Era of Hope 2011 Plenary Sessions

Session Title: Controversy Session – Setting the Bar

Title of Presentation: Molecular Diversity of Human Breast Cancers: Biologic and Therapeutic Implications

Sharon Begley, Scientific Journalist, Newsweek:Our next speaker is Dr. Dennis Slamon. Dr. Slamon serves as Director of Clinical Translational Research and as Director of the Revlon UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center. His research led to the identification of the HER2-NEU oncogene and contributed to the development of Herceptin; Dr. Slamon.

Slamon, MD PhD, University of California, Los Angeles: Thank you Sharon. So I have got just a few slides to try and put into point some of the things that have been raised, but—but coming out of the gate, I’ll say something that I’ve said to many of you in the past. And that is to repeat—never, never, never stop holding our feet to the fire in terms of what you want to see and—and the kinds of improvements that we need to have for this disease.

That said I’ve got 10 minutes to try and convince you that all of the efforts and work that you’ve done really has begun to change the equation, I think from the introductory presentations from Allen Ashworth and John Glaspy, you heard that we really do need to rethink how we do clinical trials and how we are setting them up. If you are doing a clinical trial that is a therapeutic clinical trial and it requires 3,000 or 4,000 patients to be enrolled you’ve got to scratch your head before you launch that trial as to whether or not you’re going to see a meaningful impact that takes that big a population to conduct the trial.

If we’ve learned anything from some of the effective targeted therapies is that you no longer need these huge trials if you’ve selected the right patient population. And how do we do that in breast cancer? Well breast cancer has led the way, again as I have mentioned to you in the past, in the field of oncology in teaching us that there is diversity within an organ system in terms of the malignancy that it ensues. So the biologic therapeutic diversity of this disease is what’s critical. But the global burden remains enormous in large part because in many of the developing countries, women are living longer and rather than die—die during childbearing years are living into their fifth, sixth, and seventh decade. And as you know this disease is a disease that increases with age.

Currently there are 1.5 million new cases worldwide, but the staggering statistics is between one in five and one in six women globally and one in ten of all cancers that are diagnosed globally are breast cancer. So one in five, to one in six women will develop the disease and one in ten of all the reported cases of malignancy of any histology is breast cancer.

There are over half a million deaths globally each year and in the U.S. you know the numbers, approximately 200,000 new cases and around 39,000 deaths.

Now part of the complexity that you’ve heard about again and again at the meeting comes from the fact that rather than thinking about this as a monolithic organ, we now know that there is a spectrum of cells that make up the breast and that there are cells that line the lumens, luminal cells, and cells that are below those cells known as the myoepithelial basal cells. The important take-home of all of this work is that either of these populations can become transformed into a malignant cell and form a tumor. And depending on what population is transformed and depending on the alterations that got those cells to be transformed, the approach to therapy should be quite different. And the one-size-fits-all approach that we’ve spent the last 40 to 50 years doing in most of the large clinical trials needs to really be rethought, so that you no longer are using uniform approaches to these as we’ve done. And I think that case has been made again and again as we’ve moved forward.

The paradigm has clearly shifted. There still is a movement of new concept and new ideas out of the laboratory into clinical hypotheses, into clinical testing but what’s changing is as these results become available and the material from clinical trials are available they go back to the laboratory for further evaluation, further refinement of the concepts on the hypotheses and further clinical testing and sort of this cyclic loop that will allow us to learn from clinical trials.

One of the take-home messages I’d like to leave with my colleagues in industry and my colleagues in academia is—is it right to even participate in a clinical trial where if the patient can sense we do not do tissue acquisition? It is impossible; it’s probably the worst outcome of any clinical trial to not have an answer. That’s even worse than a negative answer. To conduct a clinical trial, see a result, and not be able to make heads or tails out of it because you don’t have the material that went into that clinical trial in terms of the tumors. So that’s one of the take-homes I would leave you with.

We know that the heterogeneity of the disease is—is what’s responsible for a large parts of the various outcomes. You all know the slide very well, Laura [van’t Veer’s] work; the group from the Netherlands as well as the Scandinavian group shows that the sub-types depending on sub-types have very different outcomes. The luminal A(s), luminal B(s), the so-called triple negative which are marked by what they do not have—they don’t have the HER2 alteration, and they do not express large levels—high levels of hormone receptors, and then the HER2 population shown here in pink. And the outcome data for these are very, very different depending on the sub-type you’re dealing with. This—these are data before adjuvant therapy came into be, and therefore you’re looking at the natural history of breast cancer treated just with surgery and some of these patients received radiation therapy. When we’ve added our incremental therapies on top, we haven't made a big impact on these differences. So this is post-adjuvant therapy and still they’re tracking almost true to form in terms of the outcomes.

