DR DRULLINSKY: This 35-year-old woman developed a mass during her third pregnancy, which was ignored by her obstetrician because it was felt to be related to pregnancy changes. Then, after delivery, the mass persisted. It turned out to be a 3.5-centimeter, moderately differentiated infiltrating ductal cancer, with two sentinel lymph nodes positive for cancer. It was estrogen receptor-positive, progesterone receptor-positive, and HER2-positive by FISH.

We were participating in the CALGB trial of adjuvant trastuzumab, and she agreed to enter the study. She was randomly assigned to no trastuzumab, and she received AC times four and weekly paclitaxel for 12 weeks. She finished her therapy in January 2005, at which point she was premenopausal, and the question came up of whether we should go with tamoxifen or anastrozole and goserelin.

Since the tumor was 3.5 centimeters, two lymph nodes were positive and she had not received trastuzumab, I put her on anastrozole and goserelin, knowing that it’s not standard practice in this country but based on some preliminary information on aromatase inhibitors in HER2-positive disease. Then, after the ASCO meeting, we actually called her back, and she’s being provided trastuzumab for a year.

DR LOVE: A number of questions come up about this case. First, let’s start with the hormone therapy. Even though, as you said, it’s certainly not standard, I can tell you from our Patterns of Care studies that probably about a third of the oncologists in the United States would have done what was done here, in terms of using an LHRH agonist plus an aromatase inhibitor in a high-risk younger woman with a HER2-positive tumor. Rowan, what are your thoughts about that, off protocol?

DR CHLEBOWSKI: The data you have to support it are a couple of Phase II trials in metastatic disease with less than 100 patients. So, in a certain sense, there’s very limited information. Alternatively, you could give ovarian suppression plus tamoxifen. That’s what we’ve been doing. You deviate off these protocols in various different ways. In women under 40 with hormone receptor-positive disease, we’re routinely doing ovarian suppression with tamoxifen. We haven’t utilized the combination of aromatase inhibitors with ovarian suppression yet. But I can see how it may not be an unreasonable extrapolation to do so.

People should also know about a trial in the abstract book from the San Antonio Breast Cancer Conference a couple years ago. It was a randomized trial in metastatic disease, showing a benefit for ovarian suppression plus anastrozole versus ovarian suppression plus tamoxifen (Milla-Santos 2000). But that was a withdrawn abstract. It’s gotten into Medscape, and it’s very difficult to pull it once it’s out on the internet.

DR LOVE: This also gets into the issue of when to pull the trigger on a therapy that hasn’t been proven in a Phase III study. For the last few years prior to the release of the data from the adjuvant trastuzumab trials, I was asking research leaders on our audio series about patients like these, “Should you use trastuzumab off study?” They very strongly said, “No. Put the patient on a trial. If not, you don’t use trastuzumab.”

Now it’s been proven to reduce the relapse rate, and it raises the question of how much evidence is enough when you are dealing with a patient like this woman, with a very high risk of relapse.

So, even though you say there are only 100 patients in these Phase II trials, there are also thousands of postmenopausal women who have benefited from the aromatase inhibitors, and other people would say, “We’re making the patient postmenopausal, so let’s use the best hormonal therapy for postmenopausal women.”

Tom, what are your thoughts about this — not just specifically of a premenopausal woman with high-risk ER-positive disease — but when do we pull the trigger?

DR BUDD: It is an interesting question. I think we have no option but to try to be evidence-based, when we have evidence. Now, there are all too many situations in clinical medicine where we don’t have data. And we have to reason in other ways — by analogy to similar situations, by what we know about the biology of the disease and so on.

In the adjuvant treatment of any disease, you can’t monitor the disease to see what’s happening. The only way to approach this scientifically is with randomized trials that have control groups. So in clinical practice in general, I try to stick to what’s been proven. We’ve gone through this many other times with adjuvant chemotherapy for node-negative breast cancer and so on.

What was the wrong thing to do 10 or 15 years ago is now the right thing to do. You’re going to make mistakes if you don’t go on the basis of evidence. Where you have evidence, you ought to follow it. And where you don’t have evidence, that’s where you can be more creative.

DR LOVE: With this woman’s disease being HER2-positive, you have the question of whether tamoxifen is going to be a little less effective. What specific hormone therapy, in general, would you be utilizing off protocol?

DR BUDD: I don’t want to criticize, and I understand where you’re coming from. I think it’s quite possible — maybe even probable — that an AI and LHRH agonist will turn out to be the best treatment for this patient, and the International Breast Cancer Study Group has shown these younger patients with ER-positive disease have a bad prognosis, so some improvement in hormonal therapy is needed.

Off protocol, in general, I use tamoxifen in premenopausal women. Whether ovarian ablation adds — in terms of efficacy — to chemotherapy or tamoxifen, I don’t think we know. We do know it adds toxicity. That’s what this ECOG trial (E3193) in node-negative breast cancer showed (Robert 2003). It’s quite possible that it will end up adding efficacy, if we can select the right patient population, unconfounded by early menopause from chemotherapy.

