Edited excerpt from the discussion:

DR LASSITER: This patient is a 42-year-old woman who presented in the emergency room with abdominal distention and progressive shortness of breath. She had noted these symptoms for several months and they had progressively worsened, especially the breathing difficulties.

She was found to have a large left-sided breast mass that was essentially necrotic, with all of the normal skin being replaced. This encompassed an area from the clavicle all the way down to below the breast and from the midline over into the axilla. Essentially, no normal breast tissue remained.

An x-ray noted bilateral pleural effusions, and she also had elevated liver function tests and destructive lesions in her ribs and spine on plain films. She was hypoxic, with sats in the low seventies on admission. She was seen, admitted and had a chest tube placed for symptomatic improvement and to obtain a diagnostic specimen. This returned positive with malignant cells consistent with a likely primary breast tumor.

She subsequently had a core biopsy of the breast lesion that revealed a Grade I infiltrating carcinoma consistent with lobular features. Her tumor was hormone receptor- positive — ER: 70 percent and PR: 60 percent — and HER2-positive by FISH. She had further staging with a CT scan of the brain, chest and abdomen, revealing a normal brain and no evidence of visceral involvement in the lungs or liver.

DR LOVE: Can you talk about this woman as a person and what precipitated this type of presentation?

DR LASSITER: She is married, has no children and had previously worked in a sewing factory but was unemployed at the time. She is a quiet lady and even to this day is often at a loss for words during most of our discussions. She has what seems to be a supportive husband and a mother who accompany her to all of her visits. It appears that she had been hiding this breast tumor from her family for up to a year.

She reports that this originally started as a rash, and she thought it might have been a herpes zoster-type infection. Basically, she moved out of the bedroom to hide this from her husband, who one day walked in when she was showering and observed it.

DR LOVE: Cliff, we have a lady with an ER/ PR-positive, HER2-positive, locally advanced tumor and symptomatic disease. How would you have thought through her care at this point?

DR HUDIS: I’ve never actually seen an invasive lobular carcinoma that was HER2-positive, so this is probably invasive ductal cancer where the pathologist sees some lobular features.

Regardless, this patient is sick, and as strong as my bias is toward hormone therapy, with a symptomatic presentation of HER2-positive disease like this, I would start with chemotherapy and trastuzumab. At Memorial, we would encourage her to enter our trial with carboplatin, nanoparticle albumin-bound (nab) paclitaxel and trastuzumab, specifically (2.1). Off study, she would probably receive weekly paclitaxel with trastuzumab.

DR LOVE: Assuming she responded to that and stabilized, how would you then proceed?

DR HUDIS: We would treat her the way we treated patients in CALGB-9840 (Seidman 2004). After approximately six months of therapy, we would decide whether or not to continue chemotherapy and would continue the single-agent trastuzumab beyond progression.

There have been several randomized trials, including one by Hy Muss, that have pretty much shown that the chronic use of chemotherapy until disease progression is not necessarily any better than a period of treatment followed by a break (Muss 1991).

In fact, if we took a break and she progressed after months or even longer, we would restart that same chemotherapy to which she had previously responded.

DR LOVE: What about hormone therapy? Would you consider adding that in before progression?

DR HUDIS: Maybe. We don’t yet have data for hormone therapy with trastuzumab. I have no reason to doubt that it’s safe, but we don’t have data. Frankly, if she experienced disease stabilization on the trastuzumab, I would hold off on hormonal therapy until later, when I needed it.

DR O’SHAUGHNESSY: I definitely would have treated her with trastuzumab and two chemotherapeutic agents — carboplatin and a taxane. I would either use the BCIRG TCH regimen with docetaxel at 75 mg/m² and carboplatin with an AUC of five or six, or the NCCTG weekly paclitaxel/carboplatin/ trastuzumab regimen. I would have to see her to decide which regimen to use.

The advantage of the weekly paclitaxel/ carboplatin/trastuzumab is that it’s more compatible with chronic therapy, and usually that’s what I’ll do in the metastatic setting. I will use the three drugs for about six or seven cycles until maximum response, and then I will usually stop the carboplatin and keep going with the paclitaxel/trastuzumab. We don’t have any data here at all, but the reason I do it is because patients from the pivotal trial (Slamon 2001) and my own practice are many years out continuing on trastuzumab with paclitaxel or vinorelbine. I don’t have anybody in that category in my own practice on single-agent trastuzumab alone. So I generally stick with that.

I probably wouldn’t bring in hormonal therapy on top of it. If the patient were unable to tolerate ongoing chemotherapy, then I would keep going with the trastuzumab alone. However, at that point, I would start an aromatase inhibitor, and I would probably lean toward a laparoscopic oophorectomy.

In my mind, being 42 years old, this woman has a high probability of having her ovarian function return. Estrogen can be a strong survival signal, so I’m not sure that I would be doing the right thing by allowing her to continue to produce estrogen. That’s why, if I were going with single-agent trastuzumab, I would remove her ovaries and put her on an AI.

DR LOVE: Cliff, in the patient who has ER-positive, HER2-positive metastatic disease, how do you decide up front between hormonal therapy and either trastuzumab or trastuzumab with chemotherapy?

DR HUDIS: For somebody who is not acutely sick, I always have a bias toward hormone therapy because of the convenience and safety. However, I have seen patients with HER2-positive disease and liver metastases at presentation who progress in a matter of months. We watch those types of patients closely, and if they progress rapidly, they have clearly declared themselves as needing trastuzumab and probably chemotherapy.

