Breast Cancer Update 2004 (1)

DR HAROLD J BURSTEIN: The IBCSG is coordinating a series of three nested trials: SOFT, PERCHE and TEXT. These studies address what is probably the most important conceptual question in premenopausal breast cancer right now: Beyond tamoxifen, does planned ovarian suppression benefit patients? In particular, does it benefit women who receive chemotherapy or who don’t receive chemotherapy, and if a woman experiences chemotherapy-related amenorrhea, does she still need ovarian suppression? These are important trials that offer a wonderful opportunity for community oncologists to participate in answering this critical question. Currently, I consider ovarian suppression for two groups of patients. The first group includes patients at high risk — multiple positive nodes, very high-risk tumors — and particularly young women, less than 35 or 40 years of age, who may not go into menopause with chemotherapy.

The other group includes women who are at the opposite end of the spectrum — very low-risk tumors, smaller tumors, node-negative — for whom the benefits of chemotherapy are small. With these women, I present ovarian suppression as an option, not necessarily in addition to chemotherapy but perhaps even instead of it.

Breast Cancer Update 2006 (5)

DR DANIEL F HAYES: I believe an important issue, which has been lost, is that all of the aromatase inhibitor studies enrolled women who were postmenopausal by virtue of not having a period for at least a year prior to enrollment. We have estrogen ablation studies ongoing for premenopausal women, such as SOFT, TEXT and PERCHE. We don’t know the answers from those studies yet.

I believe estrogen ablation is a more effective therapy than a SERM, but I also believe it’s more toxic. I’m very supportive of those trials. We have enrolled 11 patients on SOFT. They’re important studies, almost as much for the toxicity as for the outcomes.

The ovaries can go to sleep and wake back up again. Ian Smith at the Royal Marsden and I discussed this recently. He went back and retrospectively reviewed his institution’s experience with women who had received chemotherapy, became amenorrheic and were then placed on an aromatase inhibitor.

About one quarter of those patients had their ovarian function reemerge, either by virtue of developing menses or by having their estrogen levels increased.

Breast Cancer Update 2006 (7)

DR ROBERT W CARLSON: If I were to treat 100 postmenopausal women with endocrine therapy for early breast cancer, the vast majority would walk out with a prescription for an aromatase inhibitor — usually anastrozole in my practice.

We have to establish a practice pattern, and mine is to lead with an aromatase inhibitor. It is interesting how expert panels interpreted the emerging aromatase inhibitor data differently. Within 10 to 14 days of the initial 2001 ATAC presentation, the NCCN panel had modified the guidelines to allow anastrozole as an alternative to tamoxifen as initial hormonal therapy for postmenopausal patients with ER-positive disease.

The ASCO panel initially believed that tamoxifen should remain the standard hormonal therapy, but that guideline, over time, has also changed. Currently, the NCCN and the ASCO guidelines are essentially identical in terms of up-front hormonal therapy.

The different methods of using aromatase inhibitors or incorporating them — initial aromatase inhibitor therapy versus sequential after two to three years of tamoxifen versus extended after five years — have never truly been studied in a randomized fashion, one against another. The BIG 1-98 trial will give us the first look at that sort of comparison. The real question is whether tamoxifen does something to prime the breast cancer cells and cause the aromatase inhibitor to be more effective in the switching studies. Or, rather, is it that the population of women and the characteristics of their breast cancer change over time in a way that would make the aromatase inhibitors — or any hormonal therapy — more effective?

I believe a substantial amount of data exists to support the selection bias theory that the population of breast cancer patients over time is changing. You would expect the endocrine-resistant, receptor-positive breast cancer to recur earlier, so those women are removed from the denominator.

If you have a sensitive population and an insensitive population with hormone receptor-positive tumors — even with no difference in efficacy between the hormonal therapies — you should expect to see an increasing effect the later in time you initiate the therapy. However, it’s hard to have a drug that’s so effective down the road that you are able to regain the loss of two to three absolute percentage points that women may experience when the drug is used in this context.

Breast Cancer Update 2006 (7)

DR VICTOR G VOGEL: How to approach a patient who has received five years of an adjuvant aromatase inhibitor is a challenging question. Up until the 2005 San Antonio meeting, I wasn’t certain what the answer was to that question. But I was heartened by the data that were presented, both by Paul Goss and Jim Ingle, on the continued follow-up of the MA17 trial patients and, particularly, those patients who had initially been assigned to placebo and then crossed over to letrozole.

