INTERVIEW WITH DR. MICHAEL BAUM

DR. LOVE: Welcome to Breast Cancer Update, an audio review journal for medical oncologists…This is Dr Neil Love. In more than 25 years of following the evolution of breast cancer clinical research, I've observed a number of truly memorable moments.…Richard Peto's electric presentation of the first international overview at the 1985 NIH consensus conference….The unprecended 1988 NCI clinical alert on adjuvant sytemic therapy of node negative patients…..The 1998 NSABP press conference when Bernie Fisher announced the unblinding of the tamoxifen prevention trial. And on December 10, 2001, sitting in a lecture hall crammed with almost 4000 researchers and clinicians at into the initial session of the 2001 annual San Antonio Breast Cancer Symposium, I sensed that another sentinel moment was unfolding. Nine months previously, I interviewed a frequent guest for this series, Dr Michael Baum, principle investigator of the ATAC trial, the largest cancer treatment study ever conducted. He shared with us that a data analysis was scheduled for several weeks before San Antonio and wouldn't even hazard a guess as to what it might reveal. Gazing around the auditorium, I saw many of the research leaders interviewed for this series, and reflected on their predictions for ATAC. Pin-drop silence greeted Dr Baum as he started his talk. To tease the attendees, he paused for a few seconds before revealing the first of a series of data slides, several of which produced audible murmurs and even a few gasps in the audience particularly the curve for second breast cancers which demonstrated a dramatic advantage for anastrozole over tamoxifen. 24 hours later, after a blizzard of meetings with researchers and press conferences, visibly weary but with his typical bemused expression, Dr Baum sat down with me to review these historic data.

DR. LOVE: So what's new Mike? (laughter)

DR. MICHAEL BAUM: What's new? Craig Jordan started his talk by saying, "Tamoxifen - the gold standard treatment for breast cancer…Until yesterday". That made my day.

DR. LOVE: I've got to say, sitting in that auditorium yesterday, for all I've thought about that and talked to people about it, I'm still in shock. How did you feel about it when you saw that data?

DR. BAUM: Well, we took wagers on it and my wager was that we didn't have a result. Because although we were powered to have a result. We'd overlooked the fact that lots of the earlier events were non-informative amongst this peculiar group of the node-negative cases and there were a disproportionate number. So, it was a reasonable bet. So, then I was told there was a result, then I predicted it was a combination.

DR. LOVE: Really?

DR. BAUM: Yes. So, I wasn't shocked, I was somewhat surprised.

DR. LOVE: It kind of reminded me when I saw the prevention trial information for the first time because in a way I was amazed, but on the other hand, after a few minutes I started to think about it, in a way there sort of wasn't any surprises.

DR. BAUM: Yeah, you shouldn't be.

DR. LOVE: I don't think there was anything there that should be a surprise other than the fact that it came out early.

DR. BAUM: Yeah, the surprise to me was that we already had something and the other surprise was the magnitude of the reduction in the contralateral breast.

DR. LOVE: That was amazing.

DR. BAUM: That's hard to believe.

DR. LOVE: If you could, why don't you summarize what the results of the trial were.

DR. BAUM: As you remember, when we last spoke in Miami, we talked about adjuvant aromatase Inhibitors and the ATAC trial. It's just great to see you so soon afterwards to have a result to describe to the San Antonio audience, and to discuss it with you in person. This has been a continuing dialog over many years.

DR. LOVE: I was thinking about the first education program I did with you. I think it was in 1986, after the first overview. This is like the end of a cycle because that was when tamoxifen was really starting and then we've had the whole entire growth of tamoxifen, and now we're here.

DR. BAUM: It looks as if there is something after tamoxifen. So let me describe the results of the trial. There are over 9000 patients in this study, from all over the world. It is a very strong Anglo-American collaboration, which is almost unique. Just over 3000 patients in each arm of the study, and on average the patients are being exposed to two and a half years of the treatment. There was a statistically predetermined number of events we were looking for, which then triggered the first formal analysis. Although along the way the data and safety monitoring committee was keeping an eye on things, and encouraging us to continue, we passed that number of events. The predicted number was 1050, and in fact the data log was 1079 as I remember, and that was in July. The steering committee only learned of the results four or five weeks ago. So, it is a rapid learning curve for us to come to terms with the results in time to present them in San Antonio. Well, the headline news is…If you take the whole population, the intention to treat population, and describe relapse free survival, then there is a significant advantage over anastrozole compared to tamoxifen. And the real surprise is that the combination of anastrozole and tamoxifen, looks no different than tamoxifen alone. The hazard rate is .83, so that is an additional 17% relative risk reduction above and beyond that which can be achieved by tamoxifen and this is early days.

