Genetics lands in primary care inboxes

Karen Titus

June 2019—It took David Ledbetter, PhD, a mere six years or so to become a hero.

Dr. Ledbetter, executive vice president and chief scientific officer, Geisinger, had helped oversee the expansion of the health system’s MyCode precision medicine project, which began as a traditional research biobank in 2007. Recent years brought giant steps: expanded enrollment (some 235,000 Geisinger patients have consented); a collaboration with Regeneron Pharmaceuticals, which had built a large DNA sequencing lab; exome sequencing of 145,000 Geisinger patients; publications in the New England Journal of Medicine, among other journals.

Tucked into all of this was a decision, in 2013, to do clinical laboratory confirmatory testing of American College of Medical Genetics and Genomics secondary findings, including those linked to hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia. “Some would say it was a controversial decision,” Dr. Ledbetter recalls. Results would no longer be rolled away into research; Geisinger would be returning clinical genetics laboratory reports that would go to the patient’s medical record, the primary care physician, and the patient.

A sense of puzzlement ran even deeper. For those first five or six years, when Dr. Ledbetter encountered clinicians—primary care physicians and specialists alike—on campus, grand rounds, etc., “They would come up to me and say, ‘David, can you explain to me one more time why we do research at Geisinger? We’re not a university, we’re not an academic medical center in the traditional sense. I came here to take care of patients. Why are we doing research in Danville, Pa.?’”

Dr. Ledbetter says he met those questions head-on, patiently explaining, again and again, how he thought this would be clinically beneficial in the not-too-distant future, how it might help them, in some cases, prevent the onset of cancer, cardiovascular events, and the like.

As happens with many earnest, thoughtful responses, “My patient explanations had pretty close to zero impact,” Dr. Ledbetter recalls.

That is, until recently, when MyCode results entered the clinical realm. “The first time a primary care doc gets a BRCA1 result on one of their patients, it’s transformative,” Dr. Ledbetter says.

And by helping his colleagues use genetic test results to practice advanced medicine, “I’ve become a hero,” he says.

Heroics aside, population genetics screening appears to be on the verge of transforming medicine in ways yet to be imagined.

Genetics testing seems to be chugging along on an Overland Route of sorts, as the traditional clinical approach (patient-by-patient, gene-by-gene, disease-by-disease) meets with whole exome or genome sequencing of patients without obvious disease or family history. Unlike with the First Transcontinental Railroad, however, no one is aiming for a triumphant, final handshake in Utah.

“I don’t know where this will end up,” says Karen Kaul, MD, PhD, chair, Department of Pathology and Laboratory Medicine, NorthShore University Health­System, Evanston, Ill. As her own institution sets up several genetic testing projects that emphasize population screening rather than diagnostics, she and others find themselves searching but confident, the way a yogi might encourage students to simply keep returning to the mat, unattached to a particular outcome. “But I am sure we will learn from our population screening program, called DNA-10K, and all of these genomic projects. Doing the work and having this information will shape the way care is delivered for years to come.”

Amy Sturm, MS, LGC, co-director, MyCode Genomic Screening and Counseling, and professor, Genomic Medicine Institute, offers one example of what this might look like, based on a recent case at Geisinger.

A woman who was concerned about her family history of cancer initially went through Geisinger’s clinical genetics testing pathway; her family didn’t meet set criteria for a cancer condition, and it was recommended that cancer genetic testing start with an affected relative.

The relative did not pursue testing. “But sure enough, this same woman had enrolled in MyCode, and we ended up finding a variant for Lynch syndrome,” Sturm says. The woman had a total abdominal hysterectomy preventively, and was found to have a very early stage endometrial carcinoma.

It’s not that the clinical pathway failed, Sturm says, because everything was done right. “But it shows you the difference between the typical clinical genetic testing pathway compared to the population genomics screening approach, where you do have the capability to find more people with variants,” says Sturm, who is also director of cardiovascular genomic counseling, Geisinger, and president, National Society of Genetic Counselors.