I don’t think a general rule exists that says you must give trastuzumab and chemotherapy first. I think you can try hormone therapy. For example, Chuck Vogel’s singleagent trastuzumab trial was for patients with HER2-positive, ER-positive or -negative disease (Vogel 2002). Many of those patients had been through hormone therapy already, so I don’t think you have to feel guilty or that you’re making a mistake by offering patients hormone therapy first.

DR LOVE: Can you follow up with what happened with this woman?

DR LASSITER: She was felt to be a little too ill to take triple therapy, so I elected to give her weekly docetaxel/trastuzumab (Esteva 2002; Raff 2004; Tedesco 2004) and follow her closely. She actually tolerated the therapy well and responded with a slow but progressive improvement in her pulmonary status. She stopped using oxygen within approximately two months and has also had a slow improvement in her skin lesions.

We are now approximately six months into treatment, and her original breast tumor has been reduced in size by approximately 75 percent. Normal skin from the edges has now replaced the necrotic skin down to an area a little smaller than a baseball. She has tolerated therapy with essentially no side effects to this point, and I’m thinking about what to do next.

DR O’SHAUGHNESSY: Generally speaking, with docetaxel you will eventually run into some toxicity that will cause you to stop therapy. So I would personally continue with the docetaxel until I needed to stop. I would probably keep going with trastuzumab, and because she was so sick and her tumor is strongly ER/PR-positive, I would lean toward aggressive hormonal therapy. One could certainly just put her on an AI. I wouldn’t be enthusiastic about tamoxifen.

Even though our data are limited regarding the AIs versus tamoxifen for HER2-positive disease, the two available trials both favor the AI, so I would use that (Ellis 2003; Dowsett 2005).

Putting her on an AI means you need to watch her estradiol and FSH closely. I’ve run into compliance issues with that, so I would probably favor a laparoscopic oophorectomy and then an aromatase inhibitor.

DR LOVE: Would you continue the trastuzumab through that?

DR O’SHAUGHNESSY: I have only seen results from one single-arm, Phase II trial with letrozole and trastuzumab (Marcom 2005). The response rates were in the high twenties, which are respectable and presumably higher than single-agent letrozole, but we just have limited data at this time.

DR LOVE: Cliff, the data from the Intergroup or the NCCTG adjuvant trastuzumab trial and NSABP-B-31 are going to be combined (Romond 2005). I’m curious about your thoughts on that decision and where you think things are going to be heading in terms of these studies.

DR HUDIS: In New Orleans at the 2004 ASCO, with all the members of the Intergroup present, a decision was made to combine the data from NSABP-B-31 and the NCCTG study. For some, this was seen not so much as a decision but as a confirmation of a pre-existing plan. These clinical trials are similar in design, as the two arms of B-31 precisely mirror two of the three arms of the NCCTG study. So putting them together in a mini meta-analysis or dual analysis makes a lot of sense.

DR LOVE: Joyce, what are these studies going to show?

DR O’SHAUGHNESSY: I’m betting they will all be extremely positive. Hopefully, we’ll see the data at ASCO 2005.* * Note: This recording took place prior to the 2005 ASCO meeting.

The HERA trial looked at placebo versus one year versus two years of trastuzumab after chemotherapy. If it’s a positive trial (Piccart-Gebhart 2005), for all of our patients who have finished up their adjuvant chemotherapy, we will have the opportunity to discuss bringing in trastuzumab. But we will be faced with the old MA17 type of question: How long can you wait off therapy before you bring it in?

I think there will be more questions than answers. Similarly, in NCCTG-N9831, the Intergroup trial, arm B is AC followed by weekly paclitaxel followed by the trastuzumab. That is a sequential versus a combination question.

I’m expecting the biggest advance in 30 years in breast cancer. I have no inside information, but I’m hopeful (2.2, 2.3). This will mean that for any of our patients who are currently receiving chemotherapy and are HER2-positive, we will need to consider adding the trastuzumab to their chemotherapy.

For patients at higher risk who have finished their chemotherapy, if the sequential approach looks positive, I expect that we would then want to bring in some trastuzumab for them.

DR LOVE: Joyce, the NSABP has reported data evaluating cardiac effects in their trial (Geyer 2003), and Edith Perez is going to be presenting some data from the Intergroup study at the 2005 ASCO meeting (Perez 2005), which she has told me are going to be similar. Right now, if you were to sit down with a patient in the adjuvant setting, what kind of numbers would you give in terms of cardiac risk?

DR O’SHAUGHNESSY: The NSABP data were extremely helpful because we don’t have to guess. We can give good numbers in the short term. I think we have to leave open the question about the long term.

The data from NSABP are fairly encouraging. There was a 4.28 percent risk of congestive heart failure. Out of the first 500 who were analyzed, 250 on each arm, only one had symptomatic congestive heart failure afterwards.

The recovery looked rather impressive, which was encouraging. I think many of us have seen that in clinical practice — even in the metastatic setting.

Patients occasionally, but rarely, develop congestive heart failure, but my experience is that it is readily treatable with good cardiology care.

However, a small number of patients will still be left with significant cardiac symptomatology. That can’t be minimized, but at least we can provide our patients with effective informed consent with several years of follow-up.

DR LOVE: Cliff, what would you say if a patient asks you, “What’s the chance that if I take adjuvant trastuzumab it’s going to cause some problems with my heart, either subclinically or long term?”

DR HUDIS: I agree with Joyce. The B-31 data that Charles Geyer presented (Geyer 2003; [2.4]) are our best answer yet, although Edith presumably is going to give us data like these from her study at ASCO (Perez 2005; [2.5]).

I would say the chance is pretty good that one out of 25 patients will have some sort of cardiac event that could be linked to adjuvant trastuzumab. I don’t know how significant that will be and what the long-term sequelae will be.

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