Edited excerpt from the discussion:

DR SEIGEL: In 1999, this 48-year-old woman identified a mass in her breast. She had a wide excision and then subsequently went on to total mastectomy and axillary node dissection.

The final pathology indicated a 3.5-centimeter, high-grade invasive ductal carcinoma. The tumor was estrogen and progesterone receptor-negative, HER2-positive, 3+ by immunoperoxidase staining. She had 11 of 16 positive axillary nodes.

She was married, had two teenage daughters and was working part-time. She was a very realistic, motivated patient. We discussed that due to multiple adverse prognostic indicators, there was a very significant risk of developing local-regional recurrence and metastatic disease.

DR LOVE: Mark, how do you approach patients with HER2-positive tumors and multiple positive nodes in terms of options for protocol and nonprotocol therapy?

DR PEGRAM: One of the most important things to do for this group of patients is to secure a staging evaluation to rule out distant metastases.

DR SEIGEL: This woman had a bone scan and a CT of the chest and abdomen, which were negative.

DR LOVE: Do you go beyond that in a situation like this? A PET scan, for example?

DR PEGRAM: We don’t routinely.

DR BURRIS: In our practice, when patients have upwards of eight, nine or 10 positive lymph nodes, we are now doing PET scans. It’s too early to comment on how often these are positive, but at least 10 percent are positive for distant disease.

DR PEGRAM: Are you doing PET CT or just PET?

DR BURRIS: They receive a PET CT. They have a CT scan of the chest, abdomen and pelvis with a whole-body PET scan.

DR PEGRAM: You do not do a bone scan?

DR BURRIS: Correct. The PET substitutes for the bone scan in that setting. PET scan machines have certainly gotten much better and it’s a rapid test.

Not too infrequently, we pick up liver or lung lesions that are suspicious on PET but are not yet recognizable on CT scan. Often this won’t change some of the initial management, but it gets you into the thought process of how you’re going to approach the patient.

DR LOVE: Mark, with 11 positive nodes and a HER2-positive tumor, what options would you present to her?

DR PEGRAM: Clearly, adjuvant chemotherapy is indicated. I would use a highly active regimen, and there are a number that contain anthracyclines and taxanes to choose from.

My view is that many of these regimens are similar to one another with regard to efficacy. I would pick one that the patient and I are comfortable with and stick with it.

Off protocol, I would not routinely say that trastuzumab would be a consideration yet, even for this patient population. Although I must admit that on occasion at our institution, we have treated patients like this with trastuzumab-based regimens. It is certainly not a standard of care, because there are no randomized clinical trial data to support that approach.

DR LOVE: Just to clarify, in a young, healthy woman like this, what chemotherapy options would you be comfortable with and what would you end up utilizing?

DR PEGRAM: We participated in a TAC versus FAC trial (Martin 2003), so we do use a lot of TAC. I know the next comment is going to be that in the TAC versus FAC trial, the greater-than-four lymph node-positive subset failed to reach statistical significance. I think that is more a function of subset analysis rather than any change in the biology and probability of response to systemic adjuvant therapy based on the number of lymph nodes.

In addition to TAC, we would certainly offer the patient AC followed by docetaxel, and we would certainly talk about dose-dense AC-paclitaxel. All those would be open to discussion. We would give the patient the pros and cons of each approach and let her help in the decision.

DR LOVE: Skip, how would you approach this patient and where would the possibility of trastuzumab fit in a nonprotocol situation?

DR BURRIS: I’ve been fortunate to not have had a patient adamant about receiving trastuzumab in the adjuvant setting. However, this is clearly a patient with whom you would want to be as aggressive as you possibly could within reason. As Mark noted, AC followed by a taxane or TAC would be what you would discuss. This is a situation in which, as was alluded to, the greaterthan- 10 positive lymph node group in the TAC arm did not show a big difference.

This is where, rightly or wrongly, I would turn to what I’ve seen from the Aberdeen data (Smith 2003) and from the pathological CRs from the NSABP results (Bear 2004), to think that if you knew it was going to turn out this way, you would have treated this patient neoadjuvantly and been very aggressive.