Two patterns were evident from those data. The first was that the longer a patient received the aromatase inhibitor following five years of tamoxifen, the greater the benefit. It is rare in medical oncology to see a benefit that increases as the duration of therapy increases. But it was clear that the longer the duration of therapy with letrozole was, the greater the benefit was.

Comparing two years to four years, the benefit almost doubled. So for our patients at high risk, especially those with larger tumors and those with positive nodes, based on those data, we’re now telling them they should continue to take their aromatase inhibitor because we know they’re at risk for a very long time — two decades or longer — for recurrence, and these data now show that longer therapy may improve their outcomes.

The other question those data helped us answer relates to patients who have a gap between the end of their tamoxifen therapy and the initiation of their aromatase inhibitor therapy.

The patients who were initially assigned to placebo after five years of tamoxifen in the MA17 trial crossed over to letrozole. Approximately 1,600 patients made the crossover, and their average duration off therapy — that is, the time between the end of their tamoxifen and the initiation of their letrozole — was about 30 months. Even with that delay in the initiation of the aromatase inhibitor, a statistically significant benefit was demonstrated with the so-called delayed initiation of the aromatase inhibitor after tamoxifen.

Breast Cancer Update 2006 (5)

DR JULIE R GRALOW: The update of the MA17 trial examined the patients who originally received a placebo after five years of tamoxifen as opposed to letrozole and then at about 30 months, when the study was unblinded, were offered letrozole. Approximately two thirds of those patients chose letrozole, and they tended to be a higher-risk group. Those patients had an average gap of 30 months without any endocrine therapy.

Despite that and the fact that they were a good eight years out from their diagnosis, a reduction appeared across the board in every type of breast cancer recurrence — contralateral, in-breast and distant. It’s impressive.

We saw the updated analysis for the MA17 trial at the San Antonio meeting in 2005, and at that point I began to at least offer patients the option of going back on an endocrine agent if they’d been off everything for a couple of years, especially if they were at high risk.

Although it might offer some benefit 10 years later, the duration off therapy in the MA17 trial was approximately 30 months, so I consider restarting endocrine therapy for patients up to three years off treatment. That’s arbitrary, but you have to pick some time period.

Cancer Conference Update, San Antonio Breast Cancer Symposium 2005

DR PETER M RAVDIN: The problem with the extended letrozole trial (NCIC-CTG-MA17) was that the patients were unblinded at 2.4 years, and because most patients then switched over to the active agent, we will never know with any certainty what would have happened had they been unblinded at five years. That is a shame because we are going to be treating these patients for five years, so it would have been nice to know the differences in toxicity and efficacy between the two arms. The data for one or two years are complete because most of the patients had gone through those years.

There were a lot of data in year three, a modest amount in year four and almost no data for the fifth year.

An analysis of relapse risk within each year could then be performed. This was possible not only for years one and two but also for year three, when it seems that the relative benefit was greater, which is interesting and reassuring. That was also the case in year four. That analysis used year-by-year hazards to determine whether benefit was attenuating, staying as strong or becoming stronger. Although we will never know what it would have been if the trial had been unblinded at five years, we are somewhat reassured by the results of this analysis that going beyond 2.4 years of treatment is reasonable.

Breast Cancer Update 2006 (8)

DR HARRY D BEAR: In my practice, by and large, the postmenopausal patients who do not have osteoporosis are receiving aromatase inhibitors up front. The ATAC results are difficult to dispute. For patients who have been on tamoxifen for a year, I haven’t jumped to switch them to an aromatase inhibitor.

I will probably follow the paradigm of some of the other trials and leave them on tamoxifen for a couple or three years. Then I’ll switch them over. I believe they will obtain some bone-density benefit by staying on tamoxifen for a while and start out at a better baseline when we switch them over to an aromatase inhibitor.

NSABP-B-42 will address the question of duration of therapy. It will look at the group of patients who have been on five years of either a combination of tamoxifen and an aromatase inhibitor or an aromatase inhibitor alone. The trial will determine whether those patients should receive an aromatase inhibitor for another five years. It’s a five- versus 10-year question, reminiscent of the NSABP-B-14 rerandomization.

Interview, September 2006

DR NORMAN WOLMARK: The NSABPB-42 trial just opened. It has a sample size of about 3,800, and of course one of the questions that remains unanswered is the duration of an aromatase inhibitor.

