Edited excerpt from the discussion:

DR TEPPER: This 67-year-old white female developed a lump in her left breast and was found to have an infiltrating ductal carcinoma on stereotactic biopsy. The lesion was ER/PR-positive and HER2-negative.

DR LOVE: Skip, how would you assess riskbenefit ratios for various chemotherapy and hormonal interventions for this patient?

DR BURRIS: The fact that this 67-year-old patient is very active is important when considering treatment. While we want to maintain her quality of life and not cause a problem with chemotherapy, she also has a good chance of being around another 20 years. More and more, I’m impressed by the data demonstrating the importance of hormonal therapy in such cases.

This patient’s odds of recurring are probably in the range of 30 percent, with two positive lymph nodes. The fact that the tumor is HER2-negative and ER-positive makes me feel better about her prognosis. Considering the data, this is one of those patients with whom I often give four cycles of AC if they want to be aggressive. I’m also comfortable with aggressive hormonal therapy if such a patient does not want chemotherapy.

The benefits of adjuvant chemotherapy in patients with ER-positive disease are always of debate. I have been impressed with the recent findings that there is possibly a difference between docetaxel and paclitaxel and effects on ER-positive disease. If I were going to give this patient chemotherapy, I would probably lean towards AC times four or TAC with pegfilgrastim support on day two.

DR LOVE: If she were in her early fifties with two positive nodes, would you still consider AC times four?

DR BURRIS: No. Her age of 67 puts me right on the cusp. If she’s 55, she probably gets TAC with pegfilgrastim support, whereas if she’s 75 years old, there’s a longer discussion about hormonal alone or with AC. At 67 years of age, a picture is worth a thousand words, and it’s a big conversation to have with the patient. It usually requires two visits to come to a decision.

DR LOVE: Mark, how would you have thought through risk-benefit ratio of chemotherapy and hormonal therapy in this patient?

DR PEGRAM: Due to her age, TAC may not be my first consideration. I do tend to use sequential AC to a taxane in such patients, particularly when they’re ER-positive and you know they will derive a lot of benefit from systemic adjuvant hormone therapy anyway.

Then, given the recent NSABP-B-27 neoadjuvant data, Skip’s comment about AC times four is all the more reasonable. Until that data was presented, I would not have recommended just four cycles of an anthracycline- based regimen alone, but now I believe it’s back on the table for discussion.

Then I would discuss hormonal therapy with this patient.

DR LOVE: Skip, what about hormonal therapy?

DR BURRIS: With the data we have today, I would use an aromatase inhibitor with this patient. For initial therapy, I use anastrozole. With patients who have been on tamoxifen for quite a while, I use exemestane or letrozole.

DR LOVE: Mark?

DR PEGRAM: I’ve been using anastrozole in these patients up front because of my concern about the few patients who relapse within the first few years on adjuvant tamoxifen. The data presented at St Gallen indicate that there are other aromatase inhibitors to consider first line as well.

DR LOVE: The BIG-FEMTA (Thurlimann 2005) trial is evaluating tamoxifen or letrozole for five years, although they may be rethinking the tamoxifen arm, and the other two arms that we don’t yet have data from are evaluating tamoxifen for two to three years and then switching to letrozole or starting with letrozole and switching to tamoxifen. Their initial data, which are at approximately 30 months, look very similar in terms of efficacy compared to the ATAC data at the same point.

Of course, the ATAC data are now at 68 months (Howell 2005). There was also an increased incidence of myocardial infarction deaths in the patients on letrozole, which wasn’t seen in the ATAC trial.

Skip, what were your thoughts about that?

DR BURRIS: Those data on cardiac deaths were very interesting in that the absolute numbers were doubled — 26 patients on letrozole versus 13 on tamoxifen.

My take on that was that this is not too far removed from the COX-2 discussion, in that now it makes me think about a patient’s cardiac risk, whether she is a smoker or overweight, when selecting an aromatase inhibitor for her.

DR LOVE: I believe they also saw hypercholesterolemia in the BIG study.

DR PEGRAM: That’s correct. It suggests that in addition to having these complex discussions about adjuvant therapy with these patients, we should be checking their blood pressure and their cholesterol.

DR BURRIS: This patient population — midsixties, ER-positive, HER2-negative — is the group that has become very muddied by the CALGB update that Dr Berry presented in San Antonio (Berry 2004). What was presented was an eloquent look at where a cooperative group has been over a 20- or 30-year time frame, something that’s not done often enough. It was very important because the cooperative group mechanism is to take the positive arm of a randomized study to the next trial and then to the next trial, without ever looking back, and the trials often have to be planned before knowing the results of the next. The CALGB designs were built on AC moving to AC followed by paclitaxel and then AC followed by paclitaxel dose dense.

