for serum HER2/neu?
It would be nice, wouldn’t it, if physicians had aserum test that
could detect breast cancer in its earliest stages? The serum HER-2/neu
oncoprotein ELISA, however, is not that test.
It would be equally nice if, when assessing HER-2/neu
status in metastatic breast cancer patients, pathologists could
cast iffy IHC and FISH results aside and turn to a simpler and cheaper
serum test. The serum HER2/neu assay, however, is not that
Serum HER2/neu is not a tumor marker—not really.
The assay has not been approved for qualifying breast cancer patients
for trastuzumab (Herceptin), nor is it clear how well patients whose
entree to Herceptin treatment was based on a positive serum HER2/neu
result respond to
The serum HER2/neu assay is not a lot of things. But
it’s certainly not useless. Far from it, say its supporters.
In one sense, these advocates are a little like the intrepid explorers
of yesteryear who sloshed around North America looking for, among
other things, a quick trade route to Asia and the Fountain of Youth.
While Ponce de León didn’t grow any younger mucking about in Florida,
and the West Indies hardly rub shoulders with Shanghai, few would
argue these discoveries were a waste (the subsequent establishment
of Disney World and a brisk trade in shell lamps notwithstanding).
Likewise, advocates of the serum HER2/neu assay point
to intriguing possibilities for using the test. They’re also wondering,
frankly, why the assay hasn’t caught on more widely.
"We developed this test in the ’80s. And I used to say, ’I’ve got a great
test, now I just have to find a clinical utility for it,’" says Walter Carney,
PhD, head of Bayer Diagnostics’ Oncogene Science Group and the inventor of the
test. Now, backed by a diverse and growing literature, its own CPT code, and
a hefty reimbursement rate, the assay is starting to pick up steam in the clinical
setting. And, predicts Dr. Carney, its real value may yet be discovered.
The assay took a big step into charted territory
last year when it received its own CPT code, 83950, with
a reimbursement of $89.01. Two years earlier the FDA approved its
use in managing and monitoring women with metastatic breast cancer.
The claim is a broad one, not limited to a particular therapy.
But the serum assay became linked in the minds of many with Herceptin,
which perhaps accounts for some of the confusion concerning its
use in the clinical setting. When trastuzumab was approved in 1998,
there was overwhelming interest in qualifying women for the therapy
by whatever means possible—if not by IHC, then by FISH; if
not by FISH, then by serum. Indeed, some physicians continue to
make compelling arguments for using the serum test this way.
One of the early voices suggesting the test might be used to qualify
patients for Herceptin belongs to Beverly Ogden, MD, chief of pathology
and director of research, Woman’s Hospital, Baton Rouge, La., who
began using the assay four years ago. In a study involving 100 patients,
Dr. Ogden and her colleagues identified 26 women who had a positive
serum HER2/neu test (15 ng/mL or higher) and had either
negative tissue by FISH or IHC or simply did not have tissue available
for such testing. "So that’s 26 patients who would have been told
they had a negative HER2/neu if we had not
done their serum," she says. Many of the 26 patients then began
Three are still alive. Dr. Ogden and her colleagues are reviewing
the chart of one of them; another patient, when contacted by the
researchers, declined to participate in the followup; in the third
case, the clinician did not want the researchers to contact his
patient. Though obviously frustrated by the inability to follow
up more completely, Dr. Ogden maintains her enthusiasm for the test.
"In our mind, we have three people who are alive today potentially
because we did that [the serum] test," she says. "Because in any
other lab they would have been told they were negative or that their
HER2/neu couldn’t be done." Even more dramatic, in Dr.
Ogden’s mind, is that the patients faced tough survival odds—as
with other patients who are placed on newer therapies, they had
very advanced metastatic disease and had already failed other available
Dr. Ogden’s work with the serum HER2/neu assay absorbed
another blow several years ago. Initially, any patient with a HER2-positive
tumor was considered to be a candidate for Herceptin; roughly a
year later, the FDA stated that patients needed to be qualified
using Dako’s HercepTest, an IHC method. Subsequently, Medicare decision-makers
in Dr. Ogden’s region decreed that physicians would have to reimburse
Medicare for Herceptin therapy administered during that one-year
window if it had not been selected using the Dako test. "It was
about $33,000 a patient," Dr. Ogden estimates. Eventually the decision
was overturned, but the damage had been done. "That scared all our
doctors away from using the serum HER2/neu test," she says.
"They’re still afraid to use it, even though they can and
should use it."
Had they not been strangled by Medicare, "We’d still be doing
the serum test the way we had been," she says. "Our doctors were
used to getting all three results [serum, IHC, FISH], and some were
starting to use it to follow their patients."
"It’s a little frustrating, because I think this is a very valuable
test that has
been neglected," she adds. "It’s a marker and then some. It’s three
times the marker that CEA or CA 15-3 could ever be, yet people still
aren’t using it."