We went through this process and it took us years to determine the optimum duration of tamoxifen therapy, and at the end of the day there was enormous surprise from the B-14 data that not only is 10 years not as good as five, but it is also somewhat detrimental. We believe it’s important to address the duration of an aromatase inhibitor, and this is what NSABP protocol B-42 will be doing.

The data with aromatase inhibitors from the multiple trials have all been positive. The duration question remains relatively unaddressed.

We have seen trials that have introduced aromatase inhibitors after a period of tamoxifen and have shown an advantage. We’ve seen direct head-on comparisons between aromatase inhibitors and tamoxifen up front also showing an advantage, and we’re waiting to see the results of a trial that starts with an aromatase inhibitor and sequences it with tamoxifen.

NSABP-B-42 Protocol July 2006; nsabp.pitt.edu.

In the adjuvant setting, AIs have demonstrated activity in three distinct clinical situations. In the first situation, an AI was compared to tamoxifen as initial adjuvant hormonal therapy in patients with resected operable breast cancer. The ATAC trial demonstrated that 5 years of anastrozole significantly improved disease-free survival (DFS) when compared to 5 years of tamoxifen.

More recently, the BIG 1-98 trial also demonstrated improved DFS as well as distant DFS for 5 years of letrozole compared to 5 years of tamoxifen.

In the second situation, an AI was compared to tamoxifen in patients who had already received 2-3 years of adjuvant tamoxifen. In three randomized trials (the IES trial [International Exemestane Study], the ABCSG-8/ARNO 95 trial, and the ITA trial [Italian Tamoxifen vs Anastrozole]), 2-3 years of an AI (exemestane or anastrozole) improved disease-free survival compared to 2-3 years of tamoxifen in patients who had already completed 2-3 years of tamoxifen therapy.

In the third clinical situation, an AI was evaluated as extended adjuvant hormonal therapy following completion of 5 years of adjuvant tamoxifen. The NCIC-MA17 trial compared 5 years of letrozole with 5 years of placebo in patients who had already completed 5 years of adjuvant tamoxifen and demonstrated significant improvement in disease-free survival in favor of the group that received the AI.

Based on the results from these trials, AIs are increasingly utilized as adjuvant therapy in these three clinical situations. At this time, there are no available results from trials that directly compare these different approaches for using AIs. Thus, the best setting for the adjuvant use of AIs cannot be readily determined at present.

Breast Cancer Update 2006 (1)

DR PAUL E GOSS: We don’t know what the appropriate approach is to selecting one of the three aromatase inhibitors in the up-front setting. I have the good fortune of chairing a key study in this regard. The MA27 study will complete accrual in 2006, and it is addressing precisely that question of whether there is an optimal aromatase inhibitor. The randomization is between the steroidal exemestane and the nonsteroidal anastrozole.

In the meantime, there are ample data to say these compounds are different in terms of their biochemical and preclinical effects. But in the clinic, with the present data, there is no evidence of a wide difference between these drugs. So I think that one has to restrict one’s choices to the approved therapies by the regulatory agencies and the published evidence-based data.

John W Berry. Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Clin Ther 2005;27(11):1671-84.

There may be important clinical differences between the AIs. However, data from direct comparative clinical trials are limited, and making comparisons across trials is difficult given differences in design, methodology, patients, and endpoints. At the present time, the choice of an AI for clinical use should be based on the strength of the data within the distinct clinical scenarios: neoadjuvant therapy, adjuvant therapy, or advanced/metastatic disease.

Breast Cancer Update 2006 (1)

DR AMAN U BUZDAR: As the safety data for the three aromatase inhibitors are emerging, we see that they are quite different. In the package insert for exemestane, a small but definite increased risk of cardiac dysfunction is noted. If you consider the letrozole data from the BIG trial, at 25 months a small but definite increased risk of cerebrovascular accident and myocardial infarct is evident. However, in the 68-month follow-up data for the ATAC trial, we see none of those risks with anastrozole. If you examine the cardiac deaths, it is 49 with anastrozole versus 46 with tamoxifen, and cerebrovascular accidents are substantially reduced with anastrozole compared to tamoxifen.

An interesting study presented at the 2005 San Antonio Breast Cancer Symposium evaluated 90 healthy, postmenopausal volunteers who received, in a blinded fashion, up to 24 weeks of anastrozole, letrozole or exemestane. When the effects on the lipids were examined, they were found to be totally different. We have to be aware of the different effects and realize that not all aromatase inhibitors are alike and that it does matter which one we select.

