Decoding Genomic Profiling: The Hype and the Hope of Precision Medicine

Genetic assays, new sequencing platforms, and growing evidence about the role mutations play in malignancies and cancer risk have given hematologists and oncologists more information to work with than ever before, but is it actually leading to better patient care? While genomic profiling can be a valuable tool for some patients, experts say it isn’t without its pitfalls.

“The hype surrounding genomic profiling is really problematic,” said Wylie Burke, MD, PhD, a professor of bioethics and humanities at the University of Washington in Seattle. “The genome has been presented to the public as ‘Your Instruction Manual’ that will tell you what to worry about and what not to worry about.” Armed with enough genetic information, it seems, a person can make the necessary adjustments to reduce his or her risk of developing a condition. “That’s erroneous, in a fundamental way.”

ASH Clinical News recently spoke with Dr. Burke and other experts in the field of genomic profiling to learn about the value of genomic profiling and genetic sequencing, as well as its limitations and potential pitfalls as researchers push to move genetic findings out of the laboratory and into the clinic.

Too Much Information, or Too Little?

There is no shortage of researchers working to find new ways to put genetic information into practice – from characterizing a patient’s genetic risk for later developing a disease to uncovering the genetic makeup of existing tumors to guide treatment and find new therapeutic targets based on patients’ genomes.

Great strides have already been made in this field, with the discovery of a slew of inherited and somatic genetic variations that contribute to the predisposition, disease progression, and treatment of a variety of hematologic malignancies. A genetic basis to other non-malignant hematologic disorders has also been uncovered, including bone marrow failure syndromes, some forms of hemoglobinopathies, and severe congenital neutropenia.

There are still unanswered questions about how much these discoveries are impacting patients, though, and if this information might unintentionally harm patients – especially when there is so much yet to be learned.

Recently, the genomic profiling movement has been gaining momentum in part due to programs like the Precision Medicine Initiative research effort introduced by President Obama in January. The initiative promotes the idea of precision medicine, or the use of people’s individual variations in genes, environment, and lifestyle to develop prevention and treatment strategies.

The President’s budget for 2016 will include $215 million to support the effort, including $130 million for the National Institutes of Health (NIH) to develop a voluntary national research cohort of a million or more volunteers who will share genetic data, biologic samples, and information about diet and lifestyle. An additional $70 million has been earmarked for the National Cancer Institute (NCI) to increase efforts to identify genomic drivers in cancer and develop more effective treatment approaches.1

The initiative should vastly improve the medical community’s ability to understand and use genetic variation and help clinicians target diagnostic and treatment efforts, according to Teri Manolio, MD, PhD, director of the division of genomic medicine at the National Human Genome Research Institute in Bethesda, Maryland. “It will also help us avoid adverse effects of therapy and identify environmental and other risk factors that may worsen or lessen their effects,” she added.

Other governmental initiatives are also underway: In 2007, NIH introduced the eMERGE (Electronic Medical Records and Genomics) Network, a consortium of researchers with expertise in genomics, statistics, ethics, informatics, and clinical medicine with the goal of developing, disseminating, and applying approaches to research that combine data from DNA biorepositories with electronic medical record (EMR) systems.

“The next phase of eMERGE will use well-defined and validated phenotype information from the electronic medical records of more than 20,000 people to determine the health impact of genetic changes in roughly 100 genes important in human health,” Dr. Manolio explained. As with the Precision Medicine Initiative, the genetic research of eMERGE is hoped to help clinicians interpret potential health implications for their patients who have similar variants – with the ultimate goal of improving clinical care.

An Unclear Call to Action

New advances in genetic testing are making genomic profiling a more frequent tool in patient care, but experts caution that just because the technology makes genetic sequencing a possibility doesn’t mean it’s always the best course of action.

“Rapid advances in genetic testing mean that we can identify moderate-risk genes or single nucleotide polymorphisms (SNPs) that are associated with tiny changes in risk,” said Wendy Kohlmann, MD, director of genetic counseling at Huntsman Cancer Institute in Salt Lake City, Utah. “The amount of information and testing methods available has grown greatly, but it’s not yet clear how clinically significant some of these gene-mediated changes in risk are.”

