Working out the kinks in HER2 testing
Using FISH for primary testing
William Check, PhD
When the therapeutic antibody trastuzumab (Herceptin, Genentech)
was approved for treating metastatic breast cancers that overexpress
the oncoprotein HER2, laboratories had to introduce an assay for
HER2 to identify eligible patients. Raymond Tubbs, DO, chairman
of the Department of Clinical Pathology at the Cleveland Clinic,
initially adopted an in-house immunohistochemistry assay. After
a time, he tells CAP TODAY, "Our oncologists told us, ’We are sending
some cases to the Mayo Clinic and they get positive results and
you get negative results on the same samples.’"
Dr. Tubbs called Patrick Roche, PhD, director of the immunohistochemistry
laboratory at Mayo, and found that he was writing a letter that
later appeared in the Journal of Clinical Oncology identifying a
problem of false-positive results with the kit Dr. Roche was using,
HercepTest (Dako), which is still the only FDA-approved method for
selecting patients for trastuzumab therapy.
Soon after, Dr. Tubbs and Dr. Roche, along with Mark Stoler, MD,
professor of pathology and associate director of surgical and cytopathology
at the University of Virginia, Charlottesville, formed a study group
to compare two forms of immunohistochemistry, or IHC, and two variants
of fluorescence in situ hybridization, or FISH, which measures amplification
of the HER2 gene. Since the manufacturer of HercepTest contended
that excess positives with IHC were true positives resulting from
protein overexpression without gene amplification, in situ measurement
of messenger RNA (mRNA) for HER2 was used as the arbiter.
"If that argument were true," says Dr. Stoler, who performed the
mRNA assays, "we would expect high levels of HER2 mRNA in HercepTest-positive
cases that were FISH-normal. And we never found any of those cases."
The investigators concluded there were significant numbers of false-positive
results with IHC methods.
Results of the study were presented in May at the annual meeting
of the American Society of Clinical Oncology. Since the investigators
agreed on the conclusions, one might think they would all now use
the same assay, and that it would be FISH. But in fact they all
use different methods, and two use IHC, showing how difficult it
is to say which is the best method to qualify patients for trastuzumab
In a meeting with breast pathologists and oncologists at his institution,
Dr. Tubbs recommended FISH as the first-line test. IHC is offered
if oncologists want it. "These molecular data and the superior correlation
of FISH with clinical outcomes underscore the superiority of FISH
as the clinical assay of choice," Dr. Tubbs says. (See "Using FISH
for primary testing," page 66.) As for the feasibility of widespread
adoption of FISH, he comments, "I think pathologists are uncomfortable
with FISH. But it can be learned like any other microscopy skill."
At Mayo, on the other hand, HercepTest remains the first-line
method of testing. Using the 0 to 3+ scoring system set up for the
kit, Dr. Roche says, "More than 80 percent of our 3+ cases are gene-amplified."
Samples read as 2+ (about 10 percent) are sent to Mayo’s Molecular
Genetics Laboratory for FISH testing. Less than 15 percent are gene-amplified.
(Most false-positives in the comparative study came from this category.)
"HercepTest is a good kit," Dr. Roche says. "My contention all along
has been that the 2+ category does not correlate with amplification.
It was a mistake to make 2+ by itself a qualifier for therapy."
(This is only one of many criticisms various pathologists have about
the way Genentech and Dako developed HercepTest.)
As for making HercepTest first-line, Dr. Roche says, "It is quicker
and more efficient to run than FISH, the cost is relatively insignificant,
and 3+ results correlate well with gene amplification." He adds, "It
is FDA-approved and that is what our oncologists here want."
Dr. Stoler also uses an IHC assay for HER2, he does not use HercepTest.
"We have validated our own IHC method," Dr. Stoler says, "and we
know how it performs relative to HercepTest and to FISH. For now
we are sticking to that assay because we don’t have a significant
false-positive rate. We have a few false negatives, but those can
be addressed by second-tier FISH testing in the minority of cases
where Herceptin is the only therapeutic choice. You really want
to identify patients who are most likely to benefit," he emphasizes,
"because Herceptin is both expensive and potentially toxic."