As institutions collect and harnessvast amounts of genetic data, they are also trying to figure out what patients and clinicians want to do with test results.

Peter Hulick, MD, medical director, Mark R. Neaman Center for Personalized Medicine, and division head, Center for Medical Genetics, calls NorthShore’s current genomics projects a naturally evolving area of interest. Over the past five or six years, he says, patients have become more cognizant of genetics and begun asking for testing. That was one reason NorthShore established its Center for Personalized Medicine, which in turn broke down many of the traditional barriers across division and department lines, he says.

The first major project was NorthShore’s Genomic Health Initiative, a research project aimed at developing a cohort of 100,000 enrollees, whose genomic information will also be tied to their electronic health record.

“What we found is that the patients—excuse me, subjects; they’re patients in our systems but subjects in the study—had the option to consent to return of results,” Dr. Hulick says. “Well over 90 percent wanted this information.”

His terminology slip-up is telling, illustrative of the converging worlds of research and clinical care. What happens when subjects become patients, when research data and previously esoteric test results become part of routine clinical care?

At NorthShore, that meant flinging open the door to let primary care physicians disseminate genetic information. “We had extensive training of our primary care docs,” says Dr. Kaul, including in the use of a screening/family history tool that allows for more structured genetic testing and directing patients to one of NorthShore’s personalized medicine programs. “We need to make this a standard part of care and educate our clinical colleagues, because nobody’s really, even now, learning this in medical school. It’s changing medicine, and for us to understand how to do that responsibly and effectively, we need to work across the medical system.”

NorthShore has gone down traditional education paths, including grand rounds, webinars, and after-dinner events, Dr. Hulick reports. When they rolled out the pharmacogenomics program, they tried a see-one, do-one, teach-one approach, in which interested primary care physicians went through the testing process themselves and learned their results to get a sense of what their patients might experience. There were also educational pre-visits—for medical assistants and nurses as well as physicians—before a site went live; when a site launched, Dr. Hulick or a colleague was on hand to provide support.

“The challenge is, especially in the primary care physician world, they’re very busy clinicians, and some you can only give a sound bite of information,” Dr. Hulick says. That’s where the screening/family history tool comes in. If there’s an indication for a test, a best-practice alert is activated during the patient’s annual history and physical. The alert includes an explanation and gives primary care providers prepopulated order sets that either refer the patient to a NorthShore specialty clinic or order the genetic testing.

“Are best-practice alerts the end-all, be-all solution? No,” says Dr. Hulick. “But it helps move the needle. I think that’s what’s key with our initiatives. We haven’t solved everything. But we can implement, and then we try to make it better.” Besides, he adds, “If you wait for ‘the perfect solution,’ you’re never going to implement anything. And each time we’ve implemented something, we’ve learned valuable information.” The final goal, he says, is to make genetic testing available to anyone who needs it or simply wants it.

The EHR is key, Dr. Hulick says. “We often talk about solving the last mile to delivery of personalized medicine or getting genomics-based care.” In a statement that might give labs pause, he continues, “So many people feel like that’s just getting the lab test completed. But that’s just the first quarter mile.” Population genetics screening is just as much about tracking data in the system as reporting a result. “If you just have a scanned-in PDF of someone’s genetic test result, it’s very hard to do anything with that in the EMR.” And remember, says Dr. Hulick, “No EMR came out of the box ready to handle genomic information.”

The ideal EHR sounds like an Aston Martin, responsive to every new turn. At NorthShore, for example, “There’s been a major effort with our urology colleagues to raise awareness with BRCA2 in particular for prostate cancer risk,” says Dr. Hulick. Having those results in the EMR in a structured format could help push educational materials to patients in addition to doctors, updating them on what to do with the information. Prescribing physicians also have pharmacogenomic information (this testing is done in-house), with a clinical decision support alert system baked into the EMR, says Dr. Hulick.

