PRecision medicine

PRecision medicine

Precision Medicine By Claudia S. Cop elan d, Ph D

HARNESSING THE EXTRAORDINARY GROWTH IN MEDICAL DATA FOR PERSONALIZED DIAGNOSIS AND TREATMENT

PRecision medicine

If the prime mission of today’s physician is medical decision-making, medical doctors are on the verge of a major upgrade in effectiveness. Advances in technology are bringing the worlds of bioinformatics, molecular biology, biochemistry, and medicine together to yield individual patient-based data as never seen before. From cancer recurrence risk to likely response to treatment, the era of using precise patient-based data to inform decision making is dawning. The potential of precision medicine extends well beyond genomics, however—future applications range from other “omics” data types, such as transcriptomics, proteomics, and metabolomics, to cutting-edge imaging technology. These advances can provide a wealth of information on individual patients and their illnesses. Together, they are laying the groundwork for a transformation in the dominant clinical paradigm: from general, illness-based medicine to patient-based, personalized medicine.

New Tools for Precision in Diagnosis and Treatment

receptor positive, HER2-positive, and tri-

and Medicare) is a gene expression assay

ple negative. Of these, all but triple negative

known as the Oncotype Dx® . To determine

have specific treatments based on expressed

the chance of recurrence of breast cancer,

To make effective clinical decisions, MDs can

genes. Even for subtypes that do not have

the test analyzes the activity of 21 genes to

use laboratory tests, histories, and physi-

individualized treatments, such as triple

yield a highly precise picture of the indi-

cal exams, but when it comes to difficult or

negative, knowledge of subtype is useful

vidual cancer the patient is suffering from,

unusual cases, finding the right diagnosis

because it clearly establishes the impor-

including the likelihood that the breast can-

or treatment has traditionally been, in large

tance of chemotherapy (in fact, some evi-

cer will return and the likelihood of benefit-

part, a process of trial and error. A number of

dence suggests that chemotherapy is more

ing from chemotherapy at the early stage

new tools are being developed to empower

effective in triple negative breast cancer

of the cancer. Based on the test results, the

physicians to make more informed decisions

than in hormone-receptor positive breast

Oncotype DX assigns a Recurrence Score

up front, especially in the realm of com-

cancers) and other tailored treatment regi-

that reflects the likelihood of the cancer

plex, individual diseases like cancer. Some

mens, such as neoadjuvant therapy (chemo-

recurring. For example, for early stage

genomic assays are already mainstream,

therapy before surgery).

invasive breast cancer, scores lower than 18

such as testing for BRCA genes. Several

!eoretically, tumor profiling based on

indicate a low risk of recurrence (suggesting

other approved genomic tests exist to clas-

gene expression could look at hundreds of

that the benefit of chemotherapy is likely

sify different types of cancer based on tumor

genes in a tumor. While this level of pre-

to be small and will not outweigh the risks

genetic profiles. Leading these are assays to

cision would have been science fiction a

of side effects); scores of 18-30 reflect an

distinguish different subtypes of breast can-

few decades ago, it is currently in devel-

intermediate likelihood of recurrence (risk/

cer, such as estrogen receptor positive (the

opment and steadily marching forward

benefit ratio unclear); and scores greater

most common type of breast cancer, with

towards approved clinical use. Already in

than 30 indicating a high risk of recurrence

a relatively good prognosis), progesterone

wide use (and covered by most insurance

(benefits of chemotherapy likely outweigh

22! NOV / DEC 2016  I  HEALTHCARE JOURNAL OF NEW ORLEANS! 

patient age. Other tailored genomic tests are also available, including the Breast Cancer Index test, used to predict the risk of nodenegative, hormone-receptor-positive breast By The U.S. Food and dr Ug adminiSTr aTion (Fda_LaB_aTLanTa_2050) via Wikimedia CommonS

cancer coming back 5 to 10 years after diagnosis; the EndoPredict test, used to predict the risk of distant recurrence of early-stage, hormone-receptor-positive, HER2-negative breast cancer that is either node-negative or has up to three positive lymph nodes; the MammaPrint test, used to predict the risk of recurrence within 10 years after diagnosis of stage I or stage II breast cancer that is hormone-receptor-positive or hormone-receptor-negative; the Mammostrat test, used to predict the risk of recurrence of early-stage, hormone-receptor-positive breast cancer;