Simply put, not all genetic variations are created equal.

Genetic risk information gathered from patients’ genomes can be highly predictive of an increased risk for later disease development, Dr. Burke added, but can also be linked to only slight increases in risk or point to variations that aren’t yet fully understood.

For instance, according to NCI, 55 to 65 percent of women who inherit the BRCA1 gene mutation will develop breast cancer by the time they reach 70 years old.2 Armed with that information, women who test positive for the mutation can make very clear treatment decisions to mitigate their risk of developing breast cancer, whether that entails undergoing a mastectomy or intensifying screening.

There are also clear actionable steps for patients with hereditary hemochromatosis, a condition that causes the body to absorb too much iron. According to Dr. Burke, patients who develop the disease after inheriting a particular gene variant from both parents are at a possible risk for cirrhosis, liver cancer, and other health concerns.

“In this particular case, knowing a patient’s genetic predisposition could lead to two things a physician normally wouldn’t do,” she said. The first is to monitor the patient’s iron with a simple blood test; the second is to prescribe phlebotomy if those iron levels are too high.

“Screening for highly predictive gene variance for high-risk conditions seems like a good idea – if they are actionable,” Dr. Burke added.

The action to take after gene variants are identified for complex conditions such as diabetes is less clear. Multiple factors often play into a patient’s risk level of developing these conditions, including diet, exercise, and lifestyle. Using genetic risk to predict a patient’s likelihood of developing diabetes could fail to account for other factors that may have a greater effect on overall risk.

And, because most diseases are influenced by multiple genetic factors, it is difficult to identify a single therapeutic target.

“There are very few disease processes entirely dependent upon a single variation,” said Mark Robson, MD, clinic director at Clinical Genetics Service at the Memorial Sloan Kettering Cancer Center in New York. “In many diseases – and particularly in cancer – there is a lot of interaction between different mutations, influencing the course of the disease and the likelihood that it will respond to treatment.”

Should a genetic variation be discovered during the course of treatment, it may not be possible to tailor treatment because there is still so much to learn about these interactions.

“Not every mutation is one that can directly lead to an intervention,” Dr. Robson noted. “There are certain variations in which we either don’t completely understand the risks or the clinical pathway is unclear after finding the variation.”

The Hazards of the Hype

Despite the significant number of unknowns and lack of actionable steps in many instances, genomics testing companies are still touting the benefits of genomic testing and promoting the idea of personalized therapy to the public.

This year, the Cancer Treatment Centers of America Global announced the creation of the Centers for Advanced Individual Medicine – a resource that will make advanced genomic testing available to qualifying patients when recommended by the patient’s physician. The organization does acknowledge that advanced genomic testing is not appropriate or recommended for every cancer patient, but “is intended primarily for patients for whom standard of care did not produce favorable results, no longer produces desired results or does not exist, and the patient may benefit from targeted therapies not considered previously.”3

At-home or direct-to-consumer genetic tests, which typically screen for inherited genetic variants, are also rising in popularity. People taking these tests may be doing so without guidance from a health-care provider, which could result in false reassurance, unnecessary anxiety, or making inadvisable health-care decisions based on an in incomplete picture of their health.

This issue is also on the U.S. Food and Drug Administration’s radar: In 2013, they issued a letter urging the personal genomics at-home testing manufacturer 23andMe to stop marketing the test after failing to produce the study results necessary to support their marketing claims.4

Processing the Genetic Information

Much of the research into genomic profiling is still in its infancy, and the role that genomic abnormalities play in predicting who will ultimately develop the disease is still unclear.

For instance, in a 2014 study published in The New England Journal of Medicine that examined specific mutations within 160 genes associated with myeloid and lymphoid cancers found that detectable somatic mutations were rare in people under the age of 40, but increased in frequency with age.5

Similar results were reported in another study published that same month in NEJM: An analysis of the whole-exome sequencing of DNA in the peripheral blood cells of 12,380 people revealed somatic mutations present in blood cancers leading to clonal hematopoiesis are increasingly common with age.6 The subset of mutated genes found in patients who had myeloid cancers were also frequently present in seemingly healthy people.