DR. LOVE: That includes some ER-negative patients.

DR. BAUM: Yeah. Now what makes it even more extraordinary is that that included some ER-negative and ER-unknown which amount to about 15% of the population. An American audience will find it surprising that they were ER- negative in this study. Well the recruitment criteria around the world were either ER-positive or ER-unknown. Initially there was about 30% ER-unknown and we retrieve those blocks, sent them to a central laboratory and we now know the all status on the majority. But it does leave us with about 8% who are known to be ER-negative, and as expected a disproportionate number of those have relapsed already, and to us these are non informative. So, a predetermined subgroup analysis of those known to be ER positive and there about 770 events within that group, and the effect comes out stronger, that the hazard ratio of Arimidex vs. tamoxifen is .79, equivalent to a 21% relative risk reduction. I personally think that is the relative number because we are not going to be treating ER negative, ER unknown, anymore. I think the whole world accepts that you got to know the ER status to treat breast cancer patients rationally. I must emphasize so far very few woman have died of breast cancer, although there are certainly differences in distant recurrence. If the behavior of this population mimics the behavior of all other populations in adjuvant trials and in the fullness of time we would expect survival advantage, but we have not seen that yet.

DR. LOVE: You mentioned the fact that there was an improvement in disease free survival with the anastrozole arm, but there was no difference in the combination arm. You speculated a little bit in the presentation about why. In affect what it seems like is that by having tamoxifen around you don't see as much benefit from anastrozole.

DR. BAUM: Or vise versa. Well, the first person to come up with an explanation, was the first person that saw the data, Jack Cuzick the independent statistician. For a statistician he is a pretty good endocrinologist. He proposed the theory that in the presence of tamoxifen the breast cancer cell recognizes tamoxifen as an agonist. Mitch Dowsett who is the endocrinologist on the team supported that view and described to us the rat uterine model and the xenograph nude mouse model, both of which showed this biphasic effect of tamoxifen. But in an estrogen-depleted environment, tamoxifen is viewed as an agonist by the cancer where in the estrogen-rich it is viewed as an antagonist. I was happy with that explanation until one hour after my talk yesterday. One hour after my talk yesterday Nancy Davidson gave a wonderful talk on the gonadotrophic-releasing hormone agonist in the management of premenapausal breast cancer and described that the addition of tamoxifen to a patient who is already estrogen depleted with cytoxic drugs and Zoladex had an additive affect. So, we can speculate. This is going to keep the endocrinologist busy and fully employed for a long time to come. It is good because I hate to see unemployed endocrinologists around the place.

DR. LOVE: The bottom line is that it's not going to be an option, at least clinically it looks very promising.

DR. BAUM: It's a most unpromising option and the steering committee is now struggling with what we should do for the patients on the trial. Our primary concern is to look after the patients on the trial. It is only a secondary concern what happens out there in the community for new patients. So, yes it is problematic.

DR. LOVE: By that, you mean whether or not to continue that therapy, the combination therapy?

DR. BAUM: Let's put it this way, it is an issue the steering committee is considering actively at this moment, and I can't divulge our current thinking on it because it isn't fully resolved.

DR. LOVE: Has that lack of benefit that was observed with the combination deter the group or yourself from thinking about other combinations? I know the one that I've heard people talking about is Faslodex and Arimidex.

DR. BAUM: Until we can begin to understand the endocrinology of this, we mustn't prejudge any other combination. You can build biological models as long as you like. I could come up with one that favors that combination and one that is not favorable to that combination. I think the endocrinologists have a lot of work on their hands.

DR. LOVE: You talked about the reduction in second breast cancers and the curve that you put up, it was almost shocking to see the shape, it stayed flat for awhile.

DR. BAUM: It is staggering. And it appeared so early on. I wouldn't worry too much about the right hand side of the curve because it's unreliable, but the odds ratio for the contralateral breast cancer favoring anastrozole over tamoxifen is .42 and the difference emerges within one year.

DR. LOVE: So, there is a 58% reduction over tamoxifen.

DR. BAUM: Above and beyond tamoxifen. If you realize that tamoxifen can produce about a 50% reduction long term. And if this holds up, and it's a big if, another 60% on top of 50% and then you start translating that into the chemoprevention of breast cancer. It's - you might say - scary.

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