“Theoretically, tumor profiling based on gene expression could look at hundreds of genes in a tumor. While this level of precision would have been science fiction a few decades ago, it is currently in development and steadily marching forward towards approved clinical use.”

and the Prosigna Breast Cancer Prognostic Gene Signature Assay (formerly called the PAM50 test), used in predicting the risk

recurrence risk. !e Oncotype DX Prostate

of recurrence for postmenopausal women

Cancer Test measures the amount of RNA

within 10 years of diagnosis of early-stage,

expressed by 17 genes predictive of risk and

hormone-receptor positive cancer.

probable treatment response. Such a test

In addition to breast cancer, molecular

may be especially helpful for this type of

testing is now a routine part of patient care

cancer, since aggressive treatment can lead

risks of side effects). Another assay assesses

for lung cancers, colorectal cancers, mela-

to sexual, bowel, and bladder side effects

the likelihood of benefiting from radiation

nomas, leukemias, and others. In fact, Onco-

that are highly distressing for patients. An

therapy for ductal carcinoma in situ (DCIS),

type Dx tests similar to the ones for breast

assay that can identify men who can safely

the most common type of non-invasive

cancer have also been developed for two

forgo aggressive treatment in favor of a pro-

breast cancer.

other cancer types: colon cancer and pros-

gram of active surveillance and monitoring

As with all genomic tools, the results are

tate cancer. !e Oncotype DX®Colon Cancer

over time can radically improve the quality

an aid to diagnosis, along with other, more

Assay analyzes the expression of 12 genes in

of life for these patients.

traditional factors such as tumor size and

a sample of colon tumor tissue to quantify

!e CDC lists over 90 genomic tests

THE GENOMIC ACCESS PROGRAM In order to assist with verifying insurance coverage and obtaining reimbursement, Genomic Health, the makers of the Oncotype Dx assay, offer a program called the Genomic Access Program. If you do not have or cannot secure insurance coverage, the Genomic Access Program may be able to help. Various forms of nancial assistance and payment plans are available for people facing nancial hardships or those who are uninsured or underinsured. The Oncotype DX test costs about $4,000. For insurance- and payment-related questions, call 1-866-ONCOTYPE (1-866-662-6897). ! HEALTHCARE JOURNAL OF NEW ORLEANS I  NOV / DEC 2016! 23

PRecision medicine

Dr. Miele believes that “a critical element in the use of precision medicine is clear clinical guidance for health care providers, patients and patient families.” with Tier 2 approval (FDA label mentions

Meanwhile, though, several small compa-

biomarkers; Medicare/Medicaid coverage

nies are moving forward with genetic tests

with evidence development; clinical prac-

that have not yet gone through the clinical

tice guidelines and systematic review either

approval process, with results given to the

support use of the test or do not discour-

physician in the form of a “research report”

age use of the test). !ese include prog-

rather than a “clinical report”. It is made

prothrombin gene (G21210A). If a G [has

nostic, preventative, or diagnostic tests for

clear to both the patient and the physi-

been mutated] to A in this gene, the patient

several diseases, including prostate cancer,

cian that this is NOT a clinical lab report,

is identified as positive for venous thrombo-

non-small cell lung cancer, acute myeloid

but the physician can use the informa-

sis or heart disease. !e NIH has spent a lot

leukemia, colorectal cancer, single gene

tion as supplementary data; it is up to the

of money and found out that this mutation

disorders, and rare familial diseases. !ere

physician to evaluate what can or cannot

is very important in humans. !ey do not

are also Tier 2 pharmacogenomic tests, to

be concluded from the data. Dr. Ayyampe-

even look at other mutations in this gene.

predict drug response for a wide array of

rumal Jeyaprakash is Chief Research Offi-

My real-time PCR test is then tried on 20-40

conditions, from arthritis and bronchitis to

cer of NCF Diagnostics and DNA Technol-

patients. !e same patients are also tested

insomnia and depression.