It was clear that with the addition of paclitaxel and then the dose-dense approach, the overall benefits were in the correct direction and helping more patients; however, the overwhelming absolute and relative benefits were in the ER-negative group.

Within the ER-positive group, the absolute benefits were very small, although we could still get into the discussion that there were some relative benefits to receiving paclitaxel than not.

But the absolute benefits were into the low single digits, and that’s in contrast with what has always stuck in my mind from the TAC trial. In the ER-positive group, the relative and absolute benefits on the docetaxel trial were of the same magnitude for patients with ER-positive and ER-negative disease.

DR LOVE: Dr Tepper, can you tell us about the follow-up with this woman to the present time?

DR TEPPER: She received AC every three weeks followed by paclitaxel every three weeks.

DR LOVE: What about hormonal therapy?

DR TEPPER: She was diagnosed about two and a half years ago, and at that time, I elected to put her on tamoxifen. Dr Burris touched on some interesting points, because this woman stopped smoking cigarettes when her breast cancer was diagnosed. She started gaining weight at the time the tamoxifen was initiated.

Her lifestyle was fine, but she continued to gain a significant amount of weight until now — on the order of about 15 percent of her body weight. She started at approximately 150 pounds, and now she weighs approximately 170 pounds. She is not too happy about it.

DR LOVE: Mark, how would you approach this patient on tamoxifen for two and a half years?

DR PEGRAM: If you look at the original placebo-controlled trials of tamoxifen in human subjects, there was no statistically significant association between tamoxifen and weight gain compared to placebo. I’m not so sure that her weight gain is caused by tamoxifen. Switching classes of drugs in order to achieve weight loss may frustrate her. In this case, I believe the smoking cessation is causing the weight gain.

DR LOVE: Skip, how do you approach the postmenopausal woman who’s been on tamoxifen for a couple of years, even if she’s completely asymptomatic?

DR BURRIS: In general, it’s a lengthy discussion. With patients with high-risk factors like positive lymph nodes or the high-grade tumors — after they’ve been through two years of tamoxifen, I look to switch them to an aromatase inhibitor.

For patients whom I’m less worried about, I’ve continued with five years of tamoxifen and then approached the subject of letrozole versus no further therapy at five years. The vast majority of my patients have chosen to continue with therapy. A subset of patients is just thrilled with that five-year anniversary and is excited to be done. For a large number of patients, there is some comfort in continuing to believe you’re doing something to try to prevent your cancer from coming back.

DR LOVE: Mark, we now have three randomized trials, a smaller Italian trial (Boccardo 2003) and two very large trials, one looking at anastrozole (Jakesz 2004), the other looking at exemestane (Coombes 2004) switching at two to three years. These trials show very similar results — 35 to 40 percent reduction in recurrence rates in the women who were switched. How do you approach this situation, clinically?

DR PEGRAM: I discuss switching after two to three years of tamoxifen in all of these patients, and I’ve been essentially switching all of them. I tend to use exemestane.

DR LOVE: What about after five years? How do you approach that?

DR PEGRAM: I also have a discussion with regard to the randomized letrozole study (Goss 2004), and if the patient agrees, I offer them letrozole.

DR SEIGEL: I have found — particularly in women in their sixties and seventies — that going in with the Adjuvant! online graphs is very useful in these discussions. Many times I’m surprised by how little benefit there is from chemotherapy and the mortality from other comorbid medical conditions. Often for patients with whom I think I’m going to be using chemotherapy, I’ll wind up not using chemotherapy.

My question is: Do you employ bone density status of these women when you’re choosing to select tamoxifen versus an AI? If a patient has osteoporosis and is receiving alendronate, does that dissuade you from using an AI?

DR PEGRAM: Absolutely, and those are excellent points. I perform DEXA scans on all patients who are being considered for aromatase inhibitors and, on occasion, when I have encountered severe osteoporosis, I’ve used the DEXA result as a reason not to switch to an AI. Maybe I should be adding bisphosphonates in those cases and pushing through. I know some practitioners do that, but I have used that as a deciding factor in some cases.

DR LOVE: Another thing about the Adjuvant! online model is that many people aren’t aware there’s also a model on the site looking at risk of recurrence and impact of AIs after five years, specifically letrozole. Data are provided on how the recurrence rate is impacted by letrozole after five years of tamoxifen. It also brings in the other point you were making, Dr Seigel, in terms of competing causes of mortality.

DR BLAUSTEIN: The data of switching from tamoxifen after two or three years are really pretty compelling, but the problem I’ve run into, at least with a certain cadre of my patients, is the cost associated with an AI versus tamoxifen.

