Kathy D. Miller, MD; Brian Leyland-Jones, MD, PhD


December 15, 2010

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Kathy D. Miller, MD: Hello, I'm Dr. Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. This is Medscape Oncology Insights in Breast Cancer, coming to you from the 2010 San Antonio Breast Cancer Symposium. Today I'm joined by Dr. Brian Leyland-Jones, Georgia Cancer Coalition Distinguished Scholar and Professor at Emory University School of Medicine in Atlanta, Georgia.

CYP2D6: Why Measure It?

I asked you to come in today to talk about some of the developments in endocrine therapy, and specifically the ongoing controversy as to whether we ought to be measuring CYP2D6 genotype in patients who are going to be treated with tamoxifen and whether that should be guiding our treatment decisions. First, can you take us back a bit and explain why it was thought that CYP2D6 might be important in tamoxifen therapy?

Brian Leyland-Jones, MD, PhD: Tamoxifen is a prodrug. It's metabolized to several active metabolites, and the enzymes that metabolize it all work at different rates. There has been a classification, and especially with this dominant 2D6 group, of what are called extensive intermediate and poor metabolizers. As you know, we've all got patients who are suffering on aromatase inhibitors. I've had one who's flipped through all 3 of them and she was still having bad problems with side effects. I've got another patient who's been taken off aromatase inhibitors just because of expense. We thought that there may be a group of patients who would benefit equally from tamoxifen as from the aromatase inhibitors. So for those patients who are extensive metabolizers of tamoxifen -- in other words, they make the right amount of the active metabolites -- it was thought perhaps that in that population, tamoxifen could be equivalent to the aromatase inhibitors in terms of efficacy.

Dr. Miller: I think there was also some concern that perhaps for premenopausal patients, if they were in the poor-metabolizer group, they're not making the active metabolite, that perhaps they wouldn't benefit, and we would need to consider other therapies.

Dr. Leyland-Jones: Absolutely. This has been intricately linked to this business of hot flashes as well. The sort of people who would make the active metabolites would have hot flashes, and that would be associated with better treatment. Some physicians are even taking their patients off tamoxifen if they aren't getting hot flashes. There's been this integral mix of poor metabolizers, doing worse, not having hot flashes; could the extensive metabolizer group do just as well with aromatase inhibitors as with tamoxifen?

Dr. Miller: This is an area that's been studied fairly extensively, with over 15 studies. However, they've all been limited, very retrospective, and had quite small subsets. Some of the efforts to use large prescription databases just ran into trouble with the data that were available.

Dr. Leyland-Jones: Naturally, we had to know the literature before we went into this. There have been 178 recent publications, 15 studies for, and 15 studies against the argument. This was a pivotal San Antonio meeting in that way because 2 large studies were presented back to back.

The ATAC Trial

Dr. Miller: 'Let's first talk about the ATAC [Arimidex, Tamoxifen, Alone or in Combination] trial.[1]The efficacy results of this trial have been presented many times at this meeting. However, this was one of the first, and perhaps one of the most important, biomarker studies looking at CYP2D6 in a subgroup of patients, focusing only on those treated with anastrozole vs tamoxifen. Did they find an association with genotype?

Dr. Leyland-Jones: The quick answer is no. As you said, the difference was that it was anastrozole. They did have concomitant meds. Their limitation was that they had a smaller number of patients than us, but it was still fairly convincing. It was about 1200 patients overall.

Dr. Miller: The concomitant meds are important because this is an enzyme that can be inhibited by medications.

Dr. Leyland-Jones: Thank you for amplifying that. Any 2D6 inhibitors, of course, can inhibit. They had 1200 patients, and Jimmy Rae, who presented this study, has come up with an algorithm of 8 or 9 key alleles that predict for what you call 2D6 phenotype. He had measured the vast majority of these. He calculated the 2D6 phenotype and showed that it had no influence on the outcome. He had also taken one of the catabolic enzymes, which is the UGT 2B7*2. He'd looked at that one as well, which is also pivotal in the breakdown of the tamoxifen metabolites, and it showed that it did not have an effect. So this was a trial that was done with anastrozole in the ATAC, showing that CYP2D6 phenotyping and UGT2B7 phenotyping did not have any effect on the outcomes.

Dr. Miller: I don't recall Jimmy showing any details of the data. I do recall him mentioning that when they looked at concurrent medications and included that in the phenotyping score, it still didn't change the outcome. There was still no association.

Dr. Leyland-Jones: Absolutely. But that area is still slightly controversial, simply because it was only about 9% of the patients. And Matt Goetz, when he did his summary at the end, said he would still not recommend using strong 2D6 inhibitors.

The BIG 1-98 Trial

Dr. Miller: You looked at this in the BIG [Breast International Group] 1-98 trial.[2]Another very large randomized trial comparing tamoxifen with anastrozole.

Dr. Leyland-Jones: With letrozole.

Dr. Miller: With letrozole. Yes, thank you. Your study had samples from a lot more patients than in the ATAC trial, but you were criticized because you didn't have the data on concurrent medications.

