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PRECISION MEDICINE CENTER PROFILE: The Center for Individualized Medicine, Mayo Clinic by Alla Katsnelson, Ph.D

In its 150-year history, the Mayo Clinic has stayed true to its patient-centered model of care. That same vision has guided the trajectory of its precision medicine initiative, the Center for Individualized Medicine. The idea behind the Center, which launched five years ago, was to create a new entity within the institution that was positioned to engage existing centers and departments as the vision and reach of precision medicine evolved. For this reason, too, the Center was conceived as an enterprise-wide effort, involving clinicians and researchers at the Minnesota, Arizona, and Florida campuses. At the three sites combined, Mayo sees some 1.4 million patients each year, and the aim was to bring genomic medicine to as many of these patients as possible. Rather than pursuing large-scale genomics or bioinformatics efforts, says Keith Stewart, professor of medicine and the Center’s director, “we’ve been more and more focused on delivering the power of genomics to the bedside.”

We’re beginning to diversify into areas that aren’t traditional grounds for such efforts.

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PRECISION MEDICINE CENTER PROFILE: The Center for Individualized Medicine, Mayo Clinic by Alla Katsnelson, Ph.D

The Mayo Clinic’s roots in precision medicine

run deep. The institution was one of the

pioneer members of the Pharmacogenomics

Research Network, a nationwide collaboration

funded by the National Institute of General

Medical Sciences studying how genetics affects

patients’ response to medicine which ran from

2000 to 2015. It also participates in another

long-standing network, the eMERGE network,

funded by the National Human Genome

Research Institute which investigates how to

join electronic health records to genomic data

to gain insights into disease pathology and drug

response. A great deal of scientific and clinical

evidence has already demonstrated the clinical

utility of pharmacogenomics testing to help

avoid drug adverse effect and maximize drug

efficacy. That makes pharmacogenomics one of

the areas in genomic medicine that can already

be implemented in the clinic.

To achieve this goal, the Pharmacogenomics

Program, one of the Center’s six translational

programs, established a Pharmacogenomics

Task Force to identify drug-gene pairs for

which there was enough clinical utility to

develop a genetic test, says Liewei Wang,

Liewei Wang, professor of pharmacology and

the Pharmacogenomics Program’s co-director.

So far, 19 such pairs have been vetted, and tests

have been adopted in the clinic and linked

to patients’ medical records. That means if

a physician prescribes one of these drugs, he

or she will be alerted by the system to test the

patient’s genotype to make sure they don’t

carry a mutation that would alter how they

metabolize the drug or put the patient at risk

for a serious adverse drug reaction. “Mayo, and

particularly the Center for Individualized

Medicine, really put a lot of resources, effort,

and talent into developing the infrastructure

needed to implement these genetic tests and

ultimately establish a program that offers

clinical genomics for everyone,” says Wang.

“To be honest I think that no other institution

is doing it on this scale.”

This set of tests was just the first step. In order

to proactively determine patients’ pharmacog-

enomic status, Mayo sequenced a set of drug

metabolism and other “pharmacogenes” in

1013 of its patients whose samples reside in the

institution’s vast biobank. “To our surprise,

what we find is that 99% of local patients have

at least one actionable variant among the top

five pharmacogenes – five well-known genes

that metabolize more than half of all drugs

on the market,” says Wang. “The finding truly

confirms that pharmacogenomics represents

clinical genomics for everyone,” she adds. Last

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The other arm of the Clinomics program

addresses what Lazaridis calls diagnostic

odysseys – rare disease cases that are suspected

to be genetic but that have never been

diagnosed. By identifying where whole exome

sequencing might be helpful and following the

path to where it might lead, the program has

been able to provide diagnoses to some 30%

of patients, and for a small percent within

that to figure out how to treat them based

on knowledge of the genetic target. “We

know that this 30% holds very well – other

centers see the same outcomes – but the

question for us is, how can we turn this 30%

into 40% or 50%,” Lazaridis says. In many

patients for whom a diagnosis isn’t reached,

he adds, there are hints that the mutation is

a new one that has not been reported before.

“We have to functionally interpret all these

genetic variations we find for all these

unsolved cases, because that’s where lots

of discoveries will be made.”

