Competition is heating
up fast in the breast cancer prognostic testing
market. Genomic Health’s Oncotype DX has been on the
U.S. market since January 2004 to guide use of
chemotherapy in certain types of patients. Now,
several other breast cancer prognosis tests are close
to approval.
Agendia, Exagen, and a
research group at the University of Texas M.D.
Anderson Cancer Center are trying to follow with tests
aimed either at competing with Oncotype DX or
complementing it. Questions about reliability,
usefulness, and cost of genomics-based tests remain,
but this is now one of the most active fronts in
personalized medicine.
These are the first
wave of tests to measure the likelihood of recurrence
or metastasis of breast cancer, and for selecting
patients for more aggressive treatment. With an
estimated 219,920 new cases this year in the United
States alone, and currently 2 million women being
treated, such tests could shift the standard of care
for this disease.
The quality of clinical
data and proper validation will be key to making the
tests successful, according to Edward Tenthoff, a
senior research analyst at Piper Jaffray & Co.
“It’s going to influence regulatory status and the
interaction with the FDA and CLIA [Clinical Laboratory
Improvement Amendments].” However, it is unclear
which tests will fall under FDA guidelines for a
diagnostic, and what process the agency will use to
regulate them.
Oncotype DX is
performed at Genomic Health’s labs, which are
regulated under CLIA. The test can quantify risk of
breast cancer recurrence among a large portion of
node-negative/ER (estrogen receptor)-positive
early-stage breast cancer patients.
“This represents
about half of all women newly diagnosed each year,”
says Steve Shak, chief medical officer. “These women
are generally going to do well, and it’s their group
that has the tough decision about whether to have
chemotherapy.”
The company created the
test by first doing three independent studies in 447
patients to select a set of 21 genes linked to
recurrence. The test uses RT-PCR, and each patient’s
recurrence score is calculated based on the expression
level of those genes. Scores range from 0 to 100, and
low scores are associated with low risk of recurrence
(as low as 3 percent to 4 percent in 10 years), while
a high score means the risk is as high as 35 percent
to 40 percent.
Revolution Begins
In late 2003, results
from a National Surgical Adjuvant Breast and Bowel
Project sponsored trial that included several hundred
women were published in the New England Journal of
Medicine. That study confirmed the test’s
accuracy, and helped make physicians, who are
generally skeptical of genomic tests, more accepting
of Oncotype DX. Larry Norton of Memorial
Sloan-Kettering Cancer Center says he has found the
test useful for patients “on the fence” about
whether or not to have chemotherapy. He adds that it
is the first test of its kind, marking “the
beginning of a revolution.”
The test costs $3,460,
which has raised questions about whether insurance
companies will pay for it. So far, it is covered
nationally through Medicare, and Genomic Health
reports that almost 300 private payers have covered
the test at least once.
Now the test is being
used in a major clinical trial aimed at fine-tuning
treatment for a subset of women who fall into a gray
zone. The National Cancer Institute is sponsoring
TAILORx (Trial Assigning Individualized Options for
Treatment) to assess which treatment course is best
for women with a recurrence score between 11 and 25.
The trial includes about 10,000 women, who will be
followed for up to 20 years. Initial results will be
available within a few years. Patients with midrange
recurrence scores will be randomly assigned to either
hormone therapy alone or hormone therapy plus
combination chemotherapy. The data should guide both
treatment and prognostic testing in this group.
Researchers at the M.D.
Anderson Cancer Center have also developed a
gene-expression based prognostic assay. This one
predicts sensitivity to chemotherapy by measuring gene
expression of 30 genes using Affymetrix microarrays. A
unique algorithm generates a score. If the number is
less than zero, the patient is more likely to be
sensitive to chemotherapy; if greater than zero, more
resistant. Results from the test were found to be
reproducible (Clin Cancer Res 12, 1721-7;
2006), and Lajos Pusztai, who helped develop it, says
the technology is ready for clinical use.
This test will be used
to triage patients into different groups: chemotherapy
sensitive/resistant and hormone therapy
sensitive/resistant. “This will help to identify
patients for whom current standard therapies are not
likely to work, but who are ideal candidates for more
aggressive or new treatment approaches,” Pusztai
says. He hopes to start using the test within the next
few months.
Using proprietary
technology, Exagen is developing two tests: one for
ER/PR-negative patients and one for ER/PR-positive
patients. These are unique in that they can test
virtually all patients with invasive ductal carcinoma
by looking for patterns of genomic amplification (PGA)
in three genes. Based on the number of gene copies, a
prognostic index is calculated and tells whether the
patient is at low or high risk for breast cancer
recurrence.
“This will be more
affordable than gene expression tests and is more in
line with current FISH testing for oncology,” says
Suzanne Mattingly, Exagen’s vice president of
business development and marketing. “We are already
working with HER-2 testing labs using FISH, so when we
receive FDA clearance, our test will be covered by
existing reimbursement codes.”
A Whole New Arena
Initial validation
studies were conducted at the University of New Mexico
with 229 patients. Results showed that the test placed
patients correctly in the low risk category 100
percent of the time for ER/PR-negative patients and 94
percent of the time for ER/PR-positive patients. The
fact that there is no in vitro diagnostic kit
to predict risk of recurrence for ER/PR negative
breast cancer patients sets the test apart. In
addition, the Exagen test can be done in one to two
days. The company is getting close to FDA submissions,
and it’s possible both tests will be available this
year. “Using genomic markers brings this into a
whole new arena of molecular testing, where you can
get individualized treatment because you are looking
at individual genes that define differences in
treatment response or prognosis. It’s a major
advance,” says Mattingly.
MammaPrint, developed
by Agendia, analyzes 70 genes that play a crucial role
in breast cancer metastasis to predict recurrence. The
gene set’s predictive power was reported in several
studies — the latest to be published soon in the Journal
of the National Cancer Institute. This test must
be done in fresh tissue, as it requires high-quality
RNA. It is run at the company’s lab on an Agilent
microarray platform and measures against a reference
using two-color fluorescent dyes that reliably
quantifies small differences.
Agendia’s proprietary
process allows fresh tissue to be shipped at room
temperature to the company’s accredited lab in
Amsterdam by regular courier. Results are available in
about five days. The prediction model is independent
of ER status or prior treatment.
The company was granted
an IDE (Investigational Device Exemption) by the FDA
in April and will be conducting a five-center U.S.
study with 50 patients. “We are having ongoing
advanced discussions with the FDA regarding how to
commercialize the test,” says Bernhard Sixt, CEO of
Agendia. He adds, “It’s a good endorsement for
molecular diagnostics on the multi-gene level to have
three companies now in this area. I think it’s good
more companies are taking up the torch to bring it
forward. This is really the start of personalized
medicine.”
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