A major difference between Dr. Stoler’s IHC assay and HercepTest
is that his assay uses a standard detection system. HercepTest’s
detection system-branched chain amplification-is very different
from other IHC tests in surgical pathology. ("Why Dako chose to
use that has been somewhat of a mystery," Dr. Stoler says.) That
has led some pathologists to use the kit antibody with their own
detection method. "A lot of people don’t do the FDA-approved method
exactly," Dr. Stoler notes. "Assay variation leads to variability
of results. So," he urges, "either use the FDA-approved method exactly
or set up and validate your own assay." Setting up a variant assay
and assuming that the validation for HercepTest applies can lead
to incorrect results.
But, like Dr. Roche, Dr. Stoler sees a fundamental flaw. "I think
the FDA approved an invalid method," he asserts. HercepTest was
not the method used in the clinical trials. Further, the data that
led to its approval were a statistical correlation, not a 1:1 match.
Dr. Stoler suggests that, while prospective clinical correlation
studies are being done, that Dako or the FDA, or both, consider
revising what is called positive.
Turning to FISH, Dr. Stoler says, "While it might seem obvious
that FISH would be a better way to test for an indication to use
Herceptin, FISH is not nearly as simple to do as IHC. So this raises
the question of how a laboratory without the equipment or experience
would do in situ hybridization."
To complicate things further, second-generation FISH assays may
not require fluorescence. And they will have a permanent record
instead of looking at dots under a microscope. "Those changes will
happen within the next six to 12 months," Dr. Stoler predicts.
Most important, he believes, is communicating with clinicians
about the realities of tests. "We have an active breast clinic here,"
he says, "and our clinicians are perfectly happy with the rate of
IHC positivity coming out of our laboratory. It meets their needs
for patient care."
HercepTest is the first-line assay adopted by Elizabeth Hammond,
MD, chair of pathology at LDS Hospital, Salt Lake City. In her experience,
intense complete membrane staining in more than 50 percent of cells-a
3+ score-has 90 percent correspondence with gene amplification.
"It is only when we deal with either complete membrane staining
that is weak or present in only a small proportion of cells-2+ samples-that
we have poor correspondence with the FISH assay," she says. Thus,
in her hospital patients whose tumors have 3+ staining qualify for
Herceptin therapy while 2+ scores are confirmed by FISH in house.
"It is very easy to train technologists to use either of the two available
FISH kits if you have a laboratory equipped to do immunofluorescence
microscopy," Dr. Hammond says. (Her hospital examines kidney and heart
biopsies by immunofluorescence microscopy; at other institutions it
is used for prenatal genetics.) She finds that both the Vysis and
Ventana kits work well. However, Dr. Hammond comments, "FISH is expensive
and time-consuming, because you have to count many cells and results
have to be confirmed by a pathologist. I prefer doing IHC. It is cheaper,
easier, and faster. But for 2+ tissues, for the sake of the patient,
you really need to confirm that they are positive by FISH."
Dr. Stoler, Dr. Hammond says, "HercepTest is very standardized,
so if you use it exactly as provided, you have a high likelihood
of getting excellent results. I think a lot of difficulties have
come from people using cheaper, non-FDA approved antibodies or modifying
the kit. Either of those approaches will cause problems if you don’t
validate against HercepTest. If you change the method," Dr. Hammond
says, "you can change the results." She endorses the quality control
guidelines in the CAP’s Laboratory Accreditation Program Checklist
8, Anatomic Pathology.
Dr. Hammond also sees a basic problem with the kit. "The scoring
system was developed when Genentech came out with Herceptin based
on antibodies they used then," she says. "That scoring system was
superimposed on HercepTest, even though it uses a different antibody,
because FDA required it. I think that is creating some confusion."
Kenneth Bloom, MD, director of laboratory operations at Rush-Presbyterian-St.
Luke’s Medical Center, Chicago, believes, too, that obtaining accurate
results is under the laboratory’s control. "What it comes down to
are really pathologist problems," he says. With a conventional qualitative
IHC assay, laboratories typically manipulate conditions for antigen
retrieval or antibody handling to get better staining. "That is
exactly what you can’t do with a quantitative test like HercepTest,"
Dr. Bloom says. The kit includes pretitrated antibody and defines
exactly how to do antigen retrieval. It assumes that tissue is cut
to a thickness of 3-4 µm, fixed in 10 percent neutral buffered formalin
for 12 to 18 hours, and processed in a routine tissue processer.
