VENTURES
Genomic Health
For many of us, the ability to
select from and customize
products to suit our individual
needs has long been a given.
From personalized ringtones to tailored
wardrobes, we consume products everyday
that match our personalities and needs.
However, some of the most important
products on the market, pharmaceuticals,
have lagged behind in their adaptation for
individualized use.
The Problem of Mass
Drugs
In a controversial statement at the end of
2003, Allen Roses, worldwide vice-president
of genetics at GlaxoSmithKline (GSK), said
fewer than half of the patients prescribed
some of the most expensive drugs actually
derive any benefit from them. Many factors,
ranging from drug concentration to rate of
absorption to target of action, all play crucial
roles in determining the functionality of a
pharmaceutical agent. However, while the
drug itself may be administered consistently,
individual genetic differences can also affect
the ultimate efficacy of drug treatments.
In life-threatening diseases such as
cancer, this is especially bad news. Drug
response rates for cancer therapeutics are
at times below 20%, and side effects from
chemotherapies include extreme fatigue,
nausea, diarrhea and hair loss. Often times,
patients and their families are further
burdened by the staggering cost of these
pharmaceuticals. Two of today’s most
popular cancer therapeutics, Herceptin
and Avastin, cost about $3,100 and $4,400
per month, respectively. As a result of the
low benefit, high risk and hefty prices of
these drugs, there is growing demand
for alternatives that will better select
the correct, individualized treatment for
patients.
The rise of molecular
diagnostics
In recent years, the push for customized
regimens and personalized care has spurred
the growth of personalized medicine.
stanford scientific
written by RYAN TONG
The completion of the Human Genome
Project in 2003 opened new doors for
research, which is in turn increasing our
understanding of genetic composition.
The subsequent application of genomic
knowledge to medical decision-making
has blossomed into a new field known as
pharmacogenomics, the tailoring of drugs to
a person’s specific genetic makeup.
At the forefront of this revolution is the
billion dollar molecular diagnostics industry.
Using biochemical assays, molecular
diagnostics measure the gene expression
profiles of patients and can correlate the
findings with disease prevalence. Molecular
diagnostics can look for biomarkers in a
patient’s genome expression pattern to
match a patient to the correct drug regimen.
Such diagnostics are already being used
by physicians to make informed treatment
decisions for HIV, Human Papiloma Virus,
Hepatitis C and cancer.
A Model Example
Genomic Health, a publicly traded
biotechnology company located in
Redwood City, California, was one of the first
to pioneer the field of molecular diagnostics.
One of the company’s primary products,
Oncotype DX, is a genomic assay which
assesses and predicts a patient’s likelihood
of breast cancer recurrence and response to
first line therapeutic treatments.
Within two weeks of receiving tumor
samples from the patient, Genomic Health
can analyze the expression of 21 genes
clinically correlated with the development
of breast cancer. These results are used to
calculate a score between zero and one-
hundred, which denotes that individual’s
risk of relapse. The raw score can be used
to identify low versus high risk patients;
however, it can also be adjusted to account
for different treatment regimens.
“The true value of our assay lies in its power
to predict how well a patient will do 5 to 10
years down the road”, says Maureen Cronin,
VP of Translational Research at Genomic
Health. “The information is valuable to
physicians, patients and payers in making
the right treatment decisions.”
Developing the Gene
Panel
The Oncotype DX is a multi-analyte assay,
meaning that it measures the mRNA
expression levels of 21 genes from multiple
families correlated with the occurrence of
breast cancer. But how did Genomic Health
select this particular panel of genes from
approximately 30,000 genes in the human
genome?
“By going through a combination of cancer
literature, genomic databases, molecular
biology studies and microarray data…we
assembled an initial panel of 250 cancer-
related genes”, says Cronin. From those
candidate genes, the company then
conducted three independent exploratory
studies with 447 patients to verify the
correlations in the expression of each one
of the genes with respect to relapse-free
survival rates in cancer patients. From the
correlation studies, 21 genes were selected
for the final panel.
Genomic Health then followed up by
validating Oncotype’s ability to assess the
benefit of Tamoxifen treatment in patients
with low to medium scores (0-30). As a
final test of their product’s predictive
rigor, the company used preserved tumor
samples of 790 patients with breast
cancer and successfully predicted their
individual outcomes after Tamoxifen and
chemotherapy treatments.
The Major Players
The 21 genes measured in the assay can
be categorized based on their functions in
the cell. The first group is involved in cell
proliferation, and includes genes such as Ki-
67, a nuclear protein regulating the cell cycle,
and STK 15, which modulates chromosome
structure during mitosis. Because most
cancer cells differ from normal cells by their
indefinite growth and proliferation, the
examination of genes involved in cell cycle
regulation is important in deciding whether
normal cells have the propensity to turn
cancerous.
