This trial will be launched pending results of a trial that's going to be reported later this year comparing Faslodex to tamoxifen in the metastatic setting. It's hoped and perhaps expected that there's going to be some superiority. In addition, the data that I presented were in postmenopausal women, and they would like to see some efficacy data in premenopausal women before launching the study.

So to review, Faslodex is an agent not yet on the market that the NSABP is talking about studying and comparing to adjuvant tamoxifen for five years. Let's go back to our patient with the next interactive question.

Recent, Select Publications

Research Leader Commentary

How would you feel about offering this patient participation in the proposed NSABP adjuvant Faslodex vs tamoxifen trial?

Commentary by Drs Morrow and Davidson

Dr Love: More than two-thirds of the audience would offer a patient like this one participation in the proposed NSABP trial without hesitation. So, generally it seems like a trial that has generated a lot of interest.

Dr Muss: I think this study is an excellent idea. Faslodex is extremely well-tolerated, and it has a unique mechanism of action — it's not a partial agonist-antagonist SERM. This is an excellent subset for this trial. The only drawback might be the IM injections, but they're monthly and very well-tolerated — there have been very few substantial reactions. They're not really that user-unfriendly. I think it's a great idea.

Dr Love: Let's go on to the second case, a 50-year-old woman who has prior benign breast biopsy and now a second breast biopsy showing atypical hyperplasia. She has no family history of breast cancer. She ceased menstruation a year ago and is doing well, with minimal menopausal symptoms. Her five-year Gail risk is 3.4 percent and her lifetime risk is 28.2 percent. So, we have a 50-year-old postmenopausal woman who has now had her second breast biopsy now showing atypical hyperplasia.

Before I ask you how you would manage a woman like this in a non-protocol setting, let's view a short video of one of the nurses at our hospital, who had a breast biopsy. She, in many ways, was similar to this patient, except the biopsy did not show atypical hyperplasia. But I want you to consider her feelings and attitudes in this situation.

Patient's Perspective

Dr Love: Many of our patients are very proactive about their health, and very concerned about risk of breast cancer. So, we're going to take this woman's attitude and mood and apply it to our patient with atypical hyperplasia as we consider the following questions.

What would your usual pharmacologic management be of case #2 in a non-protocol setting?

Commentary by Monica Morrow, MD

Dr Love: So, the vast majority of the audience would recommend tamoxifen for this case. Let's talk about some of the trials that this patient might be eligible for and how you'd feel about putting a patient like this on the trials. The two I want to talk about are the NSABP P-2 comparing tamoxifen to raloxifene and the IBIS 2 trial that's about to be launched in Europe, which will randomize to Arimidex, tamoxifen or a placebo.

Let me go through some background on these trials, and as part of this, I want to make a few points about aromatase inhibitors.

We know that in postmenopausal women, the major source of estrogen is from peripheral conversion of androgens by the aromatase enzyme. There are three inhibitors of this enzyme that are currently available: the nonsteroidals anastrazole and letrozole and the steroidal agent exemestane. There have been encouraging data on these third-generation agents, compared to tamoxifen in metastatic disease demonstrating superiority to tamoxifen. The first set of trials that came out, Trials 27 and Trials 30, compared tamoxifen versus Arimidex as first line therapy in metastatic disease. In the North American trial (30), there was a greater time to progression for patients randomized to Arimidex. It was tolerated similarly to tamoxifen; however, there were fewer instances of thrombosis and vaginal bleeding with Arimidex. When patients were crossed over to the other agent, the response rates seemed to be similar.

We're starting to see similar data with the other aromatase inhibitors as well, but these exciting data suggesting superiority of these third generation agents to tamoxifen are the basis for new trials of aromatase inhibitors earlier in the breast cancer continuum. The ATAC trial is looking at the aromatase inhibitor anastrozole (Arimidex) in the adjuvant setting, and there's a new trial being discussed by the NSABP — Dr Margolese is spearheading that effort — comparing anastrozole to tamoxifen for DCIS.

This high-risk woman with atypical hyperplasia might be eligible for NSABP P-2 in which she would be randomized to either tamoxifen or raloxifene. The other prevention study, not yet launched, is IBIS 2, in which she would be randomized between tamoxifen, Arimidex and a placebo.

What are your thoughts are about putting a patient like this on these two trials?

Which of the two major trials would you be comfortable with case #2 entering?

Commentary by Monica Morrow, MD

Dr Love: Dr Costantino, you have been very much a part of both the P-1 study and now the STAR trial. What are your thoughts about this situation and these research questions?

Dr Costantino: I think it comes down to differences in philosophies between the United States and England about the idea of having a placebo arm. The STAR trial does not have a placebo arm, because once we have a therapy that we know is effective, we believe it is unethical to withhold that therapy from someone who needs it. It would be like finding someone with extremely high blood pressure and offering to put that patient in a trial where they would not receive an intervention. That is not acceptable in this country, and our institutional review boards would not let us design a trial that way. I think that's probably what the issue really comes down to.

Dr Love: Dr Vogel, you're the principal investigator of the STAR study and, obviously, you have thought about the question of a placebo arm. I'm sure Joe is right in that the issue of placebo is what makes people uncomfortable about IBIS 2. What are your thoughts on this kind of patient?

Dr Vogel: I have a very, very hard time not recommending either the STAR trial or tamoxifen to this woman. I could not in good conscience offer her a placebo. My hierarchy would be STAR first, then tamoxifen. If she were averse to the notion of an intervention, I suppose IBIS might be a possibility, if it were available.