“Because clonal hematopoiesis is common with aging and its prevalence greatly exceeds the age-specific incidence of leukemias, caution is needed when predicting clinical consequences from a cancer-associated gene mutation in healthy persons,” wrote Janis L. Abkowitz, MD, head of the Division of Hematology and adjunct professor of Genome Sciences at the University of Washington School of Medicine, in Seattle, Washington, in an editorial accompanying the two studies.7

Another aspect under debate is whether patients who are at an increased risk for developing various hereditary conditions actually make recommended behavioral changes after receiving the results.

Most of the preventative steps related to conditions such as diabetes or heart disease have already been established, and, therefore don’t provide patients with any new information that isn’t already delivered at the population health level, said Dr. Burke. “The question could be raised: Will the new genomic information be motivating? At this point, we don’t have any evidence that it will.”

While it’s true that not all patients will adhere perfectly to physician recommendations, Dr. Kohlmann remarked, research has shown that general genetic risk testing does often lead to patients making better choices about their health.8,9

“Most long-term, follow-up studies have included patients who received extensive pre- and post-test counseling,” she noted, which may explain patients’ improved choices. “Genetic testing in and of itself may not have necessarily resulted in that outcome, but, paired with good information and discussion, genetic testing has generally led to people making better health decisions – with minimum evidence that it’s causing any significant negative psychological sequelae afterward.”

The Next Steps

Again, the biggest challenge with genomic testing is not identifying that the genetic variation exists, but interpreting what it means.

“This can be a complicated process. Figuring out whether or not a variation is meaningful, then exploring whether or not it is linked to a treatment response or risk of disease is often a research enterprise,” Dr. Robson said.

The amount of information we still don’t know about the role genes play in the body’s responses outweighs the amount that we do understand, Dr. Burke added.

“The majority of the variation we find through sequencing is a variance of unknown significance – much of that is variance we have never seen before and a lot of that is variance we have seen before but still don’t fully understand because of the lack of data,” she said. “The variance of unknown significance issue is huge.”

Researchers also have yet to identify the best “normal” reference DNA sequence. While NIH is currently working on a project to do just that, Dr. Burke said there still isn’t a gold standard of what normal looks like – making interpretation of genomic data even more difficult.

Technical issues still need to be worked out, as well, including the accuracy of screening methods used to identify highly predictive gene variance. Dr. Burke also noted that, in areas where genetic testing is already in place (such as screening for specific health conditions in newborn babies), false-positives are still a valid concern.

“Testing protocols are deliberately designed to make sure we don’t miss kids – and we do miss very few kids. But, as a result, we also get a number of false-positive results that need to be sorted out,” she said. “It’s the burden of any kind of testing, and it’s a common burden of genomic screening programs.”

While she could see society moving toward more commonplace genetic screenings to look for highly predictive variations that can lead to clear actionable steps, similar to newborn screenings, Dr. Burke said she does not see a similar value to more broad screening efforts that would identify less predictive, less actionable information.

The Thorny Ethics of Genetic Testing

The field of genomic profiling isn’t without ethical concerns either – particularly when testing leads to incidental findings.

Genetic testing typically can be grouped into two categories: genetic testing used to identify a patient’s likelihood of developing a disease, and somatic mutation testing used to learn more about the genetic makeup of existing cancers. Each category carries its own set of ethical concerns.

In somatic mutation testing, the best way to discover new therapeutic targets or mechanisms of drugs is to compare the tumor’s DNA sequence with that of a patient’s normal tissue. This requires clinicians to perform a normal DNA sequence, which could uncover other inherited variations in an individual’s genome that are unrelated to the malignancy.

After finding one of these incidental and unanticipated discoveries, is the clinician obligated to tell the patient? What if it’s information the patient doesn’t want to know? In any genetic testing scenario, information may be uncovered that patients aren’t prepared to receive.