Dr. Ogden’s travails may seem exceptional. But for one reason
or another, the test has not caught on widely beyond the bayous
Dr. Carney chalks it up to lack of familiarity with current literature.
"My biggest frustration is that a lot of people aren’t well informed,"
he says. "They usually just take old information or negative information
that they’ve heard in the past, and apply it."
"People don’t know the literature," agrees Diana Lüftner, MD,
assistant professor at Universitätsklinikum Charité, Berlin, Europe’s
largest university hospital. "They just read the ASCO [American
Society of Clinical Oncology] guidelines or the guidelines of the
German Cancer Society."
In her opinion, acceptance of serum HER2/neu has been
hampered by physicians’ misperceptions of what the test can do.
"They think they can replace tissue testing, which they cannot.
And once they realize that, they are disappointed and don’t want
to use it," she says.
Disillusion with other tumor markers has also cast a shadow on
the test. "When each one of them came out initially, there was excitement
about and expectations of each. People thought, for example, ’Oh,
CA-125 is extremely good for ovarian cancer,’ and then we find out
it doesn’t have the expected sensitivity and specificity to be used
as anything other than a surrogate marker to follow patients on
therapy," says Meeta Patnaik, MD, vice president, clinical diagnostics,
Pathway Diagnostics, Los Angeles. "So past experience with tumor
markers hasn’t been as good as tissue, and it will take time and
large clinical utility studies for these newer markers to gain acceptance."
Wishful thinking may also have tripped up the test. Those looking for an early
screening test with PSA-type sensitivity will be—and have been—disappointed.
"That’s probably one of the most common misperceptions about the test that exists,"
Dr. Patnaik says.
Behind the doubts and misperceptions, researchers
are quietly building a case for the serum assay.
Several cases, in fact, with studies looking at early diagnosis
to therapeutic response to metastatic potential.
At Penn State Milton S. Hershey Medical Center, physicians use
the assay in two metastatic breast cancer settings, reports Allan
Lipton, MD, professor of medicine and oncology. One is when no tissue
block from a previous diagnosis is available, and biopsy is not
The second use, which is becoming more common, is in cases where
the IHC result is 2+, which is considered an equivocal result. "Normally
we would go on to do FISH testing," Dr. Lipton says. "But now we’re
doing serum HER2/neu testing. Because if the serum test,
which is quicker and less expensive, is positive, then we would
treat that patient with Herceptin. If the serum test is negative,
we would then go on to FISH testing." Hershey began using the serum
assay in this manner last fall; it’s too soon to tell what clinical
impact the test may have, he says.
For several years Dr. Lipton and his colleagues have looked at
baseline serum tests in patients receiving the relatively new aromatase
inhibitor letrozole (Femara) or tamoxifen as a first-line therapy
for metastatic breast cancer. In more than 500 patients, 30 percent
were serum HER2/neu-positive and were shown to have a quite
low response rate to both therapies. "This signals that the physician
needs to become more aggressive with the therapy, and go toward
more of a chemotherapy approach in those patients who previously
would have been treated with just the antihormonal therapy," says
Laurence Demers, PhD, distinguished professor of pathology and medicine
The Hershey researchers have also shown that breast cancer patients
with estrogen- or progesterone receptor-positive malignancies usually
better compared to those with receptor-negative disease. "But there’s
a subgroup in the receptor-positive population who have elevations
of HER2/neu who don’t do as well, even with conventional
antihormonal therapy, which has been the treatment of choice for
receptor-positive tumors," Dr. Demers notes.
They also have data, recently submitted in abstract form to the
upcoming ASCO meeting (May 31-June 3 in Chicago), demonstrating
that of those with a negative baseline serum HER2/neu,
approximately 25 percent convert to a serum-positive situation as
the disease progresses. "But we’ve not yet gotten to complete serial
testing," Dr. Lipton says.
Though not yet using the assay for its approved monitoring indication,
Dr. Lipton hasn’t ruled it out. "There are some preliminary reports
that are quite encouraging from the group in Austria that the serum
test can be used to monitor patients on Herceptin therapy," he says.
Included in that group would be Wolfgang J. Köstler, MD, clinical
fellow, University Hospital of Vienna.
Though the serum HER2/neu assay is accepted as an in
vitro diagnostic in Europe for managing and monitoring women with
metastatic breast cancer, "As far as I am aware, it’s not really
used much in clinical routine anywhere in Europe," Dr. Köstler says.
He and his colleagues in Vienna use it primarily as a research tool,
at least for now.
In one recent study, which has been submitted for publication,
Dr. Köstler and his colleagues used the assay to monitor serum HER2/neu
during trastuzumab-based therapy in patients with breast cancer.
"It showed that early changes in serum HER2 during trastuzumab-based
treatment are a fairly reliable marker of what’s going on during
treatment, almost like a predictive marker," he says. "It’s not
a proper predictive marker, because you do need to initiate treatment
to see that change. But it’s probably an early indicator of how
things are going."