DR LOVE: Any situations like this where you might use an LHRH agonist plus an aromatase inhibitor off study, Jenny?

DR CHANG: We’ll try not to and try to put them on a study. We have several ongoing studies, including the SOFT study (8.1) to consider. We like to practice evidence-based medicine, and yes, I tend to agree with Dr Budd, but it’s very difficult. I understand where you’re coming from, and you’re probably making the right choice, but it’s not evidence-based.

DR LOVE: Eric?

DR WINER: I wouldn’t go so far as to say that it’s the right choice. I think that it is a choice. I think there are really four choices. One is tamoxifen. One is tamoxifen plus ovarian suppression. The third is ovarian suppression alone, which you would argue to do if you thought tamoxifen might have a stimulatory effect on the tumor, and you acknowledge that we don’t know that adding an aromatase inhibitor to ovarian suppression in a premenopausal woman improves outcome. The fourth is doing what you’ve done.

Trials examining these various issues are ongoing. I don’t think there’s a right or wrong. I probably would give her ovarian suppression and tamoxifen outside of a trial. She might be the type of person whom I would switch to an aromatase inhibitor with ovarian suppression after a couple of years, even though she was premenopausal at the time of diagnosis.

I think this is a trap that we all fall into — and I’m not suggesting that you did any more than anyone else — to bring a lot of emotion into the picture when you’re dealing with a young woman. I just think we have to make sure that doesn’t inf luence us to make decisions that we would later regret.

DR LOVE: Let’s discuss adjuvant trastuzumab. Would you consider adjuvant trastuzumab for a small (under a centimeter) node-negative tumor? Clearly, that patient would not have fallen into the eligibility criteria of the studies that were reported.

DR CHANG: Basically, it depends on her risk of relapse. If she has a small tumor with a low risk of relapse, then the addition of trastuzumab probably adds very little.

DR LOVE: Eric?

DR WINER: I don’t believe the benefits of trastuzumab will vary according to nodal status, but the risk of recurrence will vary according to nodal status and tumor size. I find it very hard to imagine treating a woman with a T1a- N0 cancer with either chemotherapy or trastuzumab.

Apart from that, I’m generally comfortable with the use of adjuvant trastuzumab in the majority of patients, based on what we know so far, although I think we have to watch the toxicity profile closely over time. One group that I do still have some concerns about are women with relatively small — under two to three centimeters — ER-positive, HER2-positive cancers because I’m not so clear that I know the event rate and the benefits of hormonal therapy, specifically the aromatase inhibitors, in that group of women.

DR LOVE: How about the issue of delayed trastuzumab in patients treated previously?

DR WINER: In terms of the woman with five positive nodes who is some time out, we’ve generally taken the approach that within six months we would offer treatment. Up to a year we’d consider it. I have trouble doing it beyond a year. One can’t be too rigid here. I think the thing to remember is, for that woman with five positive nodes who is now two years out, her risk of recurrence is actually substantially lower than it was at the time of diagnosis because events in HER2-positive patients occur early on. So there is good reason to think that the benefit may be much less for her.

DR LOVE: Tom?

DR BUDD: I’d use adjuvant trastuzumab in patients with tumors that are T1c and above and within six months post-treatment.

DR LOVE: Rowan?

DR CHLEBOWSKI: It would be size-dependent, and six months is also my cutoff. The other thing for me is ejection fraction, especially dealing with the older individual. In an older individual, I like to see a higher ejection fraction to put that into the risk-benefit calculation.

DR LOVE: We’ve really become sensitized to the time course of recurrence because of the aromatase inhibitor data. I wonder if, as time goes on, postadjuvant trastuzumab is going to start to fit into that model, just like we’re looking now whether to start letrozole at six years. We’re looking at the risk and risk reduction. Are we going to fall into the same type of model?

DR WINER: I think the fundamental difference here and the reason we saw such big differences early on is that events occur early in patients with HER2-positive disease and ER-negative breast cancer. We’re really talking about somewhat different diseases than the patient who has ER/ PR-positive, HER2-negative breast cancer. So I think we’re just going to have to see over time.

The other comment is that there is great interest in looking at nonanthracycline- containing regimens. The whole way we look at this may be different in a few years because, in fact, for that patient at low risk, on some level — not that I would do this at the moment — I’m more interested in giving her trastuzumab than doxorubicin. We’ll have to see how all this plays out.

DR LOVE: In the trastuzumab studies, about half of those patients were also ER-positive. What about the natural history of ER-positive, HER2-positive disease?

DR WINER: We know much less about that than we would like to. The one thing we do know from the metastatic trials, the preoperative trials and now the adjuvant trials is that the benefits of trastuzumab seem to be similar in ER-negative and ER-positive disease. I think what we’re less clear about is the risk of recurrence because we’re still not sure how much hormonal therapy adds in that situation, particularly if the aromatase inhibitors turn out to be as effective in HER2-positive as in HER2-negative disease. Then those women are starting from a much lower risk of recurrence than the patient with ER-negative, HER2-positive breast cancer.

Select publications