All of these system-level approaches tie back to the educational piece, Dr. Hulick notes. “The goal with the EMR is to give enough information at the time of care, so that a clinician who is not an expert in genomics will have enough understanding to use that information effectively.”

As Dr. Ledbetter learned on his hero’s journey, case-based learning is indeed an effective way to reach and teach clinicians. “When it’s their own patient, it’s much more effective,” he says. “It’s altered a lot of our thinking about how to provide genetics information and support. It really needs to be point-of-care or just-in-time information.”

Well before results began landing in EHRs, however, came the decision to start chipping away at the Berlin Wall that has long separated research endeavors from clinical care, even when the former includes laboratory data that might be clinically important.

Geisinger’s MyCode team knew they’d be uncovering mutations like BRCA1 and BRCA2. “We were uncomfortable knowing that we were going to generate data that could be beneficial to our patients’ health,” Dr. Ledbetter says. That led to numerous focus groups, where patients expressed interest in receiving genetic data relevant to their health and that of their children and grandchildren.

Since Geisinger began returning such results, some 1,000 patients have been found to have a clear disease-causing genomic variant. They’ve been offered genetic counseling. Those whose variants are related to cancer are referred for imaging. “We’ve identified a number of early-stage cancers presymptomatically that we think improves patient outcomes,” says Dr. Ledbetter.

He points to several broader highlights as well. “For many Mendelian genetic diseases, when you screen a population by genetics, by sequencing the genes—BRCA1 and BRCA2, for example—the prevalence is double that reported in the literature through clinical ascertainment. And fully 50 percent of individuals do not meet the current guidelines, based largely on family history, for ordering a BRCA genetic test.”

When they started returning results five years ago, many in the genetics and biomedical ethics communities expressed concern about the possibility of psychological harm to patients who were unaware of their risks. Others feared it could lead to unnecessary testing. But, Dr. Ledbetter says, patient response has been almost universally positive, and it was matched by enthusiastic primary care physicians—to the point that in May 2018, Geisinger’s CEO suggested expanding genetic testing beyond the subset of MyCode volunteers to offer it to all Geisinger patients.

In July 2018, two primary care clinics began offering clinical exome sequencing to patients. Some 500 have undergone testing so far. And similar to the MyCode experience, patient and PCP response has been positive. “We’re pretty enthusiastic about continuing to expand,” Dr. Ledbetter says, although cost remains an obstacle to offering it to all patients right away. (Patients are not charged for the testing.)

One irony of precision medicine is that while it ultimately ends with the patient, it doesn’t start there. As Geisinger’s Melissa Kelly, MS, LGC, explains it, “We’re saying, almost irrespective of what your health status is, we’re just going to look at what variants you have and see which ones put you at risk. Or, explain a disease, but not using health status to inform what we’re looking at,” says Kelly, variant scientist, Geisinger Genomic Medicine Institute.

Making variants the focus helps tame the enormous scope of projects like MyCode. And by targeting variants that are “beyond reproach,” Kelly says, “it allows us to quickly filter down these massive numbers of variants and patients to a much more manageable number. When we find a variant, we know who’s at risk, we know what to recommend. That’s where we are right now.”

But later? “It’s an interesting question as we start to expand down the road. What other types of results would have utility for patients?” Kelly asks. Should standard carrier screening be included during reproductive years? “It’s less likely to change medical management, but it could change reproductive decisions.” What about risks for which there is no intervention? “We’ve decided not to approach those yet, but they’re definitely things we’re continually discussing.”

When Geisinger adds new genes, Kelly and her colleagues consider the CDC tier 1 genomic applications and the definition of actionability proposed by the ACMG’s secondary findings recommendations. But they also listen to their internal clinicians and researchers. “We basically allow clinicians and researchers to propose genes or conditions that they think would be valuable and meet some of those same criteria.” These genes are then thoroughly vetted.