"But everybody changed the test a little," Dr. Bloom observes, "then
they badmouthed it." He has done between 400 and 500 cases handling
tissue exactly according to HercepTest directions and finds 92 percent
concordance with FISH. (He does both assays on all samples for a
"This is the first truly quantitative IHC test in anatomic pathology,"
Dr. Bloom says. "But there is going to be a whole wave of them.
And we will have to handle tissue properly to get accurate results."
Misreading IHC also contributes to false results, in Dr. Bloom’s
view. Calling 1+ samples 2+ "makes it look like only a small minority
of 2+ tissues respond to Herceptin," he says. "We consider cases
as 2+ positive only when there is a distinct chickenwire appearance
on high-power examination that is not visible on lower-power examination.
With this definition, 100 percent of our 2+ cases have been amplified,
although they represent less than five percent of our overall cases.
So I am not a big believer in taking our 2+ readings to FISH. However,
cases that are scored as 0 or 1+, that are ER/PR-negative and show
a high proliferation index may benefit from FISH testing."
As for doing FISH, Dr. Bloom comments, "It is not quite as easy
as what they put out." FISH is reliable and relatively easy to score,
but it has a gray zone right at the borderline of amplification.
And it is time-consuming. "I look at all FISH slides myself," he
says. "They may take five times as long to read as IHC. I can do
20 cases in one to 1.5 hours."
On the other hand, he says, "There seems to be a reluctance by
pathologists to introduce FISH into their laboratories. I don’t
see why. We easily cross-trained our immunohistochemistry technologists
to do FISH even though we had not done it in our laboratory before."
A broad view of HER2 testing was offered by Ann Thor, MD, staff pathologist
at Evanston (Ill.) Northwestern Healthcare and professor of pathology
and surgery at Northwestern University Medical School, Chicago. As
director of the pathology coordinating office board for the Eastern
Cooperative Oncology Group, Dr. Thor does central eligibility testing
for patients going into Herceptin trials. She has evaluated both the
Ventana and Vysis FISH kits and perhaps 10 different IHC reagents.
"We have found great comparability between IHC, FISH, and PCR-based
molecular assays," she says.
Clinically her hospital uses IHC with FISH backup for 2+ samples.
"I think that is a reasonable strategy based on cost and efficacy
of screening breast cancer patients," she says. "My view is that
FISH is too expensive and time-consuming to use first-line. Pathologists
are supposed to confirm FISH results by counting representative
sections, but in busy laboratories they often delegate that to technologists."
Dr. Thor identifies a lack of strict adherence to controls as
one source of problems with IHC. HercepTest has slides with three
cell line controls, but a small-volume laboratory that does only
three to five slides per run will quickly run out of control slides.
"It is worth it to buy extra controls," Dr. Thor suggests.
But she sees lack of standardization as the biggest problem. In
her experience, most U.S. laboratories either don’t use HercepTest
or don’t use it as provided. Many use the kit’s primary antibody
with their own reagents; others put it on a machine, although the
FDA-approved method is manual. (An automated method is now available,
but only for the Dako immunostainer. "Most laboratories that have
a Ventana instrument will not go out and buy a Dako just for this
test," Dr. Thor observes.) "I am a believer in the standardized
approach in the CAP guidelines," Dr. Thor says, referring to an
editorial by Clive Taylor, MD, PhD, in the July issue of Archives
of Pathology & Laboratory Medicine (2000;124:945-951). "That was
the first time anatomic pathology people were told about using consistent
technique in a semi-official sense."
This year, the CAP’s Cell Markers and Molecular Pathology committees
will jointly send fixed breast cancer tissue samples to IHC and
molecular pathology laboratories, says Raymond Nagle, MD, PhD, professor
of pathology and deputy director of the Arizona Cancer Center at
the University of Arizona, Tucson. "This will be the first large
multilaboratory comparison of IHC, FISH, and morphometric analysis,"
Dr. Nagle himself tests for HER2 with Ventana’s IHC kit, which
is awaiting FDA clearance. (He adds a standard disclaimer to reports.)
It is based on Ventana’s CB11 monoclonal antibody and, like HercepTest,
has a very specific protocol. He finds that results seem to fall
into two categories: 3+, where almost 100 percent of the cells are
unequivocally positive; and background cytoplasmic staining or a
trace of staining in a few cells. "I find there are very few tissues
where you really ponder, Is this a 2+ or not?" says Dr. Nagle, who
is a consultant to Ventana. He has a 3+ breast specimen control
on each slide.