Dr Margolese: There's a lot of meat in this question, but I would like to make two points. One is that it was quite necessary to finish the first IBIS trial and, therefore, look for confirmation of P-1 or lack thereof. And, I think it's been necessary for those in the U.K. to play down the advantages of tamoxifen in order to look at it from that point of view. Although I think that is perfectly legitimate, we have to recognize it for what it is — an attempt to interpret this from an angle that may not hold up.

The problem with IBIS 2 is that if the first trial (IBIS 1) confirms the advantage of tamoxifen, the investigators will have to drop the placebo arm. If the first trial says tamoxifen is not of use in this regard, they have to drop the tamoxifen group. So, as their data from IBIS 1 mature, they will need to revise the protocol.

My second point relates to some of the weaknesses of tamoxifen. It's necessary to put all this in perspective. The complications of endometrial cancer and thromboembolic problems are age-related. In a 50-year-old woman, there is little or no excess of these complications compared to the placebo group. I would feel safer and happier if she were a 43-year-old woman, but I think the same applies to a 50-year-old woman. We can say the benefits are there, and the risks do not seem to be as bad as if you look at the numbers in general. We're talking about a group where the benefit ratio, seems to me, is in your favor.

It's important that this all be kept in mind when we look at these issues. It's not just one number, one person. I don't even think that five years of tamoxifen is a magic number. For some women, three years is enough. For others, seven, eight and nine years may be appropriate. But we have to find out who they are.

Dr Love: I am sure that some of our U.K. colleagues on the panel would like to share their viewpoints, Mike?

Professor Baum: It's an inappropriate analogy to compare the treatment of hypertension to the treatment of someone at an increased risk of developing breast cancer. We know the long-term results of screening and treatment of high blood pressure reduce deaths and strokes. What we don't know yet about prophylactic tamoxifen is whether the prophylaxis of a number of estrogen receptor-positive breast cancers in the end is better than the treatment of the same number of estrogen receptor-positive breast cancers. Unfortunately, because of the closure of P-1, we'll never know that because of the number of women who crossed over. And I think we need to wait until we know the long-term results of IBIS I.

Dr Costantino: I agree that we do not know whether or not the reduction in risk with tamoxifen translates into a reduction in mortality. But to say that tamoxifen does not have a benefit, I think, is saying that morbidity associated with physical and emotional problems doesn't count. You've prevented the disease from occurring in these women and that's a definite benefit.

Professor Baum: Hang on! Someone caused that emotional problem in that woman. There are a great number of unnecessary biopsies being done. The cruelty here is that we now have to look this woman in the eye as a result of two unnecessary biopsies showing some pathology of borderline significance. Why did she have those biopsies? Some surgeon out there needs training.

Professor Dixon: I'd like to reinforce that point. Some of the biopsies we're doing may not be necessary. Also, even in the National Health Service in the U.K. that lady would have had an ultrasound scan, a mammogram, a fine needle aspirate reported immediately in the clinic, and she would know with a reasonable degree of certainty what was going on immediately and not have to wait. You might do a biopsy at a later date, but you'd have a fair degree of certainty that it was a benign lump. So, I agree with Mike. Some of the biopsies we're doing probably are not necessary.

Dr Margolese: There's a psychological aspect to this risk-benefit problem, too. We talk about giving someone tamoxifen, and we say, "Oh, my God! Don't forget there's a risk of endometrial cancer," and that becomes a problem that looms large. But, we give millions of women estrogen replacement therapy, which carries the same risk. Of course, we offset it with progesterone, but we don't offset it 100 percent. The same can be said about vascular problems. The estrogen replacement therapy carries the same risks. But we don't think about it as a big problem.

I think it's important to keep all this in perspective. The same is true about equating a case of endometrial cancer with a case of breast cancer. In these 13,000 women, there was only one death from endometrial cancer, and it was in the placebo group in a woman who declined treatment.

Dr Love: We could talk about this all day, but let's go through the last case. The patient is a 54-year-old woman. Five years ago, she had an ER-positive infiltrating carcinoma with three nodes positive. She was premenopausal when she was diagnosed, received chemotherapy in addition to tamoxifen and now is postmenopausal. She has now been on tamoxifen for five years, and is doing well with no evidence of recurrence. The question is, at the end of her five years of tamoxifen, what should you do?

What would your usual non-protocol pharmacologic management be of case #3?

Commentary by Drs Morrow and Davidson

Dr Love: It is interesting that two-thirds of the audience would stop the tamoxifen, but many would continue it, and some would start an aromatase inhibitor or raloxifene.

Let's talk about trials that she would be eligible for, including the one out of Oxford looking at this question — the ATLAS trial. This trial would randomize a patient like this to continue tamoxifen for another five years or stop it. Another series of studies are looking at all three of the aromatase inhibitors, including a new NSABP trial comparing exemestane to stopping.

Which of the two major trial types would you be comfortable with the patient in case #3 entering?

* continue TAM vs stop
** aromatase inhibitor vs control

Commentary by Drs Davidson and Morrow

Dr Muss: These are both very reasonable types of trials, and ATLAS (Adjuvant Tamoxifen, Long Against Short) is now available to U.S. investigators who are interested. These are excellent opportunities for practicing physicians to participate in clinical trials and will provide us at some point in the future with the right answer.