“The main ethical issue is to make sure the patient is appropriately educated before the testing is done, so that he or she understands the kind of results that the testing could produce,” Dr. Robson advised. “At that point, the patient has the opportunity to decide whether it is something he or she wants to know.”

Dr. Burke agreed that prior education and discussion is also important in testing for hereditable conditions: “The fundamental concern with genetic screening is that, when we go looking for things in healthy people, we can harm them. We need to carefully determine what we are screening for, how many false-positives we may have, the harms of those false-positives, what actions we will take, and how sure or unsure we are that these actions will help people.”

Dr. Manolio pointed out that in all genetic testing scenarios, researchers also need to examine the social, psychologic, behavioral, and cost implications of how discovering these variants affects the patient and his or her family.

In the case of hereditary conditions, that ethical quandary is placed with the individual patient because his or her family members may also be at risk. The consensus among the medical community seems to be that clinicians do not have a duty to warn other family members, Dr. Burke said – in part because it would be a violation of the individual’s privacy.

“Imagine a circumstance where a health-care provider feels it would be better to reach out to the family members – even with the privacy and confidentiality obligations,” she explained. “Should you find yourself in that ethical dilemma, the prevailing thinking would be to seek legal counsel about the best way to do that.”

Patients themselves, however, may have a greater ethical responsibility to notify family members at risk for inherited conditions. To ease the notification process, clinicians should provide patients with tips or assistance in effectively communicating that news to others.

Making sure everyone is able to benefit from genetic testing is another ethical aspect to consider, Dr. Burke said. “From an ethic perspective, as we develop beneficial applications, it is crucial that everybody with access can benefit from these advances.”

The Role of the Genetic Counselor

Genetic counselors can often serve as a resource to help patients navigate ethical considerations, ensure a patient has realistic expectations about the process, and help patients share what they have learned about their genetic risk to family members.

The first step in working with patients undergoing genetic risk assessment is to discuss the likelihood that a test will be able to identify something useful for the patient and whether there are options available to manage that risk, Dr. Kohlmann advised.

“For some conditions, like breast cancer, we have better screening methods and better medications to help reduce a patient’s breast cancer risk. In that case, our threshold for offering testing to families who may have some level of risk is lower because there are a few well-defined genes, and we have the strategies in place to triage those patients,” she said. “For some other types of cancer – where some genetic risk markers have been identified, but there are no prevention or early detection strategies in place – the threshold is higher. Those are situations where we think harder about the pros and cons of having that information.”

Once those issues have been discussed, a patient is better prepared to receive the results, she noted.

Genetic counselors can work closely with the hematologist or oncologist to help interpret the genetic testing results consistently and make the appropriate testing decisions, Dr. Kohlmann added. At her institution, genetic counselors are integrated into practice with oncologists – even attending tumor boards to discuss genetic findings and how they may impact treatment.

“While not every center has this level of integration, I believe it is important for all health-care providers to view being knowledgeable about genetic issues as part of their job so that they can be prepared to address questions or reinforce information,” she said.

The Genetic Roadmap Ahead

Researchers have only begun to scratch the surface when it comes to understanding the role genetics play in inherited and somatic conditions and how those genetics later affect treatment.

As research continues to rapidly move ahead to identify genetic factors contributing to risk, Dr. Kohlmann hopes that this work is also paired with studies exploring the penetrance of these variations, as well as efforts to study how the data can be used to meaningfully change treatments and outcomes.

“As we continue in this field, we need to be thinking comprehensively,” she said. “Many of these studies are identifying factors associated with smaller changes in risk. The challenge is to be able to answer patients definitively when they ask, “What should I do now?” Getting to that point will require consortiums, collaboration, and plenty of research, she added.

The field of genomics is also distinctive because it is not always possible to conduct randomized controlled trials, leading to varying levels of evidence and data. Dr. Burke believes the medical community needs to reach a consensus on how much evidence, exactly, is needed before drawing any conclusions about the validity of widespread genetic testing. “A crucial need now, obviously, is continued research to understand genetic variation and connections between gene variants and health outcomes, but also continued deliberation about the quality of that evidence and when we have passed an evidence threshold.”—By Jill Sederstrom


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