specific cancer types. Within a year of the Human Genome Project’s completion, for example, investigators discovered a mutation in a particular gene, the EGFR gene, which could lead to overexpression of hormone receptors, tumor development, and growth. The receptor activated by this gene, researchers discovered, could be targeted at the molecular level with new EGFR-inhibiting drugs such as gefitinib and erlotinib.

Patient-specific molecular testing of tumors enables doctors to determine how they will respond to certain treatments and to prescribe more targeted therapies.

Over the next decade, researchers discovered many more gene alterations that predicted cancer patients’ responses to specific drugs. This new paradigm for treating cancer – patientspecific molecular testing of tumors to determine whether they will respond to certain treatments, particularly with safe and effective anti-tumor (antineoplastic) drugs – is known as precision oncology.

The ability to sequence the genes of individual patients and the opportunity to develop drugs targeting these mutations have revolutionized the study and treatment of cancer – a disease that is, fundamentally, a failure to regulate cell growth. A program of molecular testing sprang up quickly within the nation’s largest integrated health care system, the Veterans Health Administration (VHA), and a regional precision oncology program, based primarily in VHA’s New England Healthcare System, began to emerge. The National Cancer Institute (NCI), meanwhile, as part of the White House’s 2016 Cancer Moonshot initiative, began supporting clinical trials at hundreds of hospitals and clinics around the country to evaluate the responses of certain tumors to both existing drugs and experimental drugs that showed promise for treatment.

Dr. Bruce Montgomery, co-lead for the Precision Oncology Program for Cancer of the Prostate, meets with Navy veteran Allen Petchnick, whose prostate cancer has been effectively treated to date with targeted therapy.

The establishment of NPOP led to a rapid increase in the number of VA facilities participating in the program and the number of tumor samples being submitted for molecular analysis. Many of these first samples were of certain types of lung tumors, which were not only common among VA cancer patients, but also associated with a high number of mutated genes that resulted in sensitivity to anti-cancer drugs. More recently, metastatic prostate cancer tumors were added as a focus for molecular analysis.

Part of the VA’s contribution to the Cancer Moonshot Initiative was the formation, in 2016, of what’s now known as the National Precision Oncology Program (NPOP). NPOP began as an effort to expand the New England program into a nationwide capability and to maximize the access of veteran patients to clinical trials of precision cancer drugs. Its core purpose is to make genetic testing available to VA cancer patients for whom testing may determine either a prognosis or a course of treatment, but NPOP extends more than the program’s geographic reach; it offers consultative services to VA oncologists, helping to interpret the often complex results of genetic sequencing, and an informatics system that supports research and a learning health care system. Clinical care is supported by VA’s sophisticated telehealth delivery system, which makes precision oncology available to a growing number of veteran patients.

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Prostate and lung cancer are the leading types of cancer among veteran patients; of the approximately 50,000 veterans who are diagnosed with cancer each year, about 15,000 are diagnosed with prostate cancer, and about 7,700 with lung cancer. For VA’s oncology care teams, dashboards are available at the NPOP website to help identify veterans at their facilities with either lung or prostate cancer who may be appropriate for testing. Other solid tumors may be sent for testing through NPOP, as well, if patients have advanced-stage cancer and are candidates for drug therapy. To date, the VA’s NPOP has sequenced more than 13,000 samples, and the program is utilized by nearly every oncologist practicing within the VA.

FROM HUBS OF EXPERTISE TO A SYSTEM OF EXCELLENCE

According to Michael Kelley, MD, VA’s national program director for oncology, the NPOP was designed from the beginning to be a platform with research built into it. As the program rolled out, VHA’s Office of Research and Development (ORD) launched its Research for the Precision Oncology Program (RePOP) and a Precision Oncology Data Repository (PODR) to advance the knowledge and capabilities necessary to improve care for veteran cancer patients. These programs work to recruit more veteran patients to trials, increasing the amount of data and tumor tissue available for study, while using that data to develop predictive models, analytic techniques, and clinical applications.

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An important research initiative prompted by the Cancer Moonshot is the APOLLO (Applied Proteogenomics Organizational Learning and Outcomes) program, a collaboration between the VA, the Department of Defense, and the NCI to classify tumors (with an initial focus on lung tumors) not only by genetic changes, but also by levels of certain proteins, which can also be biomarkers associated with cancer. APOLLO, which performs molecular analyses of every possible gene mutation and protein expression, provides new insights into the biology of various cancers and treatments that can be targeted and evaluated in clinical trials.

