INTERVIEW WITH DR. MARK PEGRAM

DR. LOVE: Although the ATAC trial presentation certainly was the headline from this year's San Antonio meeting, a number of other new clinical research data sets will have an important impact on clinical practice. Dr Baum referred to the presentation by Trevor Powles demonstrating a reduction in bone metastases and improvement in survival with the adjuvant use of the oral bisphosphonate, clodronate, which is the focus of an ongoing NSABP study. Nancy Davidson provided an update of a key Intergroup adjuvant trial evaluating tamoxifen and the LH-RH agonist goserelin combined with chemotherapy. This study continues to provide intriguing hints of the benefit of ovarian ablation in women who are not made menopausal by adjuvant chemotherapy. Another key presentation was given by Dr Robert Mass, who provided perhaps the most compelling data yet available on the superiority of the FISH technique of assessing HER2 status compared to immunohistochemisty. In San Antonio, I also attended a review lecture by Dr Mark Pegram, who reviewed the biology of HER2 and its clinical application to the use of Herceptin. I met with Dr Pegram after his lecture to specifically explore how he incorporates these concepts into patient care. He began by providing a simplified snapshot of the HER2 system.

DR. MARK PEGRAM: There are four members of the HER-receptor family. HER1, the prototype receptor, is actually the epidermal growth factor receptor. Those are synonyms. Then there's HER2, which Herceptin targets. HER3 and HER4. Now, all of these receptors interact with each other, and they like to form combinations of receptors to engage the cell to signal, to tell the cell instructions on how to behave biologically. Should they divide, should they differentiate, should they migrate, for example? All of these functions can be regulated, at least in part, by signals through this receptor family.
Now, it turns out that HER1, HER3 and HER4 have ligands that bind to them directly, whereas HER2 doesn't have a ligand. And the most obvious explanation for this lack of any ligand for HER2 is that HER2 is really the driver of signaling for all of the members of the family. So, ligands can bind to her-1, but transmit their signal and amplify their signal via HER2. So, HER2 is a real pivotal member of the family. And when HER2 binds to HER3 or HER4, it actually makes the ligands bind with much higher affinity, so the binding is much tighter when HER2 is involved in some of these complexes.
So, if you consider the whole family, since there are multiple members and multiple ligands, that opens up an entire repertoire of possibilities. And the best analogy I can think of is that this family is like a stereo system that you have at home. And, in that case, you may want a compact disk player and a tape player and a DVD player, let's say, and those are playing different types of media. And the different types of media would be DVD, CD's, what have you, and different titles. Enjoy your favorite music or favorite movie. Those are like the ligands. Okay? The cell can listen to lots of different types of ligands.

But central to the function of the system is the amplifier, and HER2 is like the amplifier of the stereo system. Whatever media is being played on whichever kind of player, it's all being amplified by HER2.
And so that would explain the pathology of HER2 in breast cancer, as well, because when HER2 gene is amplified, there is too much of the amplifier. And it's like, you know, turning the volume all the way up on the record player. And when that happens in breast cancer, it drives the cells to proliferate like crazy, which is what accounts for the poor prognosis in breast cancer.

DR. LOVE: Now, with that model, can you compare what you see in breast cancer cells and other kinds of cancer cells through normal cells?

DR. PEGRAM: Absolutely. In the case of HER2, which is, I think, a good example, there's a huge difference between the HER2 amplified breast cancer cells and normal cancer cells. When the gene is amplified, instead of there being just two copies of the HER2 gene, there may be, let's say, 50 copies, or even 100 copies of the HER2 gene. And the normal amount of HER2 on normal breast tissues is about 20,000 HER2 receptors per cell. In the case of HER2 amplification, that number is about two million of these receptors per cell. So, because of the density of these receptors, they're always stuck in the on position, causing the cell to grow, and it's a perfect target for Herceptin. Because the density is so high, it's great for antibody binding. Antibody binding by Herceptin not only interferes with signal transduction, this amplification signal we've been talking about, but it also may elicit an immune response. And the higher the density of receptors on the cell, the more antibody that will coat the cell, and the greater the immune response targeting the cancer.

