College of American Pathologists
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A supporting role for serum HER2/neu?

March 2003
Cover Story

Karen Titus

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 test.

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 treatment.

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 receiving Herceptin.

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 treatments.

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 either.

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 feasible.

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 at Hershey.

The Hershey researchers have also shown that breast cancer patients
with estrogen- or progesterone receptor-positive malignancies usually do
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 with
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 test.

"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 obviousthough 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 editor.