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.

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