ogies in Gainesville, Florida, a company

by another well-known DNA test like PCR-

Dr. Lucio Miele, head of the LSU School of

that has designed several proprietary gene

RFLP. If the tests are 100% matching, then

Medicine Department of Genetics, described

tests to detect mutations linked to herita-

I receive 6 blind samples from the Medical

some of the genomic techniques currently

ble diseases. Dr. Jeyaprakash, who uses next

Board every 6 months. My real-time PCR

being used at LSU: “We use primarily exome

generation sequencing (NGS, the power-

test should pass every 6 months and score

panels and gene expression tests. Exome

ful sequencing technique that is enabling

100%. After this, I am allowed to sell the test.

panels are used in several settings (congeni-

affordable whole-genome sequencing) for

Patients can send samples only through the

tal disorders subject to “diagnostic odysseys”,

screening crop plants for plant pathogens,

doctor. I do the testing, generate a ‘Clinical

neurology, and oncology). Gene expression

explains that NGS testing for human dis-

Report’ and pass it on to the doctor. He can

tests are routinely used in the management

eases is still in the research stage. Some

now treat the patient using this information.

of breast cancer and are being expanded to

companies are doing it, but since it is con-

I now have Heart Disease Gene tests and

other indications. Specifically in oncology,

sidered research data, insurance companies

Drug Sensitivity Gene tests.”

we are currently enrolling patients in the

will not pay for it. Instead, the current focus

DNA is not the only biological sequence

MATCH clinical trial, a large NCI-funded

in human disease is on more specific tests.

data with clinical potential. Beyond genom-

study which assigns patients to one of 24

Getting approval for a clinical test is a

ics lies the analytical potential of transcrip-

different treatment arms depending on the

highly standardized process that is quite

tomics (RNA sequence analysis), proteomics

results of a genomic panel. Additionally, we

different from that of developing a scien-

(amino acid sequence analysis), metabolo-

will soon offer pharmacogenomics testing,

tific technique, Dr. Jeyaprakash explains.

mics (analysis of small-molecule metab-

to determine how the genetic makeup of

“I will describe a test that I designed. First,

olites), and other “omics” analyses. New

specific patients affects the way their bodies

the lab needs to be approved by the Board.

Orleans-based Pine Biotech is develop-

handle different medications.”

!ey come and check that you have got all

ing a platform to provide a user-friendly

the equipment and facilities. !en the lab

interface for non-bioinformatician biolo-

workers need to get licensed to handle DNA.

gists and clinicians to harness the power

Without a molecular biology license you

of multi-omics analysis. “Collectively, we

cannot work in the clinical lab. A PCR, Real-

have been investing time and money into

New tests are being developed every day,

Time PCR, and Sanger Sequencing assay

understanding the molecular machinery

and many are moving towards approval.

was designed to detect one mutation in the

inside every cell,” states CEO Elia Brodsky,

Small Companies: The Vanguard of Clinical Genomics

24! NOV / DEC 2016  I  HEALTHCARE JOURNAL OF NEW ORLEANS! 

Dr. Lucio Miele

PRecision medicine

Infrared absorption spectra of typical constituents of cells and tissue. ABOVE Examples of two pixel spectra of liver tissue. The top represents a spectrum of diseased liver, whereas the bottom spectrum is from normal liver tissue. The two spectra differ mostly in the glycogen content.

LEFT

“Researchers now know that the complex

process is critical. Provider education is

sample to determine characteristics of chem-

network of relationships between genetic

equally important. LSUHSC will organize

icals. By looking at specific wavelengths of

code, proteins and intra-cellular commu-

CME events focused on precision medi-

light absorbed or reflected by a sample, func-

nication holds the key to solving some of

cine, beginning in the spring of 2017. Pre-

tional groups and other characteristics of the

the most pressing challenges in health-

cision medicine is the way of the future,

chemical can be determined. For example,

care - from cancer to chronic diseases, to

and we need to keep accumulating data to

proteins will have a different infrared spec-

infectious diseases. !is data can be cap-

refine our predictive algorithms and clini-

troscopy “signature” from those of lipids, fats,

tured on an individual level and analyzed

cal guidance. Additionally, the incorporation

and carbohydrates. At Cireca, they work with

for previously undetectable irregularities.”