And while a finding may be static, the knowledge behind the finding—or lack of findings—isn’t. Large screening projects will require regular queries to see what changes might be relevant to the patient population. If someone has a variant of uncertain significance, says NorthShore’s Dr. Hulick, “typically we have to be more passive in waiting for whatever lab issued the report to issue an amended report.” But “once we know what variants are in our system, we can query that against something like ClinVar [www.clinvar.com], so if some other lab has changed the classification, that may be a time when we instigate our own review.”

MyCode uses a very conservative bar to determine what pathogenic or likely pathogenic variants should be returned, Kelly says. Once the variant has been identified, it’s sent out for confirmation to a CLIA-certified clinical lab, which issues a clinical report. “That’s what we return to the patient, assuming we agree with their final classification,” says Kelly, who manually reviews every result.

Population screening versus diagnostic testing presents one possible classification hitch, Kelly says. “At least we think about it a little bit differently. If a patient has a disease and you find a variant that you think is causative, it almost starts you off at a higher a priori likelihood. But finding something incidentally in someone, particularly someone who doesn’t have any features, we feel you need a slightly higher evidence level to be able to return those variants to patients.”

Variant classifications encompass a spectrum of evidence rather than fall into discrete buckets. “A clinical lab might technically report a variant as likely pathogenic—but the evidence can range from just over the threshold from uncertain significance to just shy of pathogenic,” Kelly continues. “But we don’t want the variants that are straddling the border with uncertain significance. We want the variants that are in the middle or on the verge of being pathogenic. Because we only want to return variants that we have high confidence are putting someone at risk.”

She adds: “Collectively as a field, it will be interesting to see how this approach to variant classification evolves as more of this type of population screening happens, how much that approach is incorporated, and if there is confidence in that result not changing down the road. Our goal is to capture the variants that are so well vetted that no matter what we learn in the future, they will always stay pathogenic.”

Results are routed to patients through the genomic screening and counseling program that Sturm co-directs. “We upload the results into the electronic medical record and give them to patients’ primary care physicians, both internal and external to Geisinger,” Sturm says. A couple days after that, the genetic counseling team begins calling the patient-participants to provide them with their result.

“We send the report to their primary care physician in Epic, but we don’t release it to the patient in their MyChart portal,” Sturm says. “We make sure we call the patient to have a conversation with them first.” If, after three attempts, they fail to reach patients by phone, “we send them a packet in the mail and still ask them to call us.” Sturm and her team also refer them to specialty care and recommend family communication and uptake of cascade testing for all at-risk relatives.

Supporting the primary care physicians has also been crucial, and Sturm notes that these clinicians have been instrumental in deciding what they need; in fact, she leads a clinician advisory committee that meets every other month. Geisinger provides an on-call genomic counseling resource center, and physicians can ask questions through a number of portals.

That’s a far cry from early attempts, Sturm notes, which included lengthy CME modules to help PCPs learn about genetic conditions. No one was interested, she says. “What we heard is, Listen, I don’t need to become an expert in this condition. I just need to know the exact clinical next steps I need to take with my patient. And that may be referring them to a specialist.”

As Sturm noted earlier, anecdotal evidence has shown how the program can work for individuals. But Geisinger has also been doing health outcomes data collection. Those who’ve received results linked to familial hypercholesterolemia, Lynch syndrome, or hereditary breast and ovarian cancer syndrome appear to be using this information for positive health behavior changes, Sturm says, including cholesterol panels, colonoscopies, and mammograms. Those who opt for genetic counseling also show statistically significant correlation with higher positive behavior changes, she reports.

Her hope is that genetic screening will become the norm sooner in patients’ lives. She calls familial hypercholesterolemia “an example of what we are calling missed opportunity.” MyCode participants tend to be older and already have a significant degree of heart disease, stroke, and peripheral disease. Earlier identification and intervention would have prevented those diseases, she says. “I think this should be done at young ages,” she adds, noting that patients as young as eight can be put on statins.