Because prostate and lung cancers account for about half of the cancers diagnosed among VA patients annually, the NPOP’s early focus was devoted to these two types of cancer. VA research into precision medicine for veterans with prostate cancer was given an enormous boost when, shortly after the NPOP had been established, the VA formed a $50 million partnership with the Prostate Cancer Foundation (PCF). The initiative established by this partnership, the Precision Oncology Program for Cancer of the Prostate (POPCaP), aims to deliver precision oncology to all veterans with prostate cancer.

POPCaP has grown dramatically since it was first funded in 2018. It consists of a network of 12 hubs of expertise with the capacity to perform precision oncology, as well as a searchable data core that includes clinical notes, pathology reports, radiology and laboratory reports, and more. POPCaP provides veterans with metastatic prostate cancer access to genetic testing and genetic counseling, clinical trials, and access to on- and off-label use of U.S. Food and Drug Administrationapproved drugs matched to specific mutations.

Army veteran Roger Lupkes, who has been diagnosed with prostate cancer, lung cancer, and colon cancer, and his wife, Henrietta, travel 100 miles from their home in rural Minnesota to the Sioux Falls VA Medical Center, where he is able to see his oncologist, Dr. Michael Kelley, who is 1,400 miles away in North Carolina, via a telehealth visit. The VA’s robust telehealth infrastructure is making it possible for veterans to receive cutting-edge precision oncology care regardless of where they live.

The VA-PCF partnership funded a large pilot program called PATCH (Prostate Cancer Analysis for Therapy Choice), which attempts to leverage NPOP’s sequencing capabilities into studies. The goal of PATCH is to match each possible mutation in a veteran with prostate cancer to a different trial – ultimately, to increase the number of VHA facilities involved in precision prostate cancer clinical trials; to improve veteran access to those trials; and to increase the number of clinicians providing care and working in prostate cancer research.

According to Rachel Ramoni, DMD, ScD, VA’s chief research and development officer, PATCH isn’t really a “study,” but rather “an infrastructure for us to rapidly run through precision oncology trials for prostate cancer, so that as new ideas emerge, we don’t have to look for sites to run the trial, because we have really well-oiled machinery to be able to launch and conduct those trials. And in VA, we certainly have the scale to do that. ... PATCH is all about getting those trials open and completed as quickly as possible, so you don’t have to set up an entire system every single time; you can rapidly go from one trial to the next, or run parallel trials.”

Like most VA clinicians, Michael Kelley, the VA national program director for oncology, is also a research scientist: He’s chief of hematology-oncology at the Durham, North Carolina VA Medical Center and a professor of medicine at Duke University. POPCaP has provided a template, Kelley said, for how the VA can bring precision oncology to every veteran who needs it. “I think a lot of us have a vision of the type of care we’d want for a loved one with cancer – the quality of care, the efficiency of its delivery, and ready accessibility. That is what we were thinking about when we were establishing – initially, through our partnership with the Prostate Cancer Foundation – the Precision Oncology Initiative as an integrated clinical and research system in combination with our precision oncology and telehealth expertise.”

POPCaP provides precision oncology through a hub-and-spoke model, with NPOP sequencing and delivering services through regional hubs of expertise, and one of the things the VA has learned, Kelley said, was that with its cuttingedge telehealth capabilities – recently expanded with a $4.5 million dollar grant from the Bristol Meyers Squibb Foundation to establish a national teleoncology center aimed at more effectively reaching veterans living in rural communities – it can deliver those services anywhere. “If you look at the map of the patients who have participated [in NPOP], you’ll see it’s essentially a distribution map of where veterans are in this country. NPOP is one component of what excellent oncology care looks like, but it’s very clear that similar expertise could be in one place, or a small number of places, and we could distribute that across our system.”

Today, every veteran with prostate cancer can be tested and have DNA examined not only from somatic cells – tumor cells with DNA damaged by mutation – but also “germline” or “constitutional” DNA, which is the DNA passed down from parents to offspring, and that can contain mutations that elevate cancer risk for patients or their family members. POPCaP sites provide access to appropriate trials, precision oncology care, genetic counseling, and other services.

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“These POPCaP sites are doing a great job of implementing those services,” said Kelley. “But we’re not satisfied with that. We want that to happen everywhere. Our thinking about these sites, delivering care across the system, has evolved. Now we’re thinking we don’t need only a center that delivers excellent clinical care. We need a system of excellence.”

