20. How do you decide if a tumor is ER-positive on
immunohistochemistry?

Monica Morrow, MD

The San Antonio group looked at their very large database and found that any receptor staining with IHC techniques correlated with a response to endocrine therapy, and that’s pretty much the definition that we use. I think having both an estrogen receptor and a progesterone receptor is an indicator of a greater likelihood of response than having a single receptor. But we don’t have a cutoff of, for example, more than 10 percent or 20 percent of cells. Traditionally, laboratory reports came back saying, "Minimal staining consistent with not a response to endocrine therapy." That’s not what we believe today.

21. How do you interpret the pathology report of estrogen and progesterone receptor assays in making clinical decisions?

Monica Morrow, MD

Seeing the actual data is useful in clinical decision-making, because some of these arbitrary lab definitions were set many years ago and have never been changed. This is an area where clearly education would be useful.

Nancy Davidson, MD

I personally interpret any ER present as ER-positive. That’s a change in my thinking, and it’s based on that study that came out of the group in San Antonio — suggesting that even one percent of breast cancer cells present by immunohistochemistry predicted for benefit from tamoxifen.

We have had a big discussion at Hopkins about this with our pathologists. They read the San Antonio paper slightly differently and were not quite as enthusiastic about it. I consider both the pathologist’s qualitative reading — whether he or she thinks it’s positive or negative — and then I also consider their actual data. I put a little more emphasis on what they say in terms of percentage of positive cells, but I do look at what my pathologists say about their qualitative sense, because I think they might be giving me extra information.

I evaluate a lot of women for second opinions, so I see a lot of pathology reports from different institutions. Quite frequently, what you obtain is, "estrogen-receptor positive, progesterone-receptor positive, HER-2 weakly positive," and that’s the whole report. You may or may not have the luxury or the interest in going back and asking those pathologists what they mean by that. I suspect that practically some physicians are following the pathologist’s qualitative reading because that’s what they have in front of them.

22. The patient is an 88-year-old woman with a 3.2 centimeter, ER-borderline (1% staining), infiltrating ductal carcinoma. Five nodes are positive. What adjuvant therapy would you generally recommend?

23. The patient is an 88-year-old woman with a 3.2 centimeter, ER-negative, infiltrating ductal carcinoma. Five nodes are positive. What adjuvant therapy would you generally recommend?

Monica Morrow, MD

The fact that over half of the audience would generally recommend tamoxifen to the first patient is encouraging. I am concerned about what survival benefit one would expect to accrue in an 88-year-old woman from cytotoxic therapy, even if she does have five positive nodes. I would come down on the no therapy arm for the ER-negative patient, even recognizing that the long-term breast cancer prognosis is poor.

Nancy Davidson, MD

I would have been very much in the camp of tamoxifen in the situation where the patient had one percent staining positive cells. I don’t have much enthusiasm for giving chemotherapy to an 88-year-old woman, no matter how fit she is — partly because of the information from the Oxford overview analyses, suggesting that the quantitative absolute benefits of chemotherapy are minimal in older women. So, I would also use tamoxifen for the patient with one percent ER-positive cells.
In the same patient with a flat-out ER-negative tumor, I would not give tamoxifen, and I would be unenthusiastic about chemotherapy. If she were highly motivated and in good health, I would give it, but I wouldn’t do it with a great deal of enthusiasm. If I were going to give it, I would give a pretty standard chemotherapy, so I’d be envisioning AC or CMF or conceivably, AC followed by Taxol, although that’s hard for me to imagine. I don’t think that I would use capecitabine right now, because we have no information to guide us in the adjuvant setting. I am very supportive of the study that Hy Muss is trying to start comparing capecitabine to CA or CMF in elderly women. Capecitabine is a very interesting agent, and obviously some of the advantages in terms of oral schedule of administration and so forth might be particularly powerful for an older population. The trial is a great idea — I just wouldn’t use it as a matter of routine outside of that trial right now. I guess if I could muster the enthusiasm to put an 88-year-old woman on some form of chemotherapy, I would be very comfortable putting her into the proposed capecitabine adjuvant study.

If she’d been 78 or 76, I’d be a little bit more enthusiastic about chemotherapy in the truly receptor-negative patient, but not substantially. It’s interesting, because I participated in a recent panel with Edith Perez, where these issues came up. Perhaps this reflects a little bit about one’s patient population, because Edith takes care of, as she said, women who are out playing golf who come to the Mayo Clinic in Jacksonville. These are perhaps chronologically advanced, but incredibly fit women, and she has no qualms whatsoever about giving chemotherapy. I don’t think I see quite the same population, and so I’d be more nervous about the potential downside of the chemotherapy when faced with relatively small benefits.

24. The patient is a 58-year-old woman with a 0.4 centimeter infiltrating ductal carcinoma, ER+, node-negative. Would you generally recommend tamoxifen?

Nancy Davidson, MD

I was actually surprised it was so overwhelmingly in favor. My interpretation is that, basically the audience would use adjuvant tamoxifen for anybody who had any size invasive cancer with positive receptors. I’d certainly talk to this patient about tamoxifen, and I would probably lean in its favor, but I don’t think I would throw my body across the door if she didn’t want to take it. She has a pretty favorable outlook, so you’re taking the tamoxifen, in part, here because of the prevention benefits in addition to a very small treatment effect on the cancer. You’d have to balance it against the possible toxicity profile for this particular woman.

25. The patient is a 38-year-old woman with a 4.2 centimeter, ER+ breast cancer and four positive nodes. She receives AC-Taxol therapy and is still menstruating at the end of treatment. What additional systemic therapy would you normally recommend?

What I say to patients is, "We don’t know for sure." There are some hints from looking at retrospective data sets or subsets within trials that weren’t pre-designated for analysis that suggest that perhaps there would be additional benefit. But, we don’t have a definitive answer.

Nancy Davidson, MD

I’m not surprised by the responses at all, because I receive many phone calls about this subject. I would say that about half the people who call me are in favor of ovarian suppression in this setting, and half are looking for permission not to do it. We’re very divided as a community right now, and that’s because there’s not a lot of information for us to go on.

In my practice right now, I still recommend tamoxifen alone to these patients, but I am agonizing over it. We are just obtaining the final results from the Intergroup trial that I was lucky enough to be the director of, which speaks to this issue pretty specifically. In the next several months, we’ll have the final analysis from that trial and we’ll be able to speak about it more precisely.

I have talked to other investigators who have done some of the suppression trials, like Michael Baum, and he’s pretty routinely thinking about ovarian ablation in a woman who still retains her menstrual periods after chemotherapy. I’m not, and I guess that just speaks to a kind of uncertainty about how to use those data right now.

The most compelling trial on that for me was the ZEBRA trial, which was presented at the San Antonio meeting last December. This was a trial that took women with node-positive premenopausal breast cancer of any receptor subtype and randomized them to CMF versus two years of goserelin. I thought it was a very nice review of the effects of two years of goserelin, which struck me as not too onerous. Those women certainly had postmenopausal symptoms, but most of them regained their menstrual function afterwards. The trial also looked at their quality of life and at their bone density. There were some concrete outcomes that have come out of that trial, which are reasonably reassuring.

It shows just what you’d expect, which is that the bone density goes down when they’re on the goserelin, but then it recovers pretty well when they come off. In contrast, the women on CMF, by and large, lose some bone density and don’t rebound, because a lot of them stay postmenopausal.