Jean Marc Nabholtz, Joseph Gligorov. Cardiovascular safety profiles of aromatase inhibitors: A comparative review. Drug Saf 2006;29(9):785-801.

A significantly reduced risk of thromboembolic disease was observed for all three AIs compared with tamoxifen. Anastrozole is, at this point, the only AI with a detailed benefit-risk profile from over 5 years’ follow-up in the adjuvant setting.

Thus far, no apparent CV-safety concerns have emerged. Preliminary data on letrozole and exemestane suggest that longer follow-up is needed for these two AIs before being able to fully assess their respective long-term CV toxicity profile. The present differences in CV-safety profiles suggest that third-generation AIs should not be considered as equivalents in clinical practice.

Meet The Professors 2006 (3)

DR DEBU TRIPATHY: As time goes on, less and less of a distinction can be made between the aromatase inhibitors. Up front, I don’t have a strong preference. We certainly have data for anastrozole and letrozole. I tend to use anastrozole simply because it has longer safety data. There we have the largest number of patients that have been followed, so in my mind, there’s more confidence in the safety profile.

BONE AND AROMATASE INHIBITORS

Breast Cancer Update 2006 (5)

DR GRALOW: The five-year bone density substudy of the ATAC trial was very interesting. The fracture rates on that trial were approximately 11 percent in the anastrozole arm and about 7.5 percent in the tamoxifen arm at 68 months of follow-up.

However, we were trying to determine who should receive bisphosphonates up front and how often we should follow bone density studies. I believe the ATAC data that Rob Coleman presented at ASCO showed that not everyone needs a DEXA scan every year or a bisphosphonate up front.

What was surprising to me but very reassuring was that none of the patients who started the ATAC trial with a normal bone mineral density — a T-score better than minus one — were osteoporotic after five years of treatment, although approximately 50 percent had become osteopenic.

We expect about a two to three percent bone loss during the five years simply based on aging, but in the tamoxifen arm, approximately 15 to 20 percent of the patients went from normal to osteopenic, and the rate was 50 percent for patients who received anastrozole.

Aging happens even to the best of us, but I believe these data show us that if the patient started with a normal bone mineral density, her chance of becoming osteoporotic after five years as a result of receiving an aromatase inhibitor in that study was zero.

ADHERENCE TO LONG-TERM ORAL ENDOCRINE THERAPY

Interview, August 2006

DR VICTOR VOGEL: In terms of patients stopping long-term medications, published data show that the decay over time is very high.

There are more data published on tamoxifen than on the aromatase inhibitors, but even some aromatase inhibitor data show that as many as one third of patients stop their medication within the first year and by the second year, as many as half of patients have stopped taking their aromatase inhibitor. This should be distressing to all of us.

A number of barriers exist, such as cost and side effects. An equally important barrier is patients’ misperception that if time has transpired and they’re doing well — they’re coming back for their second and third annual visits and their mammograms are fine, their physical exams are normal and they’re asymptomatic — that their risk has passed and, therefore, it’s not necessary to continue the medications.

It’s important for oncologists to be aware that patients are stopping their medication and that we need to regularly ask patients whether they’re taking the medications daily and determine whether there are any barriers to doing so — be it cost or symptoms or perceptions about the risk of recurrence.

I don’t think it was well recognized in our treatment community that patients were stopping their medications. We are not in tune with the reality, and when you actually examine prescription refills and availability of medications over time, in fact, patients are not being compliant. I think the first step is for us to recognize that patients aren’t compliant and to stop pretending that they simply follow our directions because we told them this is what they need to do.

We need to ascertain if the patient is compliant, and there are many strategies we can use to do this, be it pill counts, pharmacy records or simply asking patients. We need to constantly ensure that what we believe the patient is doing is what they’re actually doing. The data would suggest that, in fact, patients are not following our advice.

Interview, June 2006

DR D LAWRENCE WICKERHAM: We spend a fair amount of time and energy educating our physicians, nurses and coordinators about the importance of compliance and adherence. Within the context of a clinical trial, you can pick your patients a little, so we try to identify those individuals most likely to be compliant with the regimen — not only taking their pills but also receiving their follow-up exams, mammograms and so forth. Then we institute a number of strategies to help maintain that level of compliance during the course of the trial. We design our trials with a built-in level of noncompliance. Clearly, you want patients to take their medications so they can obtain the maximum benefit and so that the study results, both benefit and toxicity data, are as accurate as possible.