When you prescribe it and they come back to you and say, “Well, my managed care program will pay X amount,” and compared to generic tamoxifen it’s such a heck of a difference that I really wonder if the end justifies the means under those circumstances.

DR LOVE: That’s interesting. We have those conversations when we do our prostate cancer education programs, in terms of maximum androgen blockade and bicalutamide. Many physicians respond, “Cost is not going to prevent me from presenting it to the patient as an option.” There’s an ethical obligation to present the data.

Dr Blaustein, is that your approach?

DR BLAUSTEIN: From a clinical perspective, the switching data are quite convincing. However, if these folks say: “Look, I just can’t afford it, Doc,” you can’t say, “Well, it’s really deleterious to you to continue on tamoxifen.”

Obviously, they can continue on it. It’s certainly the best known drug in the history of breast cancer, at least up to the present, but I believe it becomes a problem with a certain group of patients who can’t afford it.

DR LOVE: Up until a few months ago, most physicians were leaning toward exemestane because that was the largest study out there.

Now we have a trial of basically the same size with anastrozole. How do you approach the selection of an AI in that situation?

DR BLAUSTEIN: Well, from a clinical perspective, it’s good to be data driven. Exemestane seems to have the best data behind it. Whether it’s any different than switching to anastrozole or letrozole, I’ll wait for the studies to show.

DR LUEDKE: If you’re going to switch at some point during the five years of tamoxifen to one of the aromatase inhibitors, how long do you treat with the AI?

DR BURRIS: I’m very careful to tell the patients that we’re going to go for at least five years and that we’ll follow the data together and probably hear about it from the Wall Street Journal or CNN first. But I advise them that it’s an open-ended story in terms of how long they may benefit from that particular treatment.

I also qualify that we’re going to have to be aggressive about bone density testing every couple of years or so. But I’m very impressed by the zoledronic acid data, and I’m pretty aggressive about fighting with insurance companies about utilizing this agent.

DR LOVE: Just to clarify, Skip, you’re talking about five years of total therapy or five years of the AI after the switch?

DR BURRIS: I tell patients that we are planning on five years of AI after the switch, based on how the original letrozole trial was planned with a total of 10 years of therapy. Certainly, the exemestane data was a total of five. Right now, we don’t know of a reason, biologically, to stop the AI any sooner than five years of total treatment.

DR LOVE: In a recent interview for our series with Terry Mamounas, I learned that the NSABP is hoping and planning to launch a trial looking at duration of hormonal therapy in this situation. Of course, it’s a very common question. There will be many patients in the next couple of years who are going to hit their five-year point. Do you stop it at five years or not?

According to Terry, the NSABP trial will randomly assign women after five years of hormonal therapy that includes an aromatase inhibitor to either five more years of an AI or no hormonal therapy. This trial will include women who’ve switched to an aromatase inhibitor at two years.

How do you approach the premenopausal woman with multiple positive nodes, who gets out to five years of tamoxifen and is doing great?

DR KRILL-JACKSON: I don’t see that a premenopausal woman is a priori different than a postmenopausal woman. If it’s good to switch a postmenopausal woman at high risk to an AI after five years of tamoxifen, I can’t see why it wouldn’t also be beneficial to give an AI to a premenopausal woman, but, of course, to do that, you have to make her postmenopausal.

In a patient at very high risk for recurrence, even though the data are not in — for premenopausal women, I believe it is your obligation as a physician to present those data. And certainly if I had 15 positive nodes, that’s what I would want to do.

DR PEGRAM: I’m really pleased to hear your comments, because you’re thinking about the biology of the disease. Since there are no randomized clinical Phase III data to drive you in these difficult decisions, we have to make decisions based on basic biology and what is scientifically plausible.

You’ve suggested a perfectly reasonable hypothesis, that if the biology of the disease is hormone receptor driven, if we have data showing that switching to AIs is beneficial in patients who no longer have ovarian function, we might expect to see the same result by doing ovarian ablation plus an AI in the premenopausal patient. Biologically, it’s very plausible and it would certainly be open for discussion in a case like this, even though there are no data yet.

DR LOVE: That’s interesting. One of the outcomes of the MA17 trial (Goss 2003) is that it really put the spotlight on and increased people’s sensitivity to the longterm natural history of breast cancer.

In fact, we knew there was always a substantial risk of recurrence, but now we’re seeing more and more retrospective analyses, looking at relapses after five to 10 years of therapy. It looks like this is particularly common in patients with ER-positive disease. Skip, what are your thoughts?

DR BURRIS: Exactly right, Neil. The most shocking slide that gets shown during the discussions of MA17 is that such a high percentage of recurrences occur after five years. Most of us would have guessed that was 10 percent of the recurrences, but it’s much closer to 40 plus percent of the recurrences that happen during the second five years.

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