of genomic/multi-omic data into electronic

this basic principle to determine key bio-

His vision is to “enable researchers and cli-

health records in ways that are easily acces-

chemical characteristics of tissue samples;

nicians to extract real insight from omics

sible for analysis (as opposed to reports in

most notably, characteristics associated with

data; we hope that new and more effective

PDF format) is a fundamental need for clini-

cancer tissue. Key to the technique, known as

approaches to diagnostics and therapeutics

cal use of genomics. !e data science aspect

infrared spectral histopathology, is the fact

will be developed. Eventually, the efficiency

is the most crucial one, and requires close

that cancer tissue differs from normal tissue

of early detection and new targeted thera-

interactions between clinicians, geneticists,

on a biochemical level, and these differences

peutics will translate into longer, healthier

bioinformaticians and biostatisticians.”

can be visualized using spectroscopy-based

lives for patients, with fewer side effects and cheaper treatments or even completely new

imagery. Using this technique has an addi-

Visualizing Tissue Biochemistry

tional advantage: none of the sample needs to be destroyed to run the test; light is sim-

ways to manage disease.” !e view from LSU dovetails with Pine’s

Sequence data are not the only type of

ply shone through the histopathology slides,

mission of providing user friendly tools

patient information used in precision medi-

leaving the samples unaltered and available

and support for omics analyses. Empha-

cine. One particularly innovative approach to

for any other analysis.

sizing the role of guidance and accessibil-

diagnosis is being developed by Cireca !er-

Bioinformatic analysis of the spectros-

ity in the adoption of precision medicine

anostics, LLC. Cireca combines biochemis-

copy data is essential to the technique,

tools, Dr. Miele believes that “a critical ele-

try, infrared spectroscopy, and imaging tech-

explain Cireca scientists Max Diem and

ment in the use of precision medicine is

nology with powerful software to develop

Aysegul Ergin. Infrared spectral imaging is

clear clinical guidance for health care pro-

images from histological slides—images of

carried out on 5 mm-thick tissue sections

viders, patients and patient families. !e

things the human eye can’t see. Chemists

measuring from a few mm2 to cm2 in area.

role of certified genetics counselors in this

have long used light shone on or through a

!e slide image is then divided into pixels

26! NOV / DEC 2016  I  HEALTHCARE JOURNAL OF NEW ORLEANS! 

LEFT For spectral imaging, 100,000 to millions of infrared spectra are collected from pixels ca. 5 µm on the edge of the tissue sample. The pixel size is about the size of the nucleus of a cell. These spectra constitute a “hyperspectral datacube” shown at left. Here, each pixel spectrum is defined by the x and y coordinate of the pixel from which the spectrum was collected. The protein and glycogen peaks in this datacube are clearly detectable.

RIGHT Infrared spectral imaging allows the rich infrared spectral signatures of biological compounds to be exploited. Here, a section of tissue was stained using the classical H&E stain, and imaged using a standard microscope (left). The right image represents the infrared-based pseudocolor (SHP) image from the same tissue, obtained using the Cireca methodology. The structures detectable by a pathologist in the left image correspond very closely to the features in the right image.

Dr. Ayyamperumal Jeyaprakash

of about 5 mm square, which represent a

prescribe therapies with precision and tar-

cube with all edges 5 mm in length. Within

get tumors with the most effective therapy,

each of these pixels, between 100,000 and

but they first must know as much as possible

several million infrared spectra are col-

about the cancer cells and tumors they are

lected. Collectively, these spectra consti-

facing. It’s essential to know more than we

tute a “hyperspectral datacube”. Powerful

do today to improve the chances for every

computational technology then assembles

patient having this terrible disease.” !e data

this massive amount of imaging data and

Cireca provides, he continues, could be par-

either uses it for machine learning analysis

ticularly useful for both early detection of

or transforms it into a color representation,

cancer and late-disease precision treat-

called a "pseudo-color image", with all simi-

ment planning. “We bring new information

lar spectra assigned the same color. Looking

in the form of a biochemical signature of the

at such an image side-by-side with a nor-

tumor cells and microenvironment, working

mal H&E stained histopathology image, they

with very small samples that are otherwise

clearly represent the same sample, with the

not useable with conventional methods for

H&E image showing the morphology of the

diagnosis. We think this will add precision

tissue and the Cireca image visualizing the

where its needed: early in the disease cycle,

biochemical nature of the tissue. Essentially,

and when it’s so advanced that surgery isn’t

this allows a pathologist to look at the cells

possible and the remaining hope is well-tar-

in a tissue sample "inside and out", with a

geted therapy [based on] as much informa-

level of precision far surpassing anything

tion as possible.”