The program started by performing clinical

grade whole exome sequencing in just 10

patients on a diagnostic odyssey in 2012 and

will complete more than 300 exomes for the

clinical care of an equal number of patients

in 2016 alone, a thirty-fold increase, Lazaridis

said. He estimates that his Individualized

Medicine Clinic has seen about 1600 patients

over the past five years, though not all have

undergone sequencing. Early on, cases

addressed by the Clinomics Program were

neurological conditions in children, but the

aim now is to expand the offering to other

conditions that might benefit from the

approach, such as gastrointestinal, cardiovas-

cular and neurological disorders. Patients seen

in childhood tend to have severe phenotypes,

but for those with milder symptoms getting a

diagnosis later in life can still be tremendously

helpful. The program also aims to expand its

base in predictive genomics, sequencing

people with common chronic conditions,

who traditionally had no strong evidence of a

genetic disease, with the goal of sequencing

10,000 exomes in the next year, Lazaridis says.

“We would like to make sequencing for clinical

care available to patients and providers – and

then it will be part of their medical record.

Our goal is to prove this information will be

useful for years to come.”

Perhaps at an earlier stage of clinical application

compared to the other five translational

programs is the Center’s Microbiome Program.

“The major effort there is to revolutionize and

transform the way we diagnose and perhaps

even manage infectious disease,” says Stewart.

Step one is replacing classic cultures with next

generation sequencing, which can more easily

identify microbial species and is more appli-

cable for assessing outbreaks and antibiotic

resistance. “Being able to use these tools to do

forensic work to figure out how a pathogen is

transmitted will really help us in the future,”

says Heidi Nelson, professor of surgery, who

directs the Center’s Microbiome Program. As for

the longer view, though it’s still in the research

phase, the Microbiome Program aims to look

more broadly at wellness and at environmental

influences on health, focusing on areas such as

bowel health, personalized nutrition, and

probiotics. “We see the potential to really

understand what is a healthy state for each

person, and to figure out the guiding principles

for balance versus imbalance,” says Nelson.

While most precision medicine initiatives

have so far focused on cancer, Mayo is reaching

into areas such as cardiovascular disease,

neurology, gastroenterology, and most recently,

hematology. “We’re beginning to diversify

into areas that aren’t traditional grounds for

such efforts,” says Stewart. The institution is

also partnering with the San Francisco-based

consumer genomics company Helix to develop

an app for consumers to use. “Through it we

think we will introduce many of them to

genomics at the consumer level, which will

increase peoples’ interest in having medical

testing done in the genomic space.”

year, the Pharmacogenomics Translational

Program expanded this sequencing project

to include 10,000 biobanked individuals.

Collaborating with the genome center at the

Baylor College of Medicine, the plan is to

sequence these genes using a CLIA-approved

assay and identify the actionable variants,

and then include this information in patients’

electronic medical records. Ultimately, the

goal is to test all of Mayo’s patients in this

prospective manner, but meanwhile the intent

of this study is to demonstrate that collecting

pharmacogenetic information would benefit

patient care, improve clinical outcomes and

save money for the health system – and

ultimately, for insurers.

The Pharmacogenomics Program is also

tackling treatment response to cancer drugs.

In one ongoing study, called BEAUTY, women

with breast cancer who are at high risk of

recurrence have their tumors sequenced; the

sequence as well as xenografting into mouse

avatars can help both discovery and trans-

lational studies to determine whether their

unique mutations can point to additional

targets for therapy. The infrastructure from

this study is also being applied to similar

studies in other cancer types, Wang says.

Cancer is also the focus of one arm of the

Clinomics Program, another translational

program at the Center for Individualized

Medicine. The idea behind the program is

to push the application of insights gleaned

through genomic medicine into clinical

practices, says the program’s director,

Konstantinos Lazaridis, professor of medicine

at Mayo. Exome sequencing in somatic and

tumor DNA of patients with advanced cancer

can reveal treatments that might target an

individual’s mutations. Liquid biopsies, too,

are a big focus for detection. “We strongly

believe that’s very much going to be a key

part of the future of how we manage cancer

patients, and we have several large initiatives

coming out in this space,” says Stewart. Alla Katsnelson, Ph.D, is an independent science writer

and editor based in western Massachusetts.