DR. LOVE: Now, what happens when Herceptin binds with HER2? Because you said normally there's not a ligand. So, somehow, Herceptin is binding, because it's an antibody to it. It's there. And then what is the effect? Does it disable it?

DR. PEGRAM: Exactly. When Herceptin binds to HER2 receptor, number one, it paints the cell with antibodies, just like antibodies paint the cover of bacteria when you fight off an infection. All of a sudden there's a potent signal for the immune system now, to try and attack the tumor cells. So, there may be some anti-tumor immunity.
Number two, and perhaps equally important, is that when the antibody binds to HER2, it disrupts the signaling function of the receptor, as well. And the mechanism of that is not entirely clear, but what is entirely clear is that it does disrupt signaling.

DR. LOVE: Now, the common figure you hear talked about is 20 to 30 percent of breast cancers overexpress HER2. Is that the number that you go with?

DR. PEGRAM: It looks like it's going to be 20 percent. And that number looks like it's becoming very, very stable. Dr. Giovanni Pauletti and Dennis Slamon at our institute studied a large cohort from South Australia of more than 900 primary breast cancer patients who's tumor samples were provided to us by Dr Ram Seshadri in South Australia. In those 900-odd samples, the gene amplification rate for HER2 using the FISH assay was 20 percent. Dr. Mike Press at USC, our collaborator in the Breast Cancer International Research Group, has examined the first 600 samples provided to us for the Herceptin adjuvant study being conducted by the BCIRG. And out of those 600 samples, the gene amplification rate for HER2 is 20 percent. So, it looks like that that's going to be a pretty stable number for the future.

DR. LOVE: Now, how about HER2 in other tumors?

DR. PEGRAM: This is a very frequently asked question. It's still largely been not addressed with big studies. The gene amplification rate in other tumors appears to be low to even non-existent in some cancers. It seems that the level of HER2 expression in the absence of gene amplification may not be high enough to expect much clinical activity from drugs like Herceptin. It's sad that this is the case, but I think that the preliminary activity in some small pilot studies, let's say, in lung cancer, have been largely disappointing in the case of Herceptin, probably because there's just not enough HER2.

DR. LOVE: Is there some biologic reason why you would see HER2 mainly in breast cancer? When I think about what differentiates breast cancer, I start to think about estrogens. Is there some connection there?

DR. PEGRAM: No. In fact, I think the main connection is the gene amplification molecular genetic defect. There is gene amplification in breast cancer, where there can be 20 or 50 or 100 copies of the HER2 gene. In lung cancer, you don't see gene amplification. Researchers in lung cancer that have said, "Oh, these lung cancers are HER2-positive." They've changed the scale on their detection assays and they call the highest lung cancer a 3+ and the lowest lung cancer a 0 to 1+. But if you look at that scale as it relates to the breast cancer scale, the 3+ lung cancers look more like about a 1+ on the breast cancer scale. So a lot of the early reports about HER2 overexpression in lung cancer and colon cancer and prostate cancer, I think, have to be taken with a grain of salt, because the expression levels are lower than they are when the gene is amplified in the case of breast cancer.
Ovarian cancer is another disease where the gene is amplified, but only about half as frequently. We've collaborated with Dr. Beth Karlan at Cedars-Sinai at UCLA, and she and Dr. Pauletti have done a large study, I believe involving more than 300 cases of ovarian cancer now. And the gene amplification rate was on the order of about 11 percent in that series. So, it's about half that of breast cancer.
But gastric cancer, salivary gland cancer, endometrial cancer are other examples where the gene has been shown to be amplified in a fraction of cases. In those cases, even though they're fairly infrequent and in fairly rare diseases like salivary gland cancer, I think Herceptin would be among the top choices for therapy, quite frankly, even though there's no label indication and probably never will be. Some diseases are just too rare to go through all of the rigors of FDA approval.
But I think, in the future, the paradigm of molecular-targeted therapy in clinical oncology is going to change. We're not going to have drug approvals based on diseases, they're going to be based on molecular genetic alterations. Hopefully we can break the ice with drugs like Herceptin to really prove that concept.

DR. LOVE: Interesting. Let's start going from this basic discussion, into a more clinical one. Can you talk a little bit about how you see the HER2 situation, right now, in terms of assays?

