SABCS Wrap-up: Will TNT Quietly Change Practice?

Kathy D. Miller, MD; George W. Sledge, MD


December 22, 2014

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Back in the Day at the SABCS

Kathy D. Miller, MD: Hi. I am Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights, from the 2014 San Antonio Breast Cancer Symposium (SABCS). Joining me today to discuss some of the most surprising results of this year's meeting and how the meeting might have changed over the past nearly 40 years is Dr George Sledge, professor of medicine and chief of the Division of Oncology of Stanford University, and also chief of the Division of Oncology at the Stanford Women's Cancer Center. You were at the first San Antonio meeting. Take us back to that first meeting. What was it like at the beginning?

George W. Sledge, MD: It was a very regional meeting. It was a meeting for south Texas private practitioners, as a way of educating them, and as a way for Bill McGuire, who started the program, to bring in friends and colleagues from around the globe. It was tiny, perhaps 50 people in the room, with perhaps a dozen or so speakers. There were no poster sessions. There was no real exchange of scientific information outside of the talks themselves, so it was very different from what we see today.

Dr Miller: Was it a multiday meeting?

Dr Sledge: I remember it as being a 2-day meeting, although whether I can trust my memory is somewhat suspect.

Dr Miller: I'm going to stress your memory even more: Do you remember any of the scientific presentations from that first meeting?

Dr Sledge: I do, because very early on Bill was exceptionally good at getting the top talent in the world there. I remember Norm Wolmark and Bernie Fisher being there, although I may be conflating that meeting with other meetings. What was fascinating to me, to give you some idea of how unadvanced it was, was that I was charged as one of the oncology fellows with creating case studies to present to the visiting faculty—sort of "stump the band" cases.

Dr Miller: Did you stump them?

Dr Sledge: It certainly stumped me. As a very junior fellow, the number of breast cancer cases I had seen at that time, I could probably count on one hand.

One-Room School for Breast Cancer

Dr Miller: You have gotten older. The meeting has grown tremendously to become an international venue . Does the meeting still surprise you?

Dr Sledge: It still intrigues me. Bill McGuire and his colleagues, such as Kent Osborne and Chuck Coltman, did some wonderful things that serve as a model for a disease-specific meeting. First and foremost, of course, is that almost all of the sessions are in the same room, so clinicians, laboratory doctors, and everyone else who shows up at the meeting is hearing the same thing. This separates it from ASCO [the American Society of Clinical Oncology] or ACR [the American College of Radiology], where you have a multitude of different subjects being covered in a multitude of different rooms, and you are running around from place to place. Here, everyone hears the same thing. Everyone gets the same information. That allows you to develop a community that knows pretty much the same thing. And that has turned out to be very important.

The other very important thing that Bill did at an early point, probably year 3 or 4 of the meeting, was to start having poster sessions. Those poster sessions allowed younger investigators to give presentations. As a third-year fellow, I gave my first oral presentation at the SABCS. Whether that talk would get me on the podium today is a different question.

Dr Miller: Do you remember the topic?

Dr Sledge: Yes. It was on what would now be called a heat shock protein, although we didn't know that at the time.

Dr Miller: You were ahead of your time.

Dr Sledge: Yes, indeed.

Dr Miller: The other thing that, to me, still seems somewhat unusual about this meeting is the integration of breast cancer patients and advocates in the oral sessions and poster sessions, as full partners. When did that come about?

Dr Sledge: It wasn't early. That happened later, after the meeting had been going along somewhere in the range of 15 years or so. The Alamo Breast Cancer Foundation got connected with the meeting [by establishing the Patient Advocate Program, as a component of SABCS] and then provided its consumer thoughts about the meeting. That certainly helped it and continues to do so.

The Intriguing TNT Trial

Dr Miller: I want to take you to this year's meeting. Is there one result that really surprised you that you heard this year?

Dr Sledge: I don't know about surprised, but certainly intrigued. It was Andy Tutt's TNT trial,[1] even though it was asking a very old-style, almost 1980s-1990s toothpaste A vs toothpaste B question.

Dr Miller: Yes, one chemotherapy vs another chemotherapy—ho-hum.

Dr Sledge: Yes. What you would think was the most boring thing on the planet, in fact, has an immense amount of biology attached to it, which is absolutely wonderful. First off, it was as previously suspected, but the clear demonstration that platinating agents are superior in a patient who has a BRCA mutation is quite important and certainly will direct therapy for many of us. Indeed, mainly it will get us doing a whole lot more BRCA testing than we have done previously, I suspect.

The other part of that study that I actually found very fascinating—and, in fact, I asked Andy a question about this in the question-and-answer period—was regarding the nonbasal triple-negative breast cancer part of the population; there was a 78% response rate for docetaxel. That's the highest response rate for a taxane in any breast cancer study that has ever been presented. There are lots of qualifiers—small numbers, wide confidence intervals—but if it's reproducible, there is probably some fascinating biology going on there that we don't understand.

