You are here: Home: BCU 2 | 2006: Kathleen I Pritchard, MD

Tracks 1-20
Track 1 Introduction
Track 2 Role of hormone-receptor status in decision-making about adjuvant therapy
Track 3 Selection of a chemotherapeutic regimen in the adjuvant setting
Track 4 Docetaxel/cyclophosphamide versus doxorubicin/cyclophosphamide as adjuvant therapy
Track 5 Selection of up-front adjuvant hormonal therapy
Track 6 Tolerability of aromatase inhibitors versus tamoxifen
Track 7 Role of the bisphosphonates in the prevention of metastases
Track 8 Potential use of aromatase inhibitors in the prevention setting
Track 9 Duration of adjuvant therapy with an aromatase inhibitor
Track 10 Oxford Overview: Disease-free survival for patients with ER-positive and ER-negative untreated breast cancer
Track 11 Trend toward survival benefit in the trials of adjuvant aromatase inhibitors
Track 12 Benefit of delayed letrozole observed in MA17
Track 13 Cardiac toxicity associated with aromatase inhibitors
Track 14 Women’s Intervention Nutrition Study (WINS): Impact of reduction in dietary fat intake on recurrence
Track 15 Influence of TOPO II amplification on the efficacy of anthracycline-based chemotherapy in BCIRG 006
Track 16 Clinical use of adjuvant trastuzumab
Track 17 Combining trastuzumab with epirubicin
Track 18 Adjuvant trastuzumab in patients with HER2-positive, node-negative breast cancer
Track 19 Delayed adjuvant trastuzumab
Track 20 Incidence of brain metastases in patients receiving trastuzumab

Select Excerpts from the Interview

Track 5-6

DR LOVE: Dr Martine Piccart-Gebhart, in her presentation at the San Antonio Breast Cancer Symposium, suggested that some postmenopausal patients are better served with tamoxifen, at least initially (Piccart- Gebhart 2005). What are your thoughts on that?

That point of view relates to the fact that the hazard ratios in the switching trials looked somewhat better than those in the trials that compared an aromatase inhibitor to tamoxifen from the beginning. Also, many of us thought that priming with tamoxifen prior to treatment with an aromatase inhibitor might somehow be advantageous.

However, when you consider randomized studies of up-front AIs in which disease recurs more in patients on tamoxifen than in those on the aromatase inhibitor in the first two years, it’s difficult to suggest that you should begin with tamoxifen (Howell 2005; Thürlimann 2005).

Until somebody shows in a randomized fashion that patients who begin with adjuvant tamoxifen are doing better at the end of five years than the patients who use an aromatase inhibitor initially, I will discuss with virtually all my patients the idea of beginning therapy with an aromatase inhibitor.

DR LOVE: How do you find tamoxifen and aromatase inhibitors compare with regard to toxicities?

DR PRITCHARD: The aromatase inhibitors probably have a better toxicity profile. The side effects of tamoxifen are different, and while some are not of concern for everyone, such as endometrial cancer for women who have had a hysterectomy, we still have to be concerned about deep vein thrombosis, which is a serious complication.

With the aromatase inhibitors, we’re seeing more osteoporosis (2.1). In the MA17 data, Goss showed more fractures and osteoporosis in the patients on the placebo arm of the original trial who crossed over to letrozole in the last two years after unblinding compared to those who did not (Goss 2005a).

I think we will see some long-term complications from this unless these patients are properly treated for their osteoporosis. We have to consider how well we are prepared to either treat our patients or collaborate with primary caregivers to prevent osteoporosis, which I think is not well managed in the general population.

In Canada, increasingly, we find patients are not always screened or treated according to the guidelines. In addition, patients may not have a family doctor, or they don’t follow their physician’s recommendations, so it’s a bit out of our control.

Track 8

DR LOVE: A number of ongoing trials are evaluating the efficacy of aromatase inhibitors in the prevention setting and in the treatment of DCIS. When the tamoxifen prevention data were released, they generated a lot of excitement, and yet people don’t use it very much in that setting. What do you think is the potential of aromatase inhibitors in prevention?

DR PRITCHARD: People have opted not to take tamoxifen for prevention, which is actually quite startling. It seems women intuitively don’t want to take a pill to prevent something, and I’m not sure why that is, but I think we will see some of the same problems with the aromatase inhibitors.

People in general like to believe that maybe there’s a lifestyle intervention that would be equally or more effective than taking a drug. If one exists for breast cancer, I don’t think we know what it is. We are learning that exercise and keeping one’s weight down may be important, and obviously these measures are good for patients in a number of ways.

I think the BRCA gene carriers are the only women who have really embraced the idea of chemoprevention. I suspect that will be true with the aromatase inhibitors as well, particularly if osteoporosis is an issue.

DR LOVE: How do you find that aromatase inhibitors compare with tamoxifen in terms of tolerability?

DR PRITCHARD: The hot flashes with tamoxifen are real. They show up in every placebo study, whereas weight gain and a number of other complaints do not. I believe patients similarly experience hot f lashes on aromatase inhibitors, and while these may not bother some patients, they can be deal breakers for others.

If we’re going to treat patients with an aromatase inhibitor long term in the adjuvant or prevention setting, we will probably use an aromatase inhibitor plus a bisphosphonate, which may double the potential for toxicity but may double the benefit as well.

Track 8

DR LOVE: In your practice, what has been your patients’ experience with arthralgias and AIs?

DR PRITCHARD: The absolute difference between the arthralgias in patients on aromatase inhibitors versus tamoxifen is about five percent. I believe the aches and pains that patients experience with aromatase inhibitors are real, but it’s such a peculiar phenomenon.