DR. PEGRAM: Well, Dr. Bob Mass presented an update of the FISH data from the HER2 clinical trials, the Herceptin clinical trials. And this data has been evolving over a number of years, and I think this is probably the final data set. It conclusively, in my opinion, shows that the patients who benefit from Herceptin are those that are FISH positive and have amplification for the HER2 gene. Those patients that are so-called HER2, "overexpressors" on the basis of immuno assays, do not seem to benefit from Herceptin treatment. This is probably because they are mixed in with a lot of false positives, because there are difficulties with the assay system involved with these immuno-staining techniques. So, there can really be no doubt that the FISH assay is here to stay. The FDA just approved it last week for patient selection for Herceptin treatment. I think this is a very important development.
It turns out that DNA is much more stable following formalin fixation and paraffin embedding of the tumor for a long-term, archival storage. This DNA is so stable that you can get a nice FISH signal for years and years to come. Whereas these protein immuno assay approaches all suffer from the hazards of false negatives due to fixation artifacts. Then we see false positives created by trying to overcome the fixation artifact by revving up the signal too high, and then you get 3+'s in normal tissue in that case, which is obviously a false positive.

DR. LOVE: From a practical point of view, the algorithm that a lot of people use is to first go with an IHC, because of its convenience and availability. And if that's 3+, to assume that the patient's essentially HER-positive, and from your point of view FISH-positive. Is that a reasonable approach?

DR. PEGRAM: Not really. I don't think there's any question that FISH will replace IHC. And I think it's going to happen sooner than later. Clearly we're dealing with patients' lives here. This isn't an exercise of statistics. I mean, there's nice data showing, oh, we have concordance between IHC and FISH. And the concordance number is, depending on the study, anywhere from, .5 to .9, or what have you.
But, this is medicine, and .9 may be too low for medicine. I don't want to lose even 10 percent of patients that might benefit from Herceptin by having a diagnostic that's imperfect. With the FISH assay now being approved on a broader scale for Herceptin treatment, the economy of scale will really make it competitive. It's clearly more accurate, and accuracy is the only acceptable way to go in medical diagnostics. We wouldn't accept an inferior medical diagnosis assay for heart attacks in the emergency room. We want the best. And when the best is available, people will gravitate to it and use it.

DR. LOVE: So, you're saying, basically that the IHC should be just put away and everyone should be FISHed?

DR. PEGRAM: It will be. Yes. For example, on the BCIRG. This is a global research network that spans five continents. The clinical trials in Herceptin, all those patients are going to have a FISH assay. It's done in central reference laboratories, and it can be done at a reasonable cost.
Remember, if there are false positives by the immunoassays, and patients get put on Herceptin that aren't going to benefit from Herceptin, that's equally bad as the false negatives where you're denying patients effective therapy. Herceptin, remember, has some toxicity. There are infusion reactions occasionally. There's cardio-toxicity occasionally in patients who have had prior anthracyclines, for example. And it's enormously expensive. One FISH assay is cheaper than one dose of Herceptin. So, from a medical-economic point of view for treatment of all breast cancer patients, clearly FISH would be more cost effective in the large scheme of things.

DR. LOVE: How about from a practical point of view for a practitioner in the community right now?

DR. PEGRAM: FISH is widely available. It may be a send-out test at your hospital, but guess what? So are more than 50 percent of your other medical tests. In all of internal medicine, almost every test that you send down to your local hospital lab these days, except for maybe a CBC and blood chemistries, all get sent out to reference labs. So, they'll just put the FISH slides in the same box that they're going to send out to the reference lab and you'll get the result in the mail in a day or two. It's trivial.

DR. LOVE: So, if a medical oncologist is evaluating a woman with metastatic breast cancer for treatment, you're essentially saying regardless of what IHC result is available, that patient's tumor should be assayed for FISH?