The highest pathological CR rates were seen with four cycles of AC followed by four cycles of docetaxel at 100 mg/m². That would probably be my first recommendation. It’s eight cycles of therapy with noncross resistance between the drugs. Plus you give maximal single doses of the agents, so that would be my inclination.

DR LOVE: We have seen from our Patterns of Care studies that for node-positive patients in this country, the number one regimen selected by oncologists is AC paclitaxel dose dense. That, however, is followed not too far behind by AC docetaxel. TAC is actually not that commonly utilized.

I’m wondering if that is going to change at all in light of the NSABP-B-27 data looking at neoadjuvant AC followed by docetaxel that was presented in December 2004 at San Antonio. Mark, could you summarize what that showed at this point and what your thoughts are about it?

DR PEGRAM: The B-27 trial compared four cycles of AC versus four of AC followed by four of docetaxel. The docetaxel-containing arms varied with regard to the timing of the surgery.

The pathologic complete response rate in the subset that received the AC followed by docetaxel was significantly higher than in the subset that received just four cycles of AC alone. It was thought that the higher pathological CR rate observed in the patients treated with docetaxel would ultimately translate into an improvement in disease-free and overall survival. Surprisingly, with the available follow-up, the differences in the pathologic CR rate did not translate into improvements in overall survival.

I don’t have a good explanation for this, because the study that was presented right after that in San Antonio was FEC followed by docetaxel compared to six cycles of FEC alone (Roche 2004). That clearly showed an improvement in clinical outcome with docetaxel with reasonable follow-up.

DR BURRIS: It is a shame, because I thought that NSABP-B-27 was a great trial idea and it accrued quickly. An issue that confounded the findings was that more and more data suggest that giving tamoxifen at the same time as chemotherapy is not optimal. Unfortunately, there are many patients on NSABP trials with that as a complicating factor.

DR LOVE: Mark, when you see a woman like this patient, do you proactively bring up the issue of trastuzumab or do you wait for her to bring it up with you?

DR PEGRAM: I bring it up, and it is definitely on the table for discussion. The fact that we have ongoing randomized trials (3.1) suggests that all of us believe this is worth looking at seriously. The Buzdar neoadjuvant data (Buzdar 2005) may foreshadow the results of the ongoing adjuvant studies. Although there are no data yet from the major adjuvant trials, there is every reason to anticipate that the results from these trials may be favorable. In that case, it will become a new standard of care, but that has to wait until the data are available. That is why I would not recommend using offlabel adjuvant trastuzumab. However, on the other hand, I feel obligated to tell someone with such high-risk disease that there is an active targeted therapy available.

DR LOVE: Would you be comfortable utilizing trastuzumab in this situation?

DR PEGRAM: I would be and have done so with patients like this.

DR LOVE: How low of a risk are you comfortable with?

DR PEGRAM: I don’t know. I go case by case. Every patient is different, and it depends a lot on other factors such as comorbid medical conditions and whether the patient has ever had a cardiac event. All of these factors weigh into that kind of decision. I don’t know at what number of lymph nodes I would feel strongly enough to “bite the bullet” and try it off label.

DR LUEDKE: I have a large population of fairly affluent, highly educated women who come in with lots of information, requests and demands. Most patients have heard about HER2 and trastuzumab, and I have used it in some of my patients at high risk as adjuvant therapy, particularly patients with inflammatory breast cancer, but I am curious how you use adjuvant trastuzumab, when you start it and how long you give it?

DR BURRIS: I haven’t treated anyone off study, but my recommendation would be to finish the doxorubicin, initiate trastuzumab with the taxane therapy and continue trastuzumab on an every three-week schedule out to 52 weeks.

DR LOVE: Clearly this is an off-label use and we are certainly not in any way endorsing it, but this is a vexing problem that all oncologists face.

Of course, the most difficult question is: “Okay, Doc. What would you do if it were you or somebody in your family?” Mark, what do you say when a patient like this woman with 11 positive lymph nodes asks that?