Applying that information to the general population of patients who are not in clinical trials has recently become an area of interest in both the treatment and the prevention settings. As we have more oral agents in oncology, it becomes increasingly important for us to be thinking about how to keep our patients on these therapies.

The most important thing is to ask the patient in an open fashion whether they’re having any difficulties taking their medication. Without making it sound threatening, that should be asked at each follow-up visit, and the importance of taking their medication as prescribed should be reinforced. Patients should be told to announce any difficulties in taking their medications, be it side effects, toxicities or economic issues. These can all be addressed, but only if they are described.

Interview, June 2006

DR ROWAN T CHLEBOWSKI: Adherence to oral hormonal therapy has received minimal attention, but it’s an area of increasing interest.

I believe that because chemotherapy is perceived as being a burden and difficult, the concept is that when you are done with the chemotherapy, you are done with the heavy lifting. Indeed, some practices provide diplomas, like graduation, after chemotherapy.

When oncologists see patients three and four years out in a 12-minute slot, when we reassure them that they are doing fine and give them a six-month prescription for aromatase inhibitors, it’s easy to understand how patients might perceive that they are done with their cancer. If you’re taking pills, you’re admitting that you have a problem. And if you can stop the pills, mentally, in a certain sense, you are putting the problem behind you. When women get three or four years out after a breast cancer diagnosis, they’d like to think the problem is behind them.

The other issue is cost, and when a woman says, “That’s too expensive,” I ask her, “Do you have the money to pay for the medication?” Some women don’t, but many women, in effect, are spending the money on something else. Then I’ll ask them, “If you don’t want to spend the money on the aromatase inhibitor, what do you plan to spend the money on?”

That lets them know that I think it’s important that they’re making this choice. And then I remind them that this is quite different than considering a decision to get dial-up or cable internet, where, at the end of two years, you have saved $2,000, and you were willing to put up with the slowness of the internet speed.

Here, you’re doing something more than that. You’re making a bet. Because I tell the women that there’s appreciable cost to themselves and their family for a breast cancer recurrence. If the patient develops a recurrence, that could cost thousands and thousands of dollars and jeopardize their entire financial bearing. You have to judge very carefully a decision that may effect the risk of a recurrence.

Breast Cancer Update 2004 (7); 2006 (3)

DR PATRICK I BORGEN: NSABP-B-35 and IBIS-II are important trials, both comparing anastrozole and tamoxifen in postmenopausal patients with DCIS. Aromatase inhibitors have already proved to have a significant effect in invasive cancer, and it’s highly likely they will affect DCIS as well.

We know that the majority of DCIS lesions are likely to be ER-positive. Craig Allred has shown that age per age, tumor for tumor, DCIS is even more likely to be ER-positive than invasive cancer. If that’s true, then we have even more reason to be optimistic about the studies of aromatase inhibitors in DCIS.

We have viewed tamoxifen as a highly appropriate option for treating a patient with ER-positive DCIS since the NSABP-B-24 trial. However, when we consider risks, benefits and quality-of-life issues, it’s common for our New York patients to demur, so we probably have one of the lowest percentages of patients with ER-positive DCIS on tamoxifen in the country.

The same can be seen in our prevention setting, in which we’ve not been successful in getting patients to take tamoxifen.

The two most obvious concerns about tamoxifen in these settings are endometrial cancer and gynecological events. Even when we provide the raw numbers on how infrequent those events are, because we are talking about minimal, if any, impact on long-term survivorship and moderate impact on local control, it simply is not an attractive option.

We’d like more information about DCIS and aromatase inhibitors, but since the initial publication of the ATAC data, aromatase inhibitors have become our endocrine therapy of choice for postmenopausal patients with ER-positive, invasive cancers. That literally happened overnight, like gangbusters, and so a “bleed over” to postmenopausal patients with DCIS is natural.

In my clinical practice, it’s clear that the aromatase inhibitors are vastly better tolerated than tamoxifen in postmenopausal patients.

Our surgeons are beginning to give first-line endocrine therapy without a mandatory consult from medical oncology. We perform bone density tests before we start our patients on aromatase inhibitors, and treating these patients has been satisfying.

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