DR. PEGRAM: No. I'm saying that in a patient who hasn't had a HER2 assay, I would, by default, do FISH first. Now, if someone already has an IHC assay and you've already got the report, then you're just calling upon the clinician's judgment, because it may not be necessary to repeat an assay.
For example, if a patient is strongly ER-positive, has a well-differentiated, small tumor that's node negative, let's say a tubular breast carcinoma. If the HercepTest result is negative, well, I don't doubt that. Tubular breast cancers are never HER2 amplified. If you have a lobular breast cancer that's HER2-negative, I wouldn't dispute that, because they are rarely, if ever, HER2-positive.
However, if you have a high-grade, node-positive or metastatic lesion or a short time from diagnosis to metastasis, an aggressive-appearing histology, and you get a negative IHC result, well, obviously, that's somebody who you think has a HER2 phenotype. Those cases should be retested. It really boils down to clinical judgment, if an IHC assay has already been done. If one hasn't been done, it's easy for me to recommend FISH first. If one's already been done, I certainly, in my practice, don't repeat every single case. If the clinical history fits the result, then you're probably safe with an IHC assay.

DR. LOVE: With that patient you described, with an aggressive, node-positive tumor, if they have an IHC of 3+ -

DR. PEGRAM: Right.

DR. LOVE: - you treat them as HER2?

DR. PEGRAM: Sure.

DR. LOVE: What about if they're 2+?

DR. PEGRAM: The 2+'s are, by default, in most laboratories being sent out for FISH assays. All of my pathology colleagues across the country, are sending out 2+'s reflexly now for FISH assays, because 2+ is really in that gray zone where a clinician can't really be sure one way or the other.

DR. LOVE: What about the zero and 1+'s? I think a lot of people have gotten focused on the false positive, which is potentially an increased expense. On the other hand, granted, there are not that many women who are going to be IHC 0 or 1+, who turn out to be FISH positive. But you're losing a potential valuable therapeutic tool.

DR. PEGRAM: Absolutely. If you're faced with a patient, as I suggested, that has an aggressive biologic-behaving tumor, and you have a negative IHC sitting in front of you, well, that doesn't really fit. It doesn't fit the clinical picture. And, you know, these types of diagnostic algorithms in medicine are the norm. You know, when we have someone who comes into the emergency room with shortness of breath, then we get a VQ scan, let's say. Well, there's a pre-test probability that they have a pulmonary embolus, and a post-test probability they have a pulmonary embolus. If the clinical scenario doesn't fit the test results, we move on to a more accurate diagnostic test. So, in medicine, we do this all the time, and it's not asking too much of clinicians to use judgment. That's what we're best at. So, this is really not a major problem. Eventually, FISH will probably be done reflexly on everybody, and we won't even have to worry about this dilemma. But in the meantime, it's not a big step for clinicians to make these sorts of calls.

DR. LOVE: Is this clinical scenario of aggressively behaving breast cancer that reliable? Are you saying that if you have a woman who is node negative, diagnosed seven years ago and now relapses with soft-tissue disease and bone mets, and she's 0 to 1+, that, really, the clinical evaluation is that accurate, that you can say you don't have to worry about it?

DR. PEGRAM: I would not feel strongly about sending such a case for a FISH assay, to be honest. But if the time to progression were shorter or if they had some biomarkers, let's say intermediate nuclear grade and maybe aneuploidy but maybe the ER was weakly positive or what have you. Those sorts of things would start to make me second-guess the IHC result. But, in a scenario such as you just mentioned, I probably wouldn't necessarily reflexly send that for FISH.

DR. LOVE: Let's take the next step and now talk about the management of the patient identified as being HER2-positive. So, let's start with an easy one, which is ER-negative metastatic disease. What's your thought process there?

DR. PEGRAM: Well, it really boils down to disease burden, patient age and prior therapy. If they have a high disease burden, they're relatively young, and have a good performance status, I'm going to treat that patient with chemotherapy-Herceptin, which is the FDA-approved indication for Herceptin.
In my elderly patients, let's say with smaller volume disease, who are not good candidates for chemotherapy, I'm very impressed by Dr. Chuck Vogel's data showing that single-agent Herceptin can really cause a good clinical response in about a third of patients, about 34% response rate. And the clinical benefit scores, when you include patients who have prolonged disease stabilization, for six months or more, that's about half the patients, will get some clinical benefit that's meaningful with single-agent Herceptin, with no chemotherapy side effects. So, depending on the patient age, their medical condition, whether or not there's visceral disease, etc., that's going to sway my decision of chemo-Herceptin versus Herceptin alone.

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