So what are the roles in molecular alterations in the pathogenesis of breast cancer? We now know and you’ve heard over the course of the meeting that there are seven to eight different defined molecular sub-types but in reality they fit themselves into three therapeutic types—those that are driven in large part by the hormone receptors, those that are driven by alterations in the HER2 receptor, and those that have neither of those two alterations which have been left behind or so-called triple-negative or basal cancers. The critical thing to know is the percentages that these cancers make up in the total burden certainly in the U.S. and Canada and Western Europe, so about two-thirds of breast cancer is hormonally related, 20 to 25% is related to the HER2 alteration, and between 15 and 18% is the so-called triple negative population. But this pie chart doesn’t even begin to tell the tale because within each of these slices is considerable heterogeneity. There are those women within hormone receptor positive disease who respond very well to hormonal manipulation, whereas there are those who have the de novo resistance and do not do well.

HER2 positive disease there are—the new HER2 targeted therapies, Trastuzumab, patented, not so new anymore, can really change the outcome in what was the previously the worst outcome sub-type to among the best but not for all patients. Half of the patients out of the gate may not respond to this therapy and of the ones who do respond there can be recurrences. So the initial hazard ratios of .5 or 50% reduction excited us all, myself in particular, but the reality is when we follow these patients over time we do see those hazard ratios begin to deteriorate. And what’s going on there? And then in the triple negative population much has been talked about with regards to DNA repair mechanisms, PARP inhibitors, and there’s been excitement about that but the initial trial that was launched there was a trial on which tissue acquisition was not required? Perhaps 15 to 20% of the patients who went into the trial were truly hormone receptor positive and surprise, surprise—they didn't hit the end-point. Now there may be a couple of reasons for that not the least of which is it wasn’t necessarily the best PARP inhibitor going into the trial. But in addition, it wasn’t really designed to make sure that all the patients that went into the trial were the selected population. So these are important points.

A take-home message as I come to closing these comments in terms of how we design these trials quickly is in the HER2 population. We saw that we could significantly dramatically change the outcome by translating this alteration that occurs in 25—20 to 25%. But when women have this, and we identify those women and put only them in the clinical trial—that trial for the initial approval of drug required 450 patients. That’s all required. That can be accrued relatively rapidly and the follow-up time can be relatively short as opposed to the larger trial. And you can get these kinds of differences in outcome.

So the reality is the hope that we might be able to do better is something that’s—useful for us all to remember and I’ll close on that—but the reality is we’ve got to design the trials much more rationally.

The excitement is that we’re seeing now and you’ve heard the reports, we haven't seen the hard data yet for it, but for hormone receptor positive disease the mainstay has been assaults on the hormone receptor pathway through Tamoxifen, through aromatase inhibitors and through Faslodex all going after that single pathway. But we now know from some of the work that’s been supported from this program that there are other pathways that can influence resistance. And a recent clinical trial—this has been reported in the press although not the data—it’s only been reported in the press because it—the trial contained—the company has material information that they have to release by SEC regulations. But there is a significant result when you combine therapeutics that will approach the PI3 kinase pathway simultaneously with the ER pathway. That will be presented later this year. I can tell you the results are very impressive in terms of the magnitude of the difference. It’ll no longer be the incremental differences.

In the HER2 positive sub-type a new therapeutic called TDM1 is enormously effective and equally effective to Trastuzumab, perhaps better. There will be updated results on that trial presented later this year, but the most important thing is not only are you supposed to look for improvements in efficacy, certainly we want that; but the safety profile is enormously different. Alopecia is almost-nil; cytopenias don’t occur with this drug. The fatigue, the lassitude that attends all of our chemotherapy-based regimens is gone with this drug in the large clinical trial that’s been reported to date. This needs to be moved as quickly as possible into a focused targeted small and rational clinical trial. That needs to happen as well.

For the triple negative population, there is no question that the synthetic lethal approach has good scientific hypotheses and rational. Now we need to use good PARP inhibitors and an appropriate selected patient population to identify what groups of the triple negatives really benefit from that approach.

All of that said, I think what you’ll see and I think you’ll see this in the coming 12 to 24 months, so I know it’s always a risk to make a prediction, but there will be dramatic changes in at least two if not all of these sub-types in terms of the outcome. And as we learn more, you’ll begin to see more and I think that you sticking with this program for the time that you have in such difficult—difficult times in terms of funding from the government you will have a return on your investment in the scientific community. That said, do not ever let up on the pressure you put on us to make meaningful differences in these diseases as opposed to incremental differences. Thank you.