Some of these women become miserable, and when you discontinue the drug, for many, the symptoms disappear. However, I’ve had some patients that I’ve put back on tamoxifen, and they still have the aches and pains.

I guess this side effect is related to the lowering of estrogen. Aches and pains are reported as a menopausal symptom and are generally regarded as not all that common or serious, but maybe we don’t always listen to what women tell us about their menopausal symptoms.

Track 10

DR LOVE: Putting reimbursement issues aside, how do you manage women who have received five years of an aromatase inhibitor or who switched at two or three years and get to the five-year point?

DR PRITCHARD: We’re just starting to see these women now, and we don’t know what to do. I told the last patient I saw to continue her aromatase inhibitor and come back in six months because we would have a clinical trial for her. Both Jim Ingle and Paul Goss have presented data from the MA17 trial that suggest year upon year, letrozole continues to add benefit (Ingle 2005; Goss 2005a; [2.2]).

However, until we see randomized studies, we’re not going to know the best way to manage these cases. I think it’s great that the NSABP is launching a study to evaluate patients who have had five years of any aromatase inhibitor or two or three years of tamoxifen followed by an aromatase inhibitor. These patients will then be randomly assigned to an additional five years of an aromatase inhibitor or not.

Track 10

DR LOVE: Can you talk about the data that were presented at the Oxford Trialists’ meeting in September 2005, regarding disease-free survival curves for ER-positive and ER-negative breast cancer?

DR PRITCHARD: The most interesting piece of data I saw was a curve showing that disease in untreated patients with ER-negative disease recurs quickly in the first few years, but then their curves level out much more than patients with ER-positive disease.

On the other hand, untreated patients with ER-positive disease do much better in the first five years, and they’re still ahead in the next five years. However, at approximately 10 years, the disease-free survival curves for ER-positive and ER-negative disease cross over each other, and at 15 years, the survival curves are crossing.

DR LOVE: So the untreated patients with ER-positive disease have a higher delayed relapse rate than those with ER-negative disease?

DR PRITCHARD: Yes. It’s slower and steadier, but they keep recurring. It makes sense that we’re now seeing that treatment after five years can be very helpful, because these patients have an ongoing risk. We haven’t all appreciated this very well until the last few years. I believe that the Saphner paper showed this ongoing risk, and the Oxford Overview data have shown this before as well (Saphner 1996).

We all think of ER-positive disease as having a better natural history, but the fact is that by 10 years, more of the patients with ER-positive disease have recurred than the ER-negative group, both untreated. It’s shocking because we thought we could treat these patients with tamoxifen and after that they would do well and we would not have to worry about them, but they continue on having recurrences.

So I think adding additional treatment with an aromatase inhibitor or certainly evaluating these patients in clinical trials is important.

Track 11

DR LOVE: Do you think the adjuvant aromatase inhibitor trials will eventually show a mortality benefit?

DR PRITCHARD: I believe that if these trials had gone on long enough, we definitely would have seen a mortality benefit. In the MA17 trial, when the trial was stopped, approximately 70 percent of the patients crossed over to letrozole. We’re still seeing a significant overall survival benefit in patients with node-positive disease who were randomly assigned to letrozole. Had the original trial continued another six or 12 months, we would have seen that much more clearly; however, now as patients cross over and receive the benefit but receive it later, that mortality benefit may be muted.

DR LOVE: Can you talk about the meta-analysis that was presented at the San Antonio Breast Cancer Symposium on the mortality data from the aromatase inhibitor trials?

DR PRITCHARD: The Austrian group presented an analysis of three of the switching trials — the ITA trial, the ARNO 95 trial and the ABCSG-8 trial — in which patients switched at two to three years from tamoxifen up front to anastrozole ( Jonat 2005; [2.3]). The data showed a significant survival benefit among those patients who were switched to anastrozole versus those who remained on tamoxifen.

Track 13

DR LOVE: What are your thoughts about some of the recent data that have come out in terms of cardiac issues and the aromatase inhibitors?

DR PRITCHARD: My view on this is probably controversial, but I think I’m right. I believe we’re forgetting that tamoxifen is probably cardioprotective. I’ve been in the game long enough to remember that when we started studying tamoxifen as an adjuvant therapy, we knew it lowered lipids substantially, and we all believed that it was going to show a cardiac effect that was beneficial.

Indeed, the NSABP prevention study, P-1, was originally designed to examine cardiac endpoints, but since the women who enrolled in the study were younger than expected, the cardiac component was dropped because the cardiac rate was not expected to be high enough to answer the question.

The cardioprotective effect of tamoxifen was a big hypothesis, and when you examine the available data, although they are a bit mixed, I think they consistently show either no detriment or that there is a benefit with tamoxifen compared to placebo or control.

Data from a study comparing five versus two years of tamoxifen were presented at ASCO a couple of years ago by one of the Scandinavian groups and were recently published in the Journal of Clinical Oncology. They showed that the patients randomly assigned to five years of tamoxifen had a lower rate of cardiac events and cardiac deaths. I believe that what we’re seeing in all of these trials comparing aromatase inhibitors with tamoxifen is a small amount of cardioprotection from tamoxifen.

In the MA17 trial, the only study in which the aromatase inhibitor is compared to placebo, a lipid substudy shows virtually no difference in lipids or cardiac events between the two groups. I think that there’s a protective effect from the tamoxifen and maybe an extremely small effect, if any, from the aromatase inhibitor, which I don’t think is substantial.

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