The successes of POPCaP have catalyzed a VHA initiative to create a Precision Oncology System of Excellence: an enterprise-wide capability to deliver precision oncology care to veterans regardless of where they are or what type of cancer they have. Both Kelley and Ramoni, when asked to describe their vision for what this System of Excellence will look like, speak in terms of defining clinical pathways for precision oncology: evidence-based care plans established to reduce variation, improve the quality of care, and optimize outcomes for patients. “The System of Excellence we envision,” Kelley said, “is that as soon as an improvement or change in clinical care comes about, and there is a consensus that this improvement should happen in a center – well, it should happen everywhere. Veterans shouldn’t have to travel to one of the 12 centers. They should be able to get it where they are.”

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They should also, Ramoni said, immediately benefit from the latest research findings. “What you need to know about this effort is that it’s really an integration of the research and clinical areas around precision oncology,” she said. ORD works closely with clinical partners to both make these clinical pathways available everywhere, and also to support and update their implementation. “Beyond simply sharing the pathways as information about best-practice care, we want to ensure that the care is available and is being provided to our veterans. We want to know when there are places in the VA where they might need help in living up to the expectation that we provide the best care wherever a veteran may be.” Ramoni describes the System of Excellence as a learning organization fueled by research findings: “All top cancer care centers feature clinical trials,” she said, “and those inform the care pathway – so that what we learn over time leads us to provide ever better care to our veterans.”

PHASING IN

When he announced the effort to establish a Precision Oncology System of Excellence last year, VHA’s executive in charge, Richard Stone, MD, explained that it would be phased in over time, beginning with a nationwide system of precision oncology for lung cancer that will likely first be rolled out in a nationwide network of sites, analogous to those implementing the POPCaP program as both clinical and research centers. The process of selecting and operationalizing these VA medical center hubs to conduct genetic lung cancer screening and to lead precision oncology clinical trials, as part of this larger lung cancer precision oncology plan, is scheduled to occur in 2021 and 2022.

Navy veteran and cancer survivor Patrick McGuire, who was diagnosed with stage IV lung cancer, benefited from DNA sequencing of his tumors; the testing revealed a particular gene mutation for which the VA was able to prescribe a targeted drug.

Over the longer term – beginning around 2022 – the VHA will phase in infrastructure to support precision oncology for breast cancer and rare cancers. Breast cancer isn’t one of the most common types of cancer among veterans – but that’s because 97 percent of veteran cancer patients are men. According to Kelley, there are about 700 new diagnoses of breast cancer annually in the VHA, a number expected to rise as more women serve, and as more women veterans age. The VHA, Kelley pointed out, is committed to serving all veterans. He envisions a system of cutting-edge precision oncology for breast cancer delivered from a single virtual center.

“It’s going to be making sure that there is good care coordination and case-tracking, to ensure that patients get the right care at the right time, and that there is an opportunity to talk to a group of experts in breast cancer for the VA providers who are seeing and caring for patients,” Kelley said. “These experts can be directly involved in that patient’s care, if that is appropriate, or they can be overseeing what is happening through their own sets of data in the electronic medical record – or both.”

A focus on rare cancers is more logical than it sounds: “Rare cancers,” Kelley said, “are not rare, believe it or not.” As a group, they account for about 16 percent of all cancers, and gene sequencing for some rare cancers has led to seminal advances in targeted therapies not only for those cancer types, but for other types as well. Kelley foresees a likely rare cancer precision oncology partnership with the NCI and the Defense Department, to build the knowledge base necessary to produce actionable results from research.

Meanwhile, ORD is laying the groundwork for the research that will underpin clinical advances in precision oncology for breast cancer and rare cancers: establishing mechanisms to allow veterans with breast cancer greater access to clinical trials, and building networks to advance research and initiate new programs with partner agencies such as the NCI and the National Institute of Dental and Craniofacial Research.

Because of the comparatively smaller number of both of these cancer types in the VHA, Ramoni said, both will likely involve virtual clinical trials: “That simply means you don’t have to be in, say, Seattle to participate in the trial. To the extent possible, these trials will be available to people wherever they are. When we’re researching oral medications, for example, we’ll mail the medications directly to people’s homes and conduct a kind of tele-clinical trial.”

Taken together, these efforts will help expand the National Precision Oncology Program’s System of Excellence, fostering an enterprise-wide culture conditioned to push itself toward advancements in research and care, to remove any disparities in access to the VA’s cutting-edge cancer treatments, and to inform veterans – and their families – what their genes might be saying about their risk for cancer.

“I view this as not only helping the veterans, but their family members as well, to understand their risk of cancer – which may add years of healthy life for them all,” Ramoni said. “And the scale of the VA obviously means we’re going to touch a lot of American families.”