possible with a conventional image. Cireca’s goal is to enable pathologists

Visualizing Drugs in the Human Body

and oncologists to gain a highly precise picDr. Aysegul Ergin

ture of a biopsy sample. “Patients want to

In another perspective on “inside-out” imag-

know exactly what type of cancer they have,

ing, Vyripharm Biopharmaceuticals of Hous-

they need to know this,” Stan Remiszewski,

ton is focused on personalized medicine via

Vice President of Research & Development

real-time visualization of drug metabo-

at Cireca, explains. “Oncologists want to

lism. Vyripharm is developing drugs with

! HEALTHCARE JOURNAL OF NEW ORLEANS I  NOV / DEC 2016! 27

PRecision medicine

Vyripharm uses “a chelator-based technol-

this because saving time and testing means

ogy that allows us to add a metal to the drug

saving money, the value goes well beyond

that will allow for an imaging of the drug

simple efficiency—time wasted can mean

in the actual patient’s body.” So, in a hypo-

progression of a disease and unnecessary

thetical clinical use, “in the beginning, the

patient suffering.

patient will come in and the physician will

Perhaps most importantly, though, this

do the imaging with the medication, to cal-

imaging technology enables precision

culate the correct dosage with the patient--

dosing, and that can save lives. “Individu-

see how much is being taken up by the body.

als respond differently to different drugs,”

Based on that, the physician will determine

emphasizes Dr. Jackson, “there are a lot

how much to put the patient on. Depending

of deaths and serious adverse effects sur-

on the patient, the doctor may monitor him

rounding the misdosing of drugs. It’s ter-

or her, giving the drug with the imaging agent

rible that physicians have to deal with that

[as treatment]. !e patient would come in at

since their goal is to help patients.” Getting

the end of each week and we’ll take an image,

the dose right can save lives before a drug

or they could just come in at lunch and take

even gets to the doctor’s office. Precise dos-

an image. If everything’s great, they can just

ing in clinical trials could allow effective,

move forward with the medication.” If not,

life-saving drugs to be approved that would

chemical markers that allow them to be visu-

though, the doctor has gained power in a few

not have been approved otherwise. “!ere

alized as they move through the body, using

major ways: first, he or she can see what is

are drugs that have had potential, but there

standard clinical imaging methods such as

happening with the drug and decide on the

was no way to determine the correct dose.

PET, CT, or MRI. Using this technology, doc-

next drug to try based on individual patient

Many drugs haven’t made it to the market

tors can make precise, personalized deci-

characteristics; for example, the drug may

because of adverse effects; they couldn’t get

sions about optimal dose and which drug will

not localize well to the target organ in this

the right dose.” While many important tradi-

work best in that particular patient, President

patient. Second, it saves the time involved in

tional drugs, such as morphine, have narrow

of Research and Development Elias Jackson

a watch-and-wait process of trying a drug,

therapeutic index ranges, a new drug with

explains. To visualize the action of a drug—

seeing if it works, and if not, trying a differ-

a low therapeutic index will most probably

uptake, metabolism, etc.—in the patient,

ent drug, etc. While payers are interested in

not be approved, no matter how effective it

Dr. Elias Jackson

may be. “A dose of 10 mg may be good for some people, but fatal for others. It may be effective, but that therapeutic window might be so narrow that 5 people in the trial die. Now [using drug imaging technology] we can avoid those fatalities.” Dr. Jackson can’t emphasize the importance of precision dosing enough. He pauses after telling of volunteers who suffered severe neurological injury (one of them died) in a clinical trial in France. !e dose in the hospitalized volunteers was 40X the clinical dose, and this high dose overwhelmed the elimination mechanisms in their bodies. Had dosing been done with more precision, accumulation would have been detected early, the volunteers would have been taken off the drug, and the drug might be available today, albeit with an overdose warning. “If our technology had been used, the correct doses for those drugs would have been used, saving those patients. It’s basically a game-changer.” 28! NOV / DEC 2016  I  HEALTHCARE JOURNAL OF NEW ORLEANS! 

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