Trial description

Dr. Leyland-Jones: Yes. We made about 5 or 6 points in the study, but essentially, it was 8000 patients. We concentrated on the monotherapy arms, which gave us a total of 4628 samples that we had genotyped. Among the monotherapy population, we had final material on approximately 2600. This gave us a significant degree of power in terms of doing the analysis. First of all, it must be stressed that these are postmenopausal women only at this point in time. But we looked at the Jimmy Rae algorithm exactly the same way. The genotyping was done in a clear, certified laboratory approved facility which is critically important. We looked at 2D6 phenotype in tamoxifen patients and letrozole patients. Three quarters of the patients did not receive any chemotherapy. This was the first study that had a fairly significant cohort of people receiving chemotherapy as well as the hormonal therapy. We looked at the hot flashes as well. So we came up with a hazard ratio for the intermediate poor and extensive metabolizers of 1, exactly.

Dr. Miller: So not even a hint of a prayer for a teeny, tiny difference in your study?

Dr. Leyland-Jones: No hint of a prayer. You know, just going through some of the data that we presented, we looked at the 2D6 phenotype, and especially at the *4 allele. We looked with and without chemotherapy. We looked at the letrozole with and without chemotherapy. And if you actually look at the curves, the extensive metabolizers, which should have been at the top in terms of Kaplan Meier, they fell -- that extensive metabolizer curve came exactly between the intermediate and the poor. And just in terms of the correlation with the hot flashes on this, it was fascinating in that those with the lowest number of hot flashes were in fact those who were extensive metabolizers.

Dr. Miller: Who should have had the most, if this was correct.

Dr. Leyland-Jones: Who should have had the most.


Dr. Miller: There are always a lot of questions and issues that studies like this can't answer. We've talked a bit about the potential importance of concurrent or concomitant medications, but there are also issues of compliance. What do we know about how consistently and regularly the women in this trial were taking the therapy? There has been a concern that perhaps the extensive metabolizers who make most of the metabolites may have gotten greater benefit but also suffered less toxicity, and perhaps they self-moderate that by taking the therapy less reliably. Do we know about compliance in these large trials?

Dr. Leyland-Jones: It's an extremely good question. You and I have known each other for a long time, so you know I always do check in the data. So I did ask the statistician. She said that all of their surveys show that no more than 10%-15% of these women have stopped taking the drug. They have at least 85%-90% compliance.

Interpretation of results

Dr. Miller: The bottom line for our listening audience when they see a patient on Monday morning: who they're going to start on tamoxifen. Should they check CYP2D6 genotype?

Dr. Leyland-Jones: To answer that indirectly: As you know, we were together at the ECOG meeting where they did a survey, and around 12% of oncologists were frequently or always using the CYP2D6 phenotyping. I think that these 2 presentations definitively showed that there is absolutely no indication for CYP2D6 phenotyping. Now, let me say something that wasn't said in the presentation at all, which a number of people have questioned: Could you have gotten this intermediate-metabolizer or poor-metabolizer group incorrect? Previous studies have reported hazard ratios of between 1.5 and 2, and our hazard ratio was exactly 1. So if you actually combined the poor and intermediate metabolizers, the hazard metabolizers change to about 1.09. Now, if the true hazard ratio was 1.5, we would have to have misclassified 75 % of the extensive metabolizers to come up with a true hazard ratio of 1.09. So I don't think we're ever going to have a more emphatic study than the BIG 1-98. In terms of hot flashes, for goodness sakes, please do not take notice of that as a pharmacodynamic marker of tamoxifen and do not take a woman off tamoxifen if she's not having hot flashes.

Dr. Miller: I think also the message should be: Don't check the genotype, because if this is a person who would benefit from tamoxifen, whether she's pre menopausal or it's one of those patient scenarios that you mentioned -- who may be postmenopausal but simply cannot tolerate or cannot afford an aromatase inhibitor -- they should get tamoxifen and they should feel good about the benefits irrespective of genotype.

Dr. Leyland-Jones: Absolutely. So let me just make that precise. Do not check the 2D6 phenotype. We are now pursuing some of the aromatase inhibitor ones (other ones), so we're now including the CYP19A1, which is what Jim Engle and Park and others have published on. We're looking on some of the vascular endothelial growth factors. We're looking on the estrogen-receptor (ER) alphas, the ER betas, and the ATT1. That will be the subject of later presentations. But at this moment, the key CYP2D6 phenotype, genotype, the *4 allele --we should not be testing for those.

Dr. Miller: So no CYP2D6 testing, but still a lot of hope with all of the samples you've collected and other testing to look at other variance of metabolizing enzymes and enzymes important in the entire estrogen response-- this could still give us a way to individualized therapy.

Dr. Leyland-Jones: Absolutely. And as I said in the presentation, we used Jimmy Rae's algorithm. We had Matt Goetz, as a presenter, have input on the trial design. So what we're hoping now is to look across all the 4 BIG studies, including the IE [Intergroup Exemestane] as well as the ATAC, and also the TEAM [Tamoxifen Exemestane Adjuvant Multinational] trial. That will give us 15,000 patients and also the power to look at some of the genomic drivers in here that again may help us differentiate therapy.

Closing Remarks

Dr. Miller: Thank you again for coming in, Brian. Again, it was a major tour de force to get this work done.

Dr. Leyland-Jones: My pleasure.

Dr. Miller: Thanks to our audience for joining us for this edition of Medscape Oncology Insights. This is Dr. Kathy Miller at the 2010 San Antonio Breast Cancer Symposium meeting in San Antonio.


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