The Disappearing Barrier Between Lab and Clinic

Dr Miller: This was a meeting heavy on biology. I'm not sure, in one meeting, that I have seen presentation after presentation of sequencing results, some large-scale efforts, and some small, focused efforts. It was an interesting juxtaposition to a poster session that showed trial after trial of negative chemotherapy studies.

Dr Sledge: Yes, it tells us where we are moving, certainly. The rapid fall in the price of gene sequencing has made it possible, for the very first time, to do population-based studies and clinical trial-based studies in ways that we never could have before. But even more so, what is fascinating is that this means that laboratory scientists, who usually tend to be quite a distance from what we are doing in the clinic, are now absolutely integrated in the clinical trials and perhaps at a very early phase. The barrier between the laboratory scientist and clinical scientist has almost disappeared. We saw that in the Brinker awards this year. The Brinker awards typically go to a laboratory and a clinical scientist. Joan Brugge, from Harvard, won the laboratory award, but a PhD, Mitch Dowsett, won the clinical award.

Dr Miller: I found that fascinating. I actually had to look up Mitch's CV because I had never thought of Mitch as a clinical investigator, although he has done some very important work looking at estrogen receptor (ER) testing and ER signaling in many of our large clinical trials.

Dr Sledge: The ability to rapidly move laboratory observations—in particular genomic, epigenomic, and proteomic observations—into the clinic is going to be the hallmark of our era. It's where we are going. It's where we are going to learn the most in the quickest amount of time. If you ask me, that is what is really different between now and when the SABCS started. When it started, we were clearly shooting in the dark most of the time. We were outside of the ER, which Bill McGuire championed and pioneered.[2] Outside of the ER, everything we did was empiric. We are now reaching a point where at least our empiricism is at least somewhat directed by the science; that has changed everything and it is going to absolutely change everything going forward.

In the Hall of PI3K Mirrors

Dr Miller: A couple of presentations might suggest that sometimes we are shooting in a hall of mirrors or our focus might be a little fuzzy. Some phosphatidylinositide 3-kinase (PI3K) inhibitor studies—for which many of us had high hopes [because the PI3K pathway is] commonly mutated, commonly active, particularly in our ER-positive patients—but two studies looking at a broad PI3K inhibitor with hormone therapy were not strongly positive.[3,4]

Dr Sledge: It's safe to say that everything we expected about PI3K inhibitors 5 years ago was wrong. We assumed that PI3K mutation would be associated with worse prognosis. If anything, it's associated with better prognosis. We assumed that PI3K mutation would predict for a response to mTOR inhibition or PI3K inhibition. It's not at all clear that it does, and, in fact, the only data we have say that it doesn't. We assumed that because PI3K plays a central role in a very important pathway within breast cancers and other malignancies, that shutting it off would have a huge effect in terms of outcome. But what we are seeing here is what we have seen again and again with kinase inhibitors across the board: The heterogeneity of these cancers, the whack-a-mole nature of these cancers, the fact that PI3K is tied in to so many things inside the cell, means that you develop fairly rapid compensatory mechanisms of resistance. The end result of the trials that were presented at this meeting, and some emerging data elsewhere, has been disappointment.

Dr Miller: We should stipulate that the trials we saw results for here were with broad PI3K inhibitors, at least on the laboratory side.[3,4] There is maybe still a little more enthusiasm for some that are more specific to the alpha subunit, although those clinical trials are now going to get a little greater scrutiny.

Dr Sledge: Yes, we certainly hope that that will be the case. Certainly, it is dangerous to say that because the first trial with the first drug doesn't work out, that means there is something wrong with the concept. We certainly saw this in melanoma. I am sure you will remember sorafenib, with the RAF inhibitor, was going to cure melanoma. When those hopes collapsed, that, in fact, shut off RAF research for several years in melanoma until we got better drugs. To what extent the problem here is a drug problem and to what extent the problem is a biology problem remains to be seen.

You Heard It First in San Antonio

Dr Miller: In our last minute or two, was there something you saw here for the first time at this meeting that you think might be the next wave of the future?

Dr Sledge: The interesting thing that we all saw here, that we have all been hoping to see but are still not quite sure what it is, of course, is immuno-oncology. We saw the first presentation of a checkpoint inhibitor in triple-negative breast cancer.[5] Now, the results weren't stunning. There was an 18% response rate, but it was a small study, and early days, in a fairly heavily pretreated population, and some of the responders were responding for a good, long time. Going forward, are we going to see, in triple-negative breast cancer, or perhaps other breast cancers, something similar to what we have seen in melanoma, non–small cell lung cancer, lymphoma, and bladder cancer with the checkpoint inhibitors? It's early days, but there is certainly a lot of excitement there. And you saw it here first at San Antonio.

Dr Miller: George, thank you for taking us back on this little trip through memory lane of the SABCS and looking toward the future of the SABCS in the field.

Dr. Sledge: Indeed. I plan to be here at the 80th anniversary.

Dr Miller: To you, our listeners, thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from San Antonio.


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