Editor’s note: This is the second in a two-part look at efforts to change Kentucky’s worst-in-the-nation cancer mortality rate.
Fifteen years down the road from the first sequencing of the human genome, genomic medicine is yielding big steps forward in treating cancer and other diseases, say several Kentucky researchers and oncologists. Because the state has the nation’s worst rate of cancer occurrence and mortality, genomic medicine could have its greatest positive impact in Kentucky.
Within a decade or so, healthy adults could opt to have their complete genetic profile assessed to determine their future risk for disease. And for Kentucky populations, such data is expected to yield deeper insights because the Kentucky Cancer Registry recently began a first-of-its-kind project to collect and compile genomic trends for the state’s hard-hit geographies.
It’s hard to say when, but parents may soon be able to consider genetic screens for their children, said Dr. Douglas Flora, medical director of the St. Elizabeth Healthcare Cancer Center. As part of a child’s annual physical checkup, physicians could use genomics to longitudinally track risks and suggest modified behaviors and treatments to prevent or get ahead of the possible development of disease.
“The ability to see just a little piece of the future for each patient will allow physicians to make more educated decisions about screenings and tailor care to the individual patient,” Flora said.
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In terms of future cancer care, some patients might have the opportunity to take steps to prevent it from developing in the first place rather than waiting for a tumor to occur and grow to a detectable level.
“That is a goal, but we’re not anywhere near there yet,” said Dr. Jill Kolesar, a clinical pharmacologist at the University of Kentucky. Kolesar is co-director of the Precision Medicine Clinic at the UK Markey Cancer Center, which has a network of 20 affiliated hospitals in the state, and a co-chair of the Molecular Tumor Board.
She has been directly involved with genomic research for two decades as it has evolved from pure research into the realm of patient care.
“It’s only been within the last five years that genomic sequencing has even moved into the clinical setting,” she said.
Kolesar worked with two medical oncologists to establish precision medicine services at University of Wisconsin’s Carbone Cancer Center while she was on faculty there. After joining UK’s Markey Cancer Center faculty, she worked with Dr. Rachel Miller, a gynecological oncologist, and Dr. Susanne Arnold, a medical oncologist, to found the first Molecular Tumor Board in Kentucky and organize the UK Precision Medicine Clinic, which launched in February 2018.
Most genomic benefits yet to come
Before discussing the functions of those entities, Kolesar explained that the term “precision” or “targeted” medicine actually describes a broad range of cancer-fighting services, some of which hospitals have been engaged in for decades. Weapon number one remains screenings. Triggered either due to a patient’s age or because they have a family history of cancer or heart disease, doctors order colonoscopies, mammograms, prostate exams or stress tests.
“We know that genetics plays a role in a patient’s risk for developing cancer,” Kolesar said. “We try to mitigate that risk. But it’s important to remember that genetics only indicates a risk – not a guarantee (that a tendency will occur). Physical exercise, a healthy diet and cutting out smoking significantly reduces cancer risk, even for those who have a family history of disease.”
Genomic science is still comparatively new, she and her colleagues emphasize. While genetic insight offers exciting possibilities for the future of patient care, the news that has received the most public attention is a bit more hype than fact.
In terms of cancer treatment, “where the science is today is breaking down the genetic sequence of cancer tumors to identify known mutations, then matching those mutations to the most effective drug therapy available,” Kolesar said.
While that summary may sound simple, it represents a substantial breakthrough in medicine’s understanding of cancer cells. Before genetic sequencing, cancer treatment “pathways” were much the same from patient to patient, but outcomes often differed.
Some patients respond well to basic treatment, and their cancer is stabilized, shrinks or becomes undetectable. But for others, tumors persist and become metastatic despite the various interventions oncologists have at hand.
In the last decade, however, patients who don’t respond to standard chemotherapy or radiation treatment have improving opportunities for survival thanks to medicine’s increasing understanding of genetic sequencing, Kolesar said. Genetics has shown researchers that literally no two cancers are alike. The molecular composition of tumors is as individually unique as any other living organism. Meanwhile, researchers have learned there are common mutation forms among tumors that oncologists know are vulnerable to specific treatments or drugs.
This growing base of knowledge and understanding about the genetic mutations common to various human cancers led UK health care officials to assemble a unique type of cancer review board in 2016. The Molecular Tumor Board allows UK researchers to collaborate with oncologists throughout the commonwealth on treatment of patients suffering from advanced-stage cancer.