DR PEGRAM: I tell them that I would use taxotere/carboplatin/trastuzumab (TCH), which is the regimen we’ve been giving to patients like this when they elect to go onto a trastuzumab-containing regimen in the adjuvant setting.

It’s important to emphasize, however, that in the BCIRG trial 006, there is an anthracycline- containing arm that also adds trastuzumab after the completion of the anthracycline. That may be an important control in the future, because what we don’t know is whether or not there is co-amplification of the topoisomerase II gene (TOPO-2).

Approximately 40 percent of HER2-amplified cases will have TOPO-2 amplification also. We’re all familiar with the sensitivity to anthracyclines that is associated with HER2, but in fact, that may not be a HER2 phenomenon but a TOPO-2 phenomenon, because it’s so close to the HER2 gene.

It will be important to examine the difference between the TCH arm in the BCIRG study and the AC followed by docetaxel/ trastuzumab arm because the Buzdar neoadjuvant data, which incorporated an anthracycline, had very robust activity. Many people have interpreted that trial as suggesting that an anthracycline may still turn out to be an important component.

The cardiac safety issues are still paramount. The cooperative groups in the United States “dodged a bullet” with their cardiac analysis of the first 1,000 patients. The stopping rule was four percent, and the NSABP data came to three and a half percent, so they almost had to shut down one of the trials because of this. Therefore, you can’t take these decisions lightly. As a result, we’ve used TCH off label, because of the concerns about cardiac safety.

DR LOVE: Are there situations now in which you’re utilizing trastuzumab in the neoadjuvant setting for patients with HER2-positive disease?

DR BURRIS: Generally, I’ve used it for patients who have locally advanced or inflammatory disease. In that setting, I tend to choose the TCH regimen with docetaxel/ carboplatin/trastuzumab.

DR LOVE: We know now that the NCI has approved the combination of data for the NSABP and Intergroup adjuvant trastuzumab trials and that the analysis will be done very soon. Hopefully, we may even see some results this year. What about the BCIRG study and the HERA trial from Europe? Mark, when do you think we’ll see data coming out from them in terms of efficacy?

DR PEGRAM: Given the current rate of events in the BCIRG adjuvant study, it’s estimated — and this is just a guess — that the earliest we could take a look at the data would be the end of 2005. It’s a random event rate, so we just have to wait and see when the numbers come in.

The HERA study, because of the huge number — over 4,000 patients on that trial — is having a robust event rate. They are really the dark horse in this race and may actually come in, surprisingly, ahead of any of the other trials. I talked to José Baselga recently, and he said they also might be able to look at their data set at the end of 2005.

DR LOVE: Dr Seigel, can you continue with what happened to this patient?

DR SEIGEL: I would have preferred entering her in a clinical trial, but at that time, strangely enough, I didn’t think there was a study available that was aggressive enough for this situation.

My perception was that the most aggressive chemotherapy regimen was AC times four, paclitaxel times four in an every three-week cycle. That’s what she received, and this was before the dose-dense data came out (Citron 2003).

She then had radiation therapy to the chest wall and had a boost to the right supraclavicular fossa and the right axilla. At that point she received no additional treatment. She did well until May 2002, when she presented with severe occipital headaches, some vomiting, lightheadedness and blurry vision. An MRI showed a solitary cerebellar lesion.

We also restaged her at that time, and a bone scan showed a solitary lesion in the sternum and a CT of the chest revealed a couple of indeterminate subpleural nodules. Since she had limited other metastases, we opted to resect the single cerebral metastasis, and this went well.

Then, under the control of a neurosurgeon, she wound up receiving gamma knife therapy to the cerebellum. I didn’t really have much influence in that decision, and I might have recommended whole brain radiation at the time. I then treated her with trastuzumab and vinorelbine.

She did well until December 2002, when she developed a couple of additional brain metastases. At that time, she went on to receive whole brain irradiation. She continued the trastuzumab/vinorelbine, and periodic restaging studies pretty much indicated everything was under control.

