Edited excerpts from the discussion:

DR FALLON: This woman presented in March 2003 at the age of 40 with a palpable tumor in the right breast. The mammogram showed several areas of suspicion, and the ultrasound showed one large mass and possibly a second mass. On stereotactic biopsy, she had high-grade, invasive ductal, ER-negative, PR-negative, strongly HER2-positive breast cancer. At mastectomy, four separate areas of invasive tumor were found, measuring 0.6 centimeter, 0.9 centimeter, one centimeter, and another measuring 2.4 centimeters with a margin less than two millimeters deep. Two out of 19 lymph nodes were positive, and no extracapsular spread was observed on the lymph nodes.

The patient underwent modified radical mastectomy and immediate implant reconstruction. She enrolled on NSABP-B-31 and had hoped to receive trastuzumab but in fact was randomly assigned to receive AC times four followed by paclitaxel times four, without trastuzumab.

She received chest wall radiation therapy because of the close margin. By the end of the trial, she was doing extremely well. She finished her doctorate in special education and got a new job as principal of a grammar school. This summer she climbed the Adirondacks with her sister, which was about a three-week hike.

She called me in June to ask whether she could receive trastuzumab at this point, and I told her I would look into it. She didn’t want to do anything until she got back in August, and by that time the NSABP told us they would allow trastuzumab only to those who were randomly assigned after April 2004, but she was randomly assigned in April of 2003.

DR LOVE: How long has it been since she completed chemotherapy?

DR FALLON: Approximately two and a half years.

DR LOVE: Eric, would you recommend trastuzumab off study for this patient?

DR WINER: I would be inclined not to administer trastuzumab at the moment for two reasons. One is that whether trastuzumab works as a single agent when given two years after diagnosis is unknown.

Second, whatever her risk of recurrence was in 2003, she has a somewhat lower risk of recurrence, perhaps a substantially lower risk, two years later.

Unlike ER-positive breast cancer, in which events are strung out over the course of 10 to 15 years, in HER2-positive breast cancer most of the events occur in the first five years and a lot of them occur in the first couple of years. That is part of the reason why, in each of these studies, we saw a dramatic benefit early on, even in the first year (Perez 2005b; Piccart-Gebhart 2005; Romond 2005).

DR LOVE: What would you say if this patient asked you what her risk of recurrence was from this point on?

DR WINER: I don’t think we can give her a hard number, but I believe it’s more than 10 percent.

DR LOVE: Dr Fallon, do you think if this woman knew she had a 10 percent risk of recurrence, she would want therapy despite the potential risks?

DR FALLON: She’s asking for the therapy, but she’s very philosophical and she agreed that if we don’t know how much benefit she would gain at this point in time, she may just wait and use it if she needs it.

DR WINER: Initially, this patient’s risk of recurrence was in the range of 50 percent in the absence of any therapy. AC followed by paclitaxel decreased that by about 50 percent, so at the end of therapy, her recurrence risk was approximately 25 percent.

DR LOVE: Over two years have passed since this patient completed chemotherapy. What is risk of recurrence now?

DR WINER: I suspect that at least a third of all of the events occur in the first couple of years, but none of us can give you an exact answer, partially because we just don’t have a great database on patients with HER2-positive disease treated only with AC followed by paclitaxel.

DR LOVE: How would you respond if the patient asked, “I know we don’t have any data, but do you believe my relapse rate would be decreased if I take trastuzumab now?”

DR WINER: I think it’s unknown, but if you invoke the HERA data (Piccart-Gebhart 2005), you would conclude that single-agent trastuzumab given immediately after the completion of chemotherapy is a very effective approach (1.1).

If you look at Edith Perez’s data from the N9831 study, there are questions about how much benefit a patient would receive from single-agent trastuzumab (Perez 2005). Additionally, some small risk of cardiac toxicity clearly exists, in addition to the unknown risks of long-term trastuzumab after an anthracycline-based regimen.

DR LOVE: This patient is 42 years old. Assuming she has a normal ejection fraction, what is her risk of cardiomyopathy or cardiac failure with trastuzumab?

DR WINER: It’s in the range of one to four percent.

DR FALLON: I think it’s important to remind patients that MUGAs don’t prevent cardiac toxicity. I did one on a patient whom I started on trastuzumab after doxorubicin and cyclophosphamide for locally advanced disease. After day one of trastuzumab and day two of paclitaxel, she presented with an unmeasurable ejection fraction. She had received full-dose doxorubicin, but she had a normal MUGA at the beginning and end of doxorubicin and then she suddenly developed acute cardiotoxicity.

When she then came back with metastatic disease, I treated her with docetaxel alone. Since her cardiac condition had reversed, eventually I was tempted to administer trastuzumab again. I administered it to her with vinorelbine, but her ejection fraction again decreased, so now she’s on vinorelbine alone.

So while I do think cardiac dysfuction with trastuzumab is more reversible than doxorubicin- induced cardiac failure, it’s not a walk in the park. I do think it’s reasonable with the patient I presented today. But she wants to be active — that’s a big part of her lifestyle — so it’s a balance of unknown benefit against possible risk.

DR LOVE: Eric, what are your thoughts about the use of trastuzumab without chemotherapy in the adjuvant setting for patients in whom you are reluctant to use chemotherapy, either because of age or comorbidities?

DR WINER: I wouldn’t do it. As tempted as we all might be, there simply aren’t data from any of the trials. That said, I think that a regimen of some chemotherapy followed by trastuzumab, based on HERA, is justifiable (Piccart-Gebhart 2005). In this woman, I think the key issue is making sure that she’s comfortable with the decision. I try not to draw a line in the sand and say, “We can’t cross this line” but to really help patients make the decision with me. The fact is that this patient could have a recurrence no matter what you do. If she receives trastuzumab, she could develop heart failure. You just can’t predict all of this.

DR LOVE: Kevin, would you administer delayed adjuvant trastuzumab to this patient (1.2)?

DR FOX: I find that when I’ve been confronted with these agonizing situations that present an impossible calculation of risk and benefit, I have at times taken the “oh, what the heck” approach. I have administered delayed trastuzumab a couple of times, but I would not if I felt the risk of recurrence were so absurdly small that I couldn’t justify it — for example, the onecentimeter, HER2-positive cancer that was treated five years ago. That would be an easier case to decide than this one. I have to confess I’ve been a little bit “fast and loose” with delayed trastuzumab.

DR LOVE: Eric, in the data from the BCIRG 006 study, we see that patients on the TCH [docetaxel/carboplatin or cisplatin/trastuzumab] arm had a 39 percent reduction in their relapse rate, whereas patients who received AC followed by TH [docetaxel/ trastuzumab] had a 51 percent reduction (Slamon 2005; [1.3]). The conclusion was that both of the arms were better than the nontrastuzumab arm, and it was stated that there weren’t enough data to compare the two trastuzumab arms. What are your thoughts regarding these data?

DR WINER: Assuming the hazard ratios hold up and nothing further shows up in the data, I’m struck that while TCH clearly reduced the risk of disease recurrence, a trend for a better outcome occurred in the women who received AC followed by TH. It was said that these are not different from one another; however, I think it is unlikely that TCH will be better. At the moment, I would use TCH only for patients in whom I am particularly concerned about cardiac toxicity.

I’ll also add that the TCH regimen used in the BCIRG study is not an easy regimen to get a patient through, and so apart from the cardiac issues, I think it’s a more toxic regimen than AC followed by docetaxel.

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