State’s first Molecular Tumor Board
UK Molecular Tumor Board services are free and available to all surgical and medical oncologists in Kentucky, Kolesar said. The board is a multidisciplinary group of cancer specialists, including pathologists, medical oncologists, surgical oncologists, radiologists, genetics counselors, pharmacologists and basic scientists. The MTB works to uncover possible alternative treatment options for patients who are not responding to traditional therapies.
The treating oncologist submits his or her case to the MTB online with a request for a review. Usually, a tumor sample already has been subject to gene sequencing with an accompanying report identifying the known mutations.
The mutations contained in MTB request reports are cross-referenced with a national database such as The Cancer Genome Atlas (TCGA), which is maintained by the National Institutes of Health, to identify the chemotherapeutic drugs known to be most effective against them. The options found are compiled into a final report for the board.
If there are no proven drugs, Kolesar said, there might be a clinical drug trial that the patient can join or some patients may qualify for an investigational drug trial available only through the Precision Medicine Clinic at UK.
When the MTB was established two years ago, gene sequencing could compare tumor samples against an estimated 196 known gene mutations. By May 2018, (TCGA) had identified over 300 gene mutations. Those numbers will continue to climb as research continues.
The volunteer board meets every first and third Tuesday of the month to review case reports. Kolesar and fellow board co-chair Dr. Rachel Miller are among those who regularly attend. It’s a significant comment on the commitment of the cancer specialists who participate, she said, that they give their time to help colleagues find alternative or investigational treatments for their patients.
The MTB is not recommended for all cases, Kolesar said. In fact, gene sequencing is not an automatic first step for most early cancer diagnoses.
“We don’t recommend using this type of precision medicine therapy unless the track is proven to be better than standard approaches to the disease,” she said.
There are exceptions.
For example, because Kentucky leads the nation in lung cancer, the state’s oncologists already know a great deal about the types of mutations involved. While not yet a standard of care, gene sequencing of lung biopsies is an increasingly common practice today in the commonwealth.
The MTB’s work is yielding good outcomes, but a great deal of research and discovery remains to be done. Some of this will come from cancer informatics specialist Dr. Eric Durbin, director of the Kentucky Cancer Registry (KCR), who regularly sits in on the twice-monthly MTB meetings to supply research and population-based data for physicians to consider.
A population-based mutations registry
The TCGA database is a high-value resource for the MTB and advanced genomic research in general. Even so, Durbin realized the large data warehouses don’t provide an important information set to the commonwealth’s cancer treatment decision makers. As a result, he launched an ambitious effort to assemble the nation’s first population-based registry of known cancer mutations; its data will be specific to Kentucky’s population and demographics.
“National databases collect data from patients everywhere in the country. The data doesn’t represent any (localized) underlying population. It’s like basing your conclusions about Kentucky’s cancer problem by reviewing all the cases from the Mayo Clinic,” Durbin said.
A state-specific, localized mutation registry is wanted because Kentucky has the worst cancer problem in the nation; its rates of occurrence and mortality lead all states, and that is due to a concentration in a cluster of counties in Eastern Kentucky. Durbin conceived of the idea to embark on KCR’s ambitious new project while participating in MTB sessions during the past few months.
Is it possible, he wondered, to predict better courses of treatment or outcomes if there was data on the historical experience of patients who shared similar demographics? Is it possible to identify matched patients in a population-based registry who share a similar molecular profile? If the registry identifies similar cases in the registry, would it be able to inform physicians about treatments that result in longer-term survival, better quality of life and better outcomes?
Durbin believes it will. With the support of oncologists and researchers from UK and the University of Louisville, as well as several tertiary-care hospitals in the state, the KCR is already in the process of collecting genomic test data to answer those questions.
The KCR already collects population-based data on cancer incidence, treatment and a host of other measures. Creating a population-based set of tumor mutation data in the commonwealth is one natural step for the registry and “could give insights and better predictions about which patients would best respond to specific treatments because there will be information in the registry on patients (in the local population) who have tried those agents,” Durbin said.
Complying with patient privacy and confidentiality standards, the KCR is negotiating agreements with health-care systems and genomic testing laboratories to share basic information.
“We’re the first state cancer registry to build such a database. We’ll depend a great deal on mutual cooperation with health systems and laboratories to gather this data. It’s a huge undertaking, but the end result could have a significant impact on improving survival and other positive outcomes for cancer care,” Durbin said.