Dr. Hulick thinks this type of testing will become a standard offering—though not a mandatory one—that’s dependent on a patient’s age and circumstances. While the entire genome might be sequenced, “you’re not going to access it all at once. But at key clinical time points in your life you’re going to tap into it.” This might include preconception counseling, or as patients near screening ages or anticipate a stage in life where they might begin taking medications.

While it remains important to find patients with single-gene conditions, those cases are a minority. “The real population impact,” says Dr. Hulick, will be combining polygenic risk factors with other traditional risk factors. “How do you start marrying all that information together?”

Like Geisinger, NorthShore has continually expanded its genetics testing. In April it launched the DNA-10K program, offering free genetic screening—using Color Genomics’ inherited cancer panel and cardiovascular panel—to up to 10,000 patients. Testing will also include several “fun” traits, or what Dr. Hulick calls “recreational genomics.” The last of the 13 participating primary care sites went live in early May. The endeavor also allows patients to sign up for NorthShore’s research arm, i.e. the Genomic Health Initiative.

Dr. Kaul reports there are currently about 20,000 samples in the GHI biorepository; about 30,000 patients have consented, which they do online through the patient portal. The order is automatically teed up, and the next time a patient has a blood sample taken, for whatever reason, an extra tube will be collected for the research study.

Says Dr. Kaul: “We are managing all the collections and DNA production and disbursement of samples. It’s like another lab test,” involving phlebotomists, bar codes, special biorepository software. “So the lab is deeply ingrained in all that.” (The lab is less involved in the DNA-10K study, she says, though it does perform collections.)

But that’s it for the lab, at least for now. Says Dr. Hulick: “We’ve worked quite a bit with Dr. Kaul in terms of prioritizing what we should do in-house.” Clearly the expertise was there, he says, but the capacity was not. “We do somatic testing in-house because turnaround time is more critical,” Dr. Hulick says, and NorthShore’s own lab can work with very small sample sizes and integrate genomic with other testing needed to optimally use the tissue or cells. For the population genomics testing, however, NorthShore has partnered with multiple outside companies, including Ambry Genetics, Invitae, and Helix, as well as Color.

Dr. Kaul says she was a bit disappointed when she first learned that the projects would be relying on outside labs. “But it makes sense,” she says, given the focus on population screening rather than diagnostics. “The throughput and price points are much different than we could accommodate, and much different than most hospital labs could accommodate.” Down the road, of course, it might be a different story.

At Geisinger, it likewise made sense to outsource the sequencing to Regeneron, says Dr. Ledbetter, but “We’re still evaluating what it will take to build a high-throughput sequencing capability within Geisinger’s pathology lab medicine department. They’re very interested,” he says, “but we are not yet at the point of doing this in-house.”

As the cost of sequencing drops and databases for interpreting pathogenic variants improve, will every hospital do its own sequencing? Or will this become centralized in a smaller number of national reference labs? Both approaches have their pluses and minuses, says Dr. Ledbetter. “I’m not sure yet where it’s going to end up.”

For now, Dr. Kaul says, labs need to understand a key point. “This is happening. We need to recognize there’s a lot going on outside our walls. Our colleagues in primary care do get patients coming in with a 23andMe report.” She says she’s thrilled to see her PCP colleagues embrace the programs that are bringing them into the center of this. “It’s great for our whole hospital system that they’re really engaged and are driving this.”

She remains struck by one novelty in particular. “Something that’s been interesting to watch here at NorthShore is that it’s not all about the lab,” says Dr. Kaul. Then again, in the years ahead it might be. “Someday, are we going to have whole genome sequencing on every bench? I don’t know. I used to think I would never utter the words ‘point-of-care PCR’ in the same sentence, and obviously that’s come to pass.”

“It may be that we have whole genome sequencers, with all the data analytics onboard, sitting in every lab in 10 years, and this will be commonplace and done in every hospital,” she says. Despite having spent 30-plus years in molecular medicine, Dr. Kaul says the field continues to amaze her. “It’s just mind-boggling. I have learned not to doubt any possibility.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.