"Our clinicians treat on the basis of 3+," he adds. "I have had
no requests to have testing done by FISH, either by patients or
clinicians. We intend to set up FISH, but will use it only as a
second-line test because of its expense." To validate the Ventana
kit, an internal study was done of a series of cases that were ER/PR-negative
with a high proliferative index, tumors that are typically strongly
positive for HER2. "We haven’t done a study correlating it with
FISH or with clinical response," Dr. Nagle says.
Dr. Hammond evaluated Ventana’s kit on her own, comparing it in
a blinded fashion with HercepTest in 200 breast cancer cases that
had been followed for 10 years. She found complete concordance among
3+ cases. In the 11 (5.5 percent) instances where her readings of
the assays disagreed (all 2+/1+), she showed the slides to two other
"What we found," Dr. Hammond says, "was that the other two pathologists
agreed with my readings on HercepTest, but we disagreed in our readings
of the CB11 slides. Interobserver variation with CB11 could not easily
be resolved." Dr. Hammond attributes this to high background cytoplasmic
staining with CB11 that made it difficult to evaluate the cell membranes.
"And," she adds, "we did it with their recommended method and on a
Dr. Bloom did the trial for Ventana that provided
the data submitted to the FDA. "We followed exactly the protocol
that Ventana set up," Dr. Bloom says. Antibody was pretitrated to
cell lines with known numbers of HER2 surface molecules, just like
the initial assay Genentech used to qualify patients for Herceptin
trials. Dr. Bloom’s results were similar to those generated by Dr.
Hammond: Seven (4.7 percent) out of 150 samples were discrepant,
all with 1+/2+ scores.
"Anecdotally we have seen a fair number of blocks that were 3+
on immunostaining with CB11 but 0 or 1+ with HercepTest," Dr. Bloom
says. These samples were not amplified on FISH. "This is not because
CB11 is a bad antibody. But when a laboratory is not adhering to
an established protocol, it may lead to false results."
Some laboratories’ difficulties interpreting IHC results
have led one company, ChromaVision, to market a cellular image analysis
system, called ACIS, to read HercepTest slides. Underlying this
device is the assumption that quantitatively judging the amount
of dye taken up by cells on a slide is something that people are
inherently very bad at doing. "We humans have great accommodation
to variations in brightness," says Jose de la Torre-Bueno, PhD,
ChromaVision vice president of R&D. "We can see in anything from
starlight to bright sunlight." But a computerized instrument is
much better at judging absolute intensity. ACIS uses a bright-field
microscope with no filters, can run unattended, and reads slides
and presents images for later review.
Douglas Harrington, MD, chairman of the board and CEO at ChromaVision,
notes that HER2 is the first in a series of tests that will require
anatomic pathologists to give quantitative rather than yes or no
answers. "Pathologists will need some sort of imaging assistance
to produce results adequate to guide therapy," Dr. Harrington believes.
In one series of 129 cases read by nine pathologists with and
without ACIS, the imaging system significantly increased concordance
between IHC and FISH, mostly by improving scores among pathologists
inexperienced at reading HercepTest. Eight of nine pathologists
had concordance values >90 percent when using ACIS, including four
whose concordance level without ACIS was <65 percent. Taking the
pathologists as a group, the fraction of samples read as 2+ and
3+ that were nonamplified dropped from 54 percent without ACIS to
22 percent with the system. Most samples moved from 2+ to 1+. (Results
of this study will be presented in December at the San Antonio Breast
In several cases read positive by IHC/ACIS but nonamplified by
FISH, it turned out that FISH results were scored in the wrong region
of the slide. "Pathologists are used to using dyes like H&E to classify
areas in a specimen," notes Kenneth Bauer, PhD, chief science officer
at ChromaVision. "FISH substitutes fluorescent dyes that tend to
fade rather quickly under the microscope. And the great majority
of pathologists are not used to recognizing specimens of invasive
cancer versus non-cancer with fluorescent dyes."
ACIS is sold on a per-use basis. Reimbursement for this technology
is "very favorable," Dr. Harrington says. "Pathologists can make
incremental revenue based on existing CPT codes."
Randy Judd, MD, director of Special Technologies at AmeriPath’s Center
for Advanced Dia1gnostics, Orlando, Fla., is using the ACISnow. Dr.