The need for additional predictive parameters is strong. Even
optimal patient selection for trastuzumab (that is, FISH positivity
and/or grade 3+ HER2/neu overexpression as determined by
approved IHC tests and no prior cytotoxic treatment for metastatic
disease), response rate to treatment is 30 to 50 percent. The serum
test may let physicians identify nonresponders earlier.
Dr. Köstler offers up another interesting possibility. Patients
who receive trastuzumab in combination with chemotherapy are more
likely to respond than those receiving only trastuzumab, though
he notes it’s not yet known whether this higher response rate translates
into actual benefit in terms of progression-free or overall survival.
What is certain is that toxicity is higher in the combined approach.
"So the idea—which we haven’t proven—is that if we do
know who is likely to respond to Herceptin alone, we could start
all patients on Herceptin, and then just add chemotherapy to those
who are at high probability of not responding."
Referring back to work done by the Hershey team (Lipton A, et
al. J Clin Oncol. 2002;20: 1467-1472) that indicates serum
HER2/neu can be used as a predictive marker for response
to a second-line hormone therapy, Dr. Köstler says, "Probably we’ll
find the same thing is true for trastuzumab. If we do get more patients
monitored for their baseline levels of serum HER2, we are certainly
also going to find, I think, that in patients with HER2/neu
overexpressing tumors, those with higher serum HER2/neu
levels are more likely to respond to Herceptin." In fact, a series
of retrospective studies, including one by Dr. Köstler, indicates
this is true. "But there are still too few patients in all these
trials to know for sure," he says.
Dr. Lipton also points to data from researchers in Spain that
indicate the serum test may predict for resistance to chemotherapy,
particularly taxanes (Colomer R, et al. Clinical Cancer Research.
2000;6: 2356- 2362).
Preliminary work done by another group in Spain hints that the
serum test may be useful in monitoring patients for relapse, says
Dr. Lüftner, who also suggests other potential uses for the serum
"I think that serum HER2/neu is a very practical tool
to confirm the HER2/neu tissue status," she says.
In some cases, an initial test result may simply be wrong. Clonal
changes may also account for some of the discrepancies between tissue
and serum results—individual HER2/neu-positive cells
that are present in a negative tissue-based diagnosis may later
be selected into metastatic spread, Dr. Lüftner explains. Therapy
may also induce certain regulatory processes during the course of
the disease; it may be upregulated by hormonal treatment, for example.
"So HER2/neu isn’t 100 percent stable," she says. "And
we know that about 10 to 15 percent of all breast cancers change
their HER2/neu status during the course of the disease.
So the tissue result of the primary tumor might be misleading for
later therapeutic decisions."
With the possible exception of trastuzumab, patients with higher
serum levels appear to have a worse chance of responding to any
kind of hormonal or chemotherapeutic treatment. "The higher the
level, the worse the outcome," Dr. Lüftner says. As for the Herceptin
exception: "It could be true, but we only have preliminary data
that a higher level [of serum HER2/neu] predicts response
to Herceptin," says Dr. Lüftner.
"When I heard that at first, I didn’t believe it in the beginning,"
she continues. "I couldn’t imagine how that could be. But several
groups have shown similar results, and this could mean Herceptin
really changes the biology of the disease."
Dr. Patnaik, of Pathway Diagnostics, says interest in using the serum assay
to identify patients with metastatic potential has turned into another fertile
area for investigation. "This has really exploded over the last year or so,
and the parameters for that are starting to be recognized and established."
Not to be overlooked in all this is an obvious—though
not always acknowledged—impediment, says Dr. Demers.
"The problem that we face in any kind of study is when you first
do the study, they only allow you to do these studies on end-stage
patients. And if you look at the recruitment efforts for a lot of
these drugs to treat breast cancer, they’re really done on patients
in whom it’s a last-ditch effort to try to save them. So the impact
will become more clear when you start dealing with stage 2 or stage
3 disease, to see over a long period of time how successful this
approach to diagnosis has been."
Dr. Carney expands the vision even further when he notes that
the presence of the HER2/neu oncoprotein is not limited
to breast cancer. "We’re doing studies, for instance, looking at
serum levels in lung cancer, in prostate cancer, in pancreatic cancer,"
he says. "I firmly believe this test is going to have some value
in these other cancers as well."
Moreover, Herceptin may be only the first in what he predicts
will be a long line of HER2/neu-directed therapies. "Some
of the pharmaceutical companies have already caught on to that,"
Dr. Carney says. "Their drugs are not going to be directed toward
prostate or breast or lung; their drugs are going to be directed
toward HER2/neu. We’re going to see treatment of HER2/neu-activated
pathways as opposed to just treating breast cancer or prostate cancer."
Though the serum HER2/neu assay has been around for some
two decades, "from a scientific point of view it’s still very young,"
Dr. Carney says. "So its ultimate clinical utilities—and I
think there will be a few more uses for it—aren’t fully clear.
I think that only after a few more years of clinical research will
we understand the real value of this test."
Karen Titus is CAP TODAY contributing editor and co-managing