Greater understanding of the science will lead also to better analytic methods to process this information. In addition to a catalog of the genetic mutations that may be particular to Kentucky, the raw data will allow oncologists to re-analyze those files against what will be learned in the future.
“Who knows what insights we’ll discover? It’s exciting to think about,” Durbin said.
Immunotherapy ‘miraculous’ for some
Up until this point, the discussion of sequencing genetic tumors has focused on identifying specific gene mutations in cancer cells as if patients only suffered from one or two. But the disease is rarely that simple, Kolesar said. There are patients whose cancers have a “high mutation burden.”
One of the little-known functions of the body’s immune system is to track down cell mutations and engulf them as they would an invading virus. But cancer is smart, said Dr. Mark Evers, director of the Markey Cancer Center. Forms of the disease have evolved a survival mechanism to mask its presence. It tricks the body into thinking it’s a normal cell and, therefore, the body’s immune system doesn’t activate.
Immunotherapy uses drugs to boost and reactivate the immune system, Evers said.
The treatment is very much a type of precision medicine. It’s a specialized type of treatment that works only for certain individuals, Kolesar said. Immunotherapy treatment can pose too much risk for other patients.
“The procedure basically takes the brakes off the body’s immune system,” she said, and an immune system going out of control can pose as serious a threat as the cancer.
However, immunotherapy has proven quite effective on patients with melanoma. Less than a decade ago, Evers said, there wasn’t much to offer patients with metastatic melanoma except for some toxic therapies that, frankly, didn’t do much.
“We’ve seen miraculous effects from immunotherapy drugs. For some patients, those drugs are really helping,” he said.
Genetics counseling
Growth in genomics-based services has spurred the creation of new health professions. One new profession to emerge in recent years is genetics counseling, which helps patients interpret and understand the results of a genetics laboratory report.
In recent years, researchers have started identifying and documenting genetic mutations that can indicate a genetic propensity to certain cancers. For example, the presence of some form of the “BRCA” mutation could indicate a predisposition to breast cancer. Its presence, combined with a host of other variables, could mean a patient has a 50 to 80 percent chance of developing the disease. Knowing this information, there are ways in which patients can organize their lifestyles to reduce those risks.
Some patients have chosen to undergo surgical procedures as a precaution against breast cancer, which has attracted media attention. Using genomic reports as a means to be proactive in cancer control does not mean that people should take such radical steps, Flora said.
The St. Elizabeth Health System in Northern Kentucky, like many others in Kentucky, offers some form of a hereditary cancer program in its menu of patient-care services. For a nominal fee, a blood test is submitted to an accredited commercial genetics laboratory for analysis, and the report is reviewed by a clinical medical director and pharmacologist, who in turn advise the patient on what the results mean.
“In the near future, we plan to expand this service to ‘the worried well’ – people who are concerned that they may be at risk for heart disease or cancer but never had a meaningful way to address those concerns until now,” Flora said.
If there is a serious concern, a patient can be referred to a specialist – a precision medicine expert in pharmacy, oncology, cardiology, or even psychiatry – to develop a personal treatment regimen.
Baptist Health offers a similar service. Patients may have to travel to a laboratory to submit blood or tissue for analysis, but the meeting with genetics counselors usually occurs at home.
“Baptist uses telehealth services so patients can consult with a genetics counselor from their home hospital. A few of my patients at Baptist Health La Grange do this,” said Dr. John Huber, director of cancer care services for the Baptist Health Medical Group. “A genetics visit is not difficult to get, and our counselors will help patients understand if there is a concern. Most of the time, there is not.”
Even though genomic services in health care is becoming increasingly popular, there are some valid criticisms that the field is still too new and may be hyped more than it should at this point.
Dr. Scott Pierce is a medical oncologist with KentuckyOne Health with over 25 years of practice experience in the Lexington area. Advances in genomic medicine have been a leap forward in cancer care, he said, but he also argues the field is still not advanced to the point where every patient needs to undergo some molecular study.
“There is popular media that makes genetic testing seem like the perfect screening tool. But unless there is an extensive family history or other serious concern, the results may not be worth the cost,” Pierce said.
Other oncologists and researchers agree. Evers emphasizes that there are ongoing national discussions regarding ethical concerns as the clinical applications of genomics expand in cancer care and other clinical applications.
“There is a need for more data and more research. But these concerns shouldn’t dissuade us from moving down the path. As we gain more knowledge and understanding, our ability to predict who will benefit most from genomics will improve,” Durbin said.
Josh Shepherd is a correspondent for The Lane Report. He can be reached at [email protected].
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