Judd had developed an in-house assay for HER2 testing using the Dako
polyclonal antibody and Ventana’s automated immunostainer. When the
HercepTest was released, he used controls from the Dako kit to adjust
the antibody titer to produce staining equivalent to the HercepTest.
"However, once we began using the ACIS, we discovered that the nonspecific
cytoplasmic staining that can be induced by antigen retrieval was
being falsely interpreted as a positive result by ACIS," Dr. Judd
explains. "We eventually eliminated this problem by adding an avidin-biotin
blocking step to our procedure."
Since bringing ACIS into his
laboratory, Dr. Judd says, "We have been very happy with the consistency
of our results. The automated Ventana stainer minimizes variability
caused by technical factors, and the ACIS minimizes variability
due to pathologist subjectivity."
In collaboration with Jane Gibson, PhD, director of molecular
genetics at the Center for Advanced Diagnostics, Dr. Judd is evaluating
the correlation of ACISHER2 scores with FISH. "We are finding that
the problem of false-positive and false-negative IHC results is
restricted to a fairly narrow range of ACIS scores," Dr. Judd reports.
"These are the cases that benefit most from followup FISH testing."
As for reimbursement, Dr. Judd says, "Although the ACISfee is
high, reimbursement revenue has been more than adequate to cover
our costs." Dr. Judd and his colleagues eventually plan to narrow
the range of cases requiring ACISquantitation to only those with
intermediate (1+ to 2+) staining. "Our goal is to develop an algorithm
that maximizes the benefit of these new technologies at a reasonable
cost," Dr. Judd says.
Dr. Bloom, who took part in the ChromaVision study, says, "Image
analysis levels the playing field for reading IHC slides. It puts
novices on a par with experts. With ACIS, even untrained pathologists
can achieve greater than 90 percent concordance with FISH." Pathologists
experienced in reading HercepTest also get some benefit from the
addition of ACIS, he adds.
Important to note is that the study used preprocessed slides.
"Using ACIS doesn’t change the fact that you have to get tissue
handling right first," Dr. Bloom emphasizes. "It won’t help you
with a poor immunostain." The results of Dr. Roche’s independent
evaluation of the ACIS at the Mayo Clinic are under discussion with
ChromaVision’s Dr. Bauer referred to the importance of analyzing
for HER2 in an area of invasive cancer, which demands special care
when fluorescent microscopy is used. In practice this can be a problem.
As a central testing laboratory for clinical trials, Dr. Thor sometimes
gets discrepant results from a sending laboratory. She may call
and ask them how they did the test. "Some laboratories have told
me they do not try to separate invasive from in situ cancer," she
says. "When it comes to breast cancer, this is quite important."
Many studies have looked separately at the in situ and invasive
components of breast cancer. Dr. Thor says the vast majority of
in situ disease picked up on mammography is the large cell comedo
subtype and about two-thirds have altered HER2 status. The same
is true for the in situ component of invasive disease detected by
mammography: About two-thirds have HER2 alterations. In contrast,
only about one-third of invasive disease has altered HER2 status.
Because such a high percentage of in situ lesions are abnormal for
HER2, this marker is not a useful predictive or prognostic factor.
"CAP guidelines stipulate that HER2 must be scored on the invasive
component of breast cancer," Dr. Thor notes. It can be difficult
to score histology on FISH. "To look at tissue under the fluorescence
microscope is hard," Dr. Thor says. "For small tumors especially,
differentiating in situ from invasive becomes a tricky business.
"Which is why," Dr. Thor continues, "it is important for pathologists
to be very careful in the slide or block that they select for HER2
testing." In these days of small lesions, this is especially true.
To do multiple stains on one block of a 3-mm cancer confirmed on
frozen section takes thought and conservation. "For a small tumor,
especially for cores," Dr. Thor suggests, "what you can do, instead
of tossing most of the sections, is to cut very carefully on the
facing, then float 10 slices on a ribbon. Pick up every slice and
put them onto slides for staining or FISH." In some places a block
is cut for diagnosis, then stored. It may be remounted and recut
for additional tests, but there is not always enough tissue. Making
a larger number of slides at the initial sectioning can prevent
Dr. Bloom, too, underscores the importance of carefully matching HER2
analysis with tissue histology, especially on FISH analysis. "We recently
outright missed one case on a liver biopsy," he relates. One section
level had tumor and liver tissue, which was circled. On the next level
down, which was used for FISH, all the cells looked big, and they
were thought to be tumor cells under fluorescence microscopy. In fact,
tumor had disappeared and there were only liver cells. "When we recognized
the discordance with IHC, we looked again, and saw that there were
no tumor cells on that level," Dr. Bloom says.
