Fifteen years after the first sequencing of the human genome, genomic medicine is yielding big steps forward in treating cancer and other diseases, Kentucky researchers and oncologists say. Because the state has the nation’s worst rates 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 genetic profile assessed to determine their future risk for disease. 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.
Parents may be able to consider genetic screens for their children, said Dr. Douglas Flora, medical director of the St. Elizabeth Healthcare Cancer Center. During annual checkups, physicians could use genomics to longitudinally track risks and suggest behavior modifications and treatments to prevent or get ahead of possible disease development.
“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.
Future patients might have the opportunity to take steps to prevent cancers from developing in the first place rather than waiting for tumors 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 two decades of direct involvement with genomic research as it has evolved from pure research into actual 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 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.
Screening remains weapon No. 1
Before discussing those entities’ functions, Kolesar explained that “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 new, she and her colleagues emphasize, and while genetic insight offers exciting possibilities for future patient care, the news reaching the public so far is a bit more hype than fact.
“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.
That may sound simple, but 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 stabilizes, shrinks or becomes undetectable. But for others, tumors persist and metastasize despite the various interventions.
In the last decade, however, patients who don’t respond to standard chemotherapy or radiation treatment have better survival opportunities 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, indeed, 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 HealthCare officials to assemble a unique type of cancer review board in 2016. The Molecular Tumor Board allows researchers to collaborate with oncologists throughout the state on treatment of patients suffering from advanced-stage cancer.
State’s first Molecular Tumor Board
UK Molecular Tumor Board services are free to all surgical and medical oncologists in Kentucky. The volunteer 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 not responding to traditional therapies.
The treating oncologist submits his or her case report to the MTB online with a request for a review. Usually, a tumor sample has been gene sequenced and its known mutations identified. Mutations 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. 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 the patient can join, or some patients qualify for an investigational drug trial available only through the Precision Medicine Clinic at UK.
When the MTB was formed two years ago, sequencing could compare samples against 196 known gene mutations. By May 2018, TCGA had over 300 gene mutations, with those numbers climbing as research continues.
The MTB is not recommended for all cases and 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,” Kolesar said.
However, because Kentucky leads the nation in lung cancer, the state’s oncologists already know much 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 in Lexington and advanced genomic research in general. Even so, Durbin realized the large data warehouses don’t provide information 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, with its data 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 population-specific mutation registry is wanted because Kentucky has the worst cancer problem in the nation 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 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, would it 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, UofL and several tertiary-care hospitals in the state, the KCR is already collecting genomic test data to answer those questions.
The KCR 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 that “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 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 labs 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.
Immunotherapy ‘miraculous’ for some
To 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. Some patients’ 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 to trick 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 procedure basically takes the brakes off the body’s immune system,” Kolesar said, but an out-of-control immune system can pose as serious a threat as 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 creation of new health professions. One new profession to emerge in recent years is genetics counseling, which helps patients interpret the results of a genetics lab report.
In recent years, researchers have started identifying and documenting genetic mutations that can indicate a genetic propensity to certain cancers. Knowing this information, there are ways in which patients can organize their lifestyles to reduce those risks.
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.
Baptist Health, which has hospitals around the state, 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,” 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.”
Josh Shepherd is a correspondent for The Lane Report. He can be reached at [email protected].
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