In April 2004, she popped up with one or two new brain metastases and received additional gamma knife. She has continued on the trastuzumab/vinorelbine and is doing fairly well. She has no evidence of any significant systemic progression and is restaged every three to six months.

DR LOVE: Skip, I increasingly hear about patients like this woman who are controlled peripherally with trastuzumab yet have recurrent problems in the brain. Is that something you’re seeing?

DR BURRIS: It is, and it’s troubling. I would agree completely with the approach of being aggressive in a young woman, including the use of surgery. In the setting of other tumors, there are active chemotherapeutic agents that get into the brain a little bit better — the topoisomerase inhibitor, CPT- 11, topotecan and drugs like temozolomide.

In a setting like this, the continuation of trastuzumab is certainly reasonable, but I almost wonder at this point if you should consider giving a drug with a better likelihood of getting across the blood-brain barrier, like capecitabine or one of the 5-FUtype drugs.

There’s certainly evidence that 5-FU crosses the blood-brain barrier well, and capecitabine is something we’ve used in this setting and had some positive responses to.

There are mixed messages out there about the capecitabine/trastuzumab interaction. There is not the level of synergy to it, but it’s clearly not antagonistic.

What to do about it is something we really need to research.

DR LOVE: Skip, capecitabine/vinorelbine is a common combination used in HER2- negative patients. Are you suggesting that capecitabine should be added to the vinorelbine, or just substituted?

DR BURRIS: A logical choice would be to add the capecitabine to the vinorelbine. The continuation of vinorelbine is interesting, and she has obviously tolerated it very well. But if a patient seems to be in best response six or eight months into her chemotherapy, I will often stop the chemotherapy and continue the trastuzumab by itself. That would have been more typical for me, and then I would add it back in.

Dr Perez and some others have published data on the use of irinotecan in breast cancer (Perez 2004), and if you can get insurance reimbursement, it may be reasonable to consider that as an option, knowing that it is one of those drugs that crosses the blood-brain barrier very well.

DR LOVE: Dr Seigel, many of us have a “don’t rock the boat” concept when patients are doing well. Have you thought about the possibility of adding in capecitabine or substituting it for vinorelbine?

DR SEIGEL: No, but it seems to be a very attractive option, because I’m sure she is destined to develop additional brain metastases. Actually, at this point, it would be attractive to discontinue the vinorelbine and start capecitabine because she quite frequently develops neutropenia that requires filgrastim shots, which she is selfadministering. That is a bit of a nuisance, so I think I’m going to seriously consider your suggestion.

DR LOVE: What has her lifestyle been like over the years and how has she and her family responded to this situation?

DR SEIGEL: She is functioning very normally. Her two daughters are now in their early twenties. She has an extremely supportive family.

Except for the inconvenience of coming to the office for treatment, she is more or less leading a normal life.

DR LOVE: Mark, what are your thoughts about what is happening in these patients with CNS-specific progression?

DR PEGRAM: I think it is all probably due to the lack of penetration of trastuzumab through the blood-brain barrier.

I would imagine if you did a careful analysis, you would find that the reason we’re seeing so many brain metastases in these HER2-driven cases is simply due to the fact that it’s an aggressive-behaving disease that would have gone there anyway.

It is amazing how often this happens. We’ve seen a lot of brain metastases on our trastuzumab trials at UCLA. I can recall during the Phase II trials, all the women on trastuzumab would come to the clinic for the trial on the same day, and they would have a conference in the waiting room. After a time, it came to pass that my patients were essentially demanding MRIs of their brain, though they were asymptomatic.

I remember on one specific occasion where one such patient had a positive MRI, after I insisted to her that she didn’t need it. It is a frightening situation, but I don’t think that there is any difference in terms of the natural behavior of the disease. It means that we’re controlling the systemic disease so well now with these active trastuzumab regimens.

Let me just make one final comment about temozolomide. I have tried this in my patients, and unfortunately, I’ve never seen a response. I don’t know if you have had any more anecdotal luck than I have.

DR BURRIS: I mentioned temozolomide as an example of a drug that we know crosses the blood-brain barrier and as the kind of thing you’d want to bring into the mix.