Dr. Judd cites a case in which an invasive tumor was HER2-negative
by IHC while a microscopic focus of DCIS was positive. "Since the
invasive portion is most relevant clinically, we scored the case
as HER2-negative," he says. However, the FISH laboratory picked
up on this small area of amplification and scored the case as positive.
Drs. Judd and Gibson reviewed the slides together and concluded
this represented a false-positive FISH result. The clinical significance
of HER2-positive DCIS associated with an invasive tumor that is
HER2-negative remains unknown.
So what is the bottom line in HER2 testing? "I don’t believe
we have the data to recommend a single method," Dr. Thor says. "I
think the answer will come from treatment trials. The only important
factor is how do our assay data compare to Herceptin response."
To generate such data, Dr. Thor is performing several HER2 assay
methods in an Eastern Cooperative Oncology Group trial of Herceptin
therapy. Two other cooperative trials groups, NSABP and CALGB, are
conducting similar studies. But it will be two to three years before
data emerge from these trials.
Dr. Roche is measuring HER2 by IHC and FISH in two Herceptin clinical
trials. "These studies are really going to be the telling tale as
to which test is the better predictor of outcome to therapy," he
Dr. Bloom is now collating clinical outcomes of 150 or so cases
treated with Herceptin as a single agent on which both IHC and FISH
were done. But he is also doing markers other than HER2. "Even with
FISH, HER2 measurement is not very predictive of response," he says.
"We need to do better."
Dr. Thor agrees. Current Herceptin-only response rates based on
HER2 IHC testing are 20 to 30 percent. "Other assay cut points,
downstream markers, or heterodimer data in addition to HER2 by immunohistochemistry
may better predict Herceptin response," she says. "I think we’re
not likely to continue to accept response rates that low, because
we are now seeing some patients dying while being treated with Herceptin-not
many, but some." In the future, Herceptin treatment might be limited
to patients who have a better than 50 percent chance of responding.
For now, Dr. Tubbs says, "First there has to be good communication
between pathologists and oncologists. Second, all IHC 2+ samples
should be confirmed with FISH at a minimum. Even this approach will
miss some false negatives and false positives. Third, we clearly
need to evolve a chromogenic in situ hybridization assay that can
be evaluated with conventional optical microscopy and that does
not require copy-by-copy signal enumeration." He and his colleagues
are now working to develop this system.
Getting it right with HER2 has long-term consequences. "New antibodies
will be coming out that must be read quantitatively and that will
present the same problems all over again," Dr. Bloom warns. "This
is the wave of the future-therapeutic monoclonal antibodies followed
by quantitative laboratory tests to select patients. So we have
to get into the habit of handling tissue appropriately."
"This level of specificity [with HER2] is frankly quite different
than what we are used to in anatomic pathology and an example of what
is going to be repeated many times in the near future," Dr. Stoler
agrees. "Every time someone comes up with a new drug based on a genetic
marker, we will have to go through how best to test for that analyte.
It will require a lot of work to sort out." He adds, "Anatomic pathologists
have never before been forced to have this kind of precision."
To Dr. Tubbs, the issue’s importance must be viewed in the context
of breast cancer’s prevalence. A new diagnosis of invasive breast
carcinoma was made for 175,000 women in the United States last year,
the American Cancer Society estimates. An IHC false-positive rate
of 10 to 12 percent "may not appear to be significant at first glance,"
he notes, "but it assumes greater importance when one considers
that thousands of IHC assay results may be spurious."
Dr. Stoler, referring to the collaborative study of IHC, FISH,
and mRNA that he did with Drs. Tubbs and Roche, says, "One of the
things that motivated us is that we don’t think it was done right
the first time. We believe that systems and models should be developed
for getting it right before a test is approved by FDA."
Dr. Thor is clear about who should devise and implement these
systems. "Next time we need to do these pathology studies up front
during clinical trials instead of letting industry create controversy,"
she says. "It is not companies that should be doing these tests;
it is pathologists and laboratories."
William Check is a freelance medical writer in Wilmette, Ill.