Genes in the second group are indicative
of a tumor cells’ propensity to metastasize
and include genes like Stromelysin 3,
which codes for a matrix metalloproteinase
implicated in cell migration.
The third family is comprised of genes
involved in the expression of the Her2
cell surface receptor. Her2 receptors
are believed to homodimerize and
autophosphorylate each other when over-
expressed. This activates a cascade of
intracellular signaling pathways that result
in uncontrolled cell proliferation and tumor
development.
The final set of genes is those which
govern the activities of the estrogen and
progesterone receptors. Because hormones
such as estrogen and progesterone are
important in stimulating cell and tumor
growth, a measurement of the receptors’
response to hormone signals can suggest
whether a patient would benefit from
hormone therapy.
Aside from these four main families of
genes, the assay also measures a set of
control genes, like GAPDH, a constitutively
expressed housekeeping gene which can
be used to normalize changes in specific
gene expression levels between patients.
Normalization is especially important
because the contribution of each gene’s
expression to the score calculation is
weighted depending on its family’s overall
correlation in causing breast cancer. For
example, over-expression of genes in the
Her2 and proliferation groups has been
shown to cause breast cancer, and is thus
more heavily weighted than over-expression
of the hormone receptor family, which
decreases the likelihood of recurrence.
“This is a much more accurate prediction of
patient outcome than traditional prognostic
measures like tumor size, tumor grade or
immunohistochemistry markers that lack
standardization and validation”, says Cronin.
“It saves patients the pain of needlessly
going through chemotherapy and the high
cost of drugs.”
From Expression to
Results
The expression levels of the 21 genes are
measured using a process known as Reverse
Transcriptase Polymerase Chain Reaction
(RT-PCR). In RT-PCR, mRNA from a tumor cell
is incubated with DNA nucleotides, primers,
reverse transcriptase, and DNA polymerase.
Reverse transcriptase transcribes the mRNA
into single-stranded DNA, which DNA
polymerase then replicates into double-
stranded cDNA fragments. After undergoing
multiple cycles of heating and cooling to
activate and deactivate the reaction, PCR
exponentially amplifies the original RNA
fragments into over one billion copies of
DNA.
Next sample is then run through an
agarose gel to separate DNA fragments
corresponding to the different genes. The
relative expression level of each gene is
measured by the fluorescence strength of its
respective fragments upon UV exposure.
Finally, these results are subjected to analysis
by a standard algorithm to generate the
recurrence score.
A Revolutionary
Business Model
Because of its assay’s predictive power,
Genomic Health has redefined the potential
for the molecular diagnostics industry. “No
one paid much attention to diagnostics in
the past because they were general blood
or urine tests that cost under $100”, says
Vance Vanier, a partner at Mohr Davidow
Ventures. “Genomic Health was one of the
RYAN TONG is a senior majoring in Biological Sciences. He is currently CFO of Stanford
Scientific Magazine.
To Learn More
For more information on Genomic Health and its products,
visit http://www.genomichealth.com.
first to truly break through the price barrier
with a specialized genomic assay.”
At $3,650 per test, the success of Oncotype
DX has revolutionized the pricing of
diagnostic products. “The reason we can sell
our diagnostic test above traditional costs is
because of the immense value that we bring
to both patients and payors”, explains Kim
Popovits, President and COO of Genomic
Health. “Given that chemotherapy costs tens
of thousands of dollars per patient per year,
our test is a cost-effective predictive screen
that allows doctors to tailor the treatment
for the patients and scale down unnecessary
costs for insurance providers.” In this sense,
Genomic Health is at the forefront of
personalized medicine.
Investing more than $168 million in the
research, development and clinical trials
for its Oncotype product, the company
is mirroring the business models of the
pharmaceutical giants, who invest heavily in
R&D in order to secure high margins (>70%)
on their products. “We are witnessing a
trend towards higher priced diagnostics
and lower priced pharmaceuticals”, says
Popovits. “As more and more people
realize that big drugs on the market aren’t
for everyone and realize the benefits of
individually tailored drug treatments, the
demand for diagnostic assays will continue
to grow.”
Genomic Health plans to expand its line of
diagnostic tests for various types of solid
tumors. The company plans to launch a
diagnostic for prostate cancer next fall, and
studies are under way for colon cancer. “The
ultimate goal is to deliver maximum benefit
to patients through individually designed
treatments. The days of blockbuster
pharmaceuticals are over and personalized
medicine is here to say.”
Credit: sxc.com
volume VII