However, the TOPO-1 inhibitors are probably a little more attractive here. My first choice would be capecitabine. My second choice would be probably irinotecan in the setting of selecting a drug we know gets across the blood barrier.

DR LOVE: Mark, what about the issue of capecitabine and trastuzumab? Work from your lab actually led a lot of people to push this aside, and now it sounds like they’re reconsidering this. Can you track that story?

DR PEGRAM: It’s important to remember the definition of antagonism in these cell-based assays used in the laboratory. Suppose you have agent A, which has a 30 percent response rate, and another agent, B, which has a 40 percent response rate. A plus B should equal 70 percent but if you observe a 60 percent response rate, by definition there must have been some type of antagonism between the two agents to prevent it from reaching the additive line.

However, if you did a randomized trial and found a 60 percent response rate with a combination, it would be statistically significantly better than either one of the single agents alone. That is exactly the clinical situation with capecitabine and trastuzumab.

It suggests, however, that maybe by staggering the agents you could do just as well, or perhaps even better, but it does not mean that they are antagonistic enough to thwart the activity of either one of the single agents.

I think that is the best explanation for the observation in the laboratory. It is, by definition, antagonistic because it doesn’t hit the additive line, but it can still be better than either single agent alone.

DR LOVE: Skip, of course you have a convenience issue also as you can give the trastuzumab every three weeks and the capecitabine by mouth. Is that a combination you’re using in your practice, and where do you place it?

DR BURRIS: It has fallen into the mix of second- and third-line options with trastuzumab, and it has been well tolerated. There are no overlapping toxicities, and there are no untoward effects with the combination. It’s just that your level of benefit may not be as great as with some of the first-line options with the taxanes and vinorelbine.

DR PEGRAM: For the record, I have to say that at UCLA we use that combination all the time, because these patients run out of chemotherapy options. I personally have seen responders on salvage capecitabine/ trastuzumab regimens. It is not real common, but it can happen.

DR KRILL-JACKSON: How many lines of therapy are you using trastuzumab in?

DR PEGRAM: That is very patient individualized. It depends a lot on other factors. When I’m moving through various lines of salvage therapy, I always take the opportunity to reassess the whole clinical picture, including re-evaluating cardiac ejection fraction and looking at issues like IV access and distance traveled to the clinic.

If everything is going well, then our habit has been to keep it on board through subsequent salvage regimens, though there is no randomized controlled trial that supports that. If you elected, for any reason, to stop the trastuzumab sooner, that would be perfectly reasonable in my view.

However, I wouldn’t stop it short of the first progression, because all of the pivotal trials that won FDA approval of the drug in the first place were based on time to progression. You should treat at least that long, and after that it’s clinical judgment.

DR LOVE: When we look at our Patterns of Care data, 90 percent of oncologists continue trastuzumab at least until the second line, but surprisingly there are some physicians who stop the trastuzumab even when the patient is responding. Your point that this wasn’t done in the trials is important.

DR PEGRAM: In that situation, a rechallenge with trastuzumab might result in a secondary response. This has been shown with other antibodies, like rituximab in lymphomas. Since we don’t have those data, I would be a little leery of stopping short of the first progression.

After that, then it is a balanced discussion with the patient. The patient should be aware that there are no data showing an advantage for the continuation of trastuzumab beyond the first line (albeit cf Gelmon 2004).

DR DRESDNER: Now that patients are being kept on trastuzumab so much longer, how often do you monitor their cardiac function? Other than a physical examination, are you doing echocardiograms and MUGAs routinely?

DR BURRIS: We learned a little bit about this from the interim analysis of the adjuvant trials, but if you’re going to have a cardiac event with trastuzumab, you are more likely to have it in the first six months. Once a patient gets past the six-month mark and then the year mark, it actually looks like the incidence of developing a problem is quite low.

Typically, I get an echocardiogram and a MUGA every three months through that first year of therapy. From that point on, based on symptoms or something that would cause concern, I would obtain additional cardiac testing. But after that first year, I’m not routinely doing any monitoring.

Select publications