Edited excerpts from the discussion:

DR REEVES: This is a 68-year-old mother of one of my previous patients who had breast cancer. In 1997, she developed breast cancer, but it was primarily an intraductal carcinoma. It was four centimeters, nodenegative, estrogen receptor-positive, with one small focus of microinvasion. She had a mastectomy with clear margins and did not receive any additional treatment.

DR LOVE: Aman, what about the approach to the patient who has a tiny focus of invasion in the tumor?

DR BUZDAR: In these patients who have a small tumor with microinvasion that is one or two millimeters and the tumor is ER-positive, you can offer appropriate endocrine therapy to reduce the risk of a contralateral or ipsilateral cancer. If the patient has an ER/PR-negative tumor with multiple areas of microinvasion, we need to discuss the risks with those patients, but overall only two to three percent of patients with DCIS develop disseminated disease and die from metastatic disease. The highest risk is developing an invasive cancer in the ipsilateral and contralateral breast.

DR LOVE: That was back in 1997. Dr Reeves, what happened with this patient?

DR REEVES: In 1998, she had a fallopian tube carcinoma, which was completely resected. She received six cycles of adjuvant carboplatin and paclitaxel, which she tolerated very well.

In October of 2002 — four years after treatment of the fallopian tube cancer and five years from the original breast cancer — she experienced a local chest wall recurrence, which was completely resected. All margins were clear, and once again, the tumor was estrogen receptor-positive. She received chest wall irradiation and was started on letrozole.

DR LOVE: Gersh, how would you approach treatment in this Stage IV NED situation?

DR LOCKER: It’s easy when the patients are ER/PR-positive. You put them on hormones. The question is, What do you do with these patients who, 10 years later, are still on hormones and haven’t recurred? Do you continue it forever, or do you stop? I have been inconsistent.

The problem is the patient who has ER/PRnegative disease, has a local recurrence and is NED. Do you give them “adjuvant chemotherapy”? I’ve done it. I have no data to support it, but I believe a lot of people do it. This lady is particularly interesting because she had carboplatin/paclitaxel adjuvant therapy for her breast cancer, and it recurred again. So if she were ER/PR-negative, I’m not sure which chemotherapy I would have given her. I believe putting her on an AI after resection is reasonable.

DR LOVE: Aman, how do you approach patients with Stage IV NED disease whose tumors are ER-positive versus ER-negative?

DR BUZDAR: Considering the natural history of these patients who have an isolated chest wall recurrence, we used to believe that just doing local therapy cured these patients. Actually, 70 to 80 percent of the patients will develop a second recurrence somewhere else within a year if they don’t receive any systemic therapy.

At MD Anderson, we’ve been offering these patients systemic therapy. In our initial experience with six cycles of a FAC-type of combination with this type of patient, about a third are alive and free of disease beyond 20 years. The natural history would be that within a year or two, close to 90 percent of the patients would have developed recurrent disease.

We conducted another study in which most of the patients had been treated with anthracycline-based chemotherapy in the adjuvant setting. If they had an isolated recurrence, we administered six cycles of docetaxel, and if they had an ER-positive tumor, we put them on hormonal therapy. Again, in that subset of patients, about a third of the patients are alive and free of disease.

So I think in this patient population, the risk of recurrence is great, and the addition of systemic therapy can substantially improve their odds and a sizable fraction of these patients can remain alive, free of disease, five, 10 and 20 years down the line.

DR LOVE: Dr Reeves, would you update us further on what happened to this patient?

DR REEVES: She started letrozole and was on that for almost eight months when depression became an issue for her, and she believed it was drug related. We discontinued the letrozole for a month and she felt better. She switched to exemestane, but after about four months on exemestane, her liver function tests began to rise. We checked the CAT scan, and it was fine. There was no evidence of any intrahepatic abnormality. We stopped the exemestane and within a month, the LFTs were normal again. So we went back to the letrozole. She fought with that for about six months, and finally, after about 18 months of hormonal therapy, she didn’t want to take anything.

Four months after that, in October 2004, metastases in the bone, liver and lung were identified. We started her on capecitabine at that point — initially at 2,000 mg/m²/ day. Within two cycles, we reduced her dose because of palmar-plantar erythema, and by three cycles, we reduced the dose a second time. A significant reduction occurred in the size of the three liver metastases and a significant improvement in the pulmonary metastases.

Her second daughter was then diagnosed with breast cancer in a distant town, and she said she couldn’t continue with treatment. She went to help her daughter, who is single. We lost track of her for about three months. She returned off treatment and was feeling okay, but because of restaging, the lung metastases had worsened again. She went back on capecitabine and responded. Improvement occurred after another three months of capecitabine. The liver metastases were completely resolved, the lung metastases were stable, but the palmarplantar erythema was a bit of a bother to her, so we switched to fulvestrant in June 2005. She’s been on fulvestrant for about four months and seems to be tolerating it reasonably well, except her tumor markers are just starting to rise, and they had come down significantly with capecitabine.

DR LOVE: What was the dose and schedule of fulvestrant?

DR REEVES: Initially, we gave her 250 milligrams every two weeks times three and now she receives it monthly. So we did give her a loading dose — a “miniload,” if you will.

DR LOVE: Aman, you talked before about the differential effect of LFTs and exemestane. What are your thoughts about what happened here?

DR BUZDAR: One of the metabolites of exemestane has androgenic properties, so it’s theoretically possible that some of the LFT abnormalities may be related to the metabolite of exemestane. It could be that she had subclinical disease, which was causing all the problems and was being blamed on the drug.

DR LOVE: Have you seen depression associated with the AIs?

DR BUZDAR: I have not seen depression with any of the AIs.

DR LOVE: Was it evaluated in the ATAC trial?

DR BUZDAR: In the ATAC trial, where we have 99-plus percent safety data, depression was not an issue.

DR LOCKER: There were no mental status changes of any kind.

DR LOVE: The other thing that’s interesting about this case is the response to capecitabine with liver metastases. Any comments, Aman?

DR BUZDAR: Capecitabine is an effective drug, and when it works, it works very well. Hand-foot syndrome is a problem in some patients, and transiently stopping the therapy was a reasonable option in this patient, but now it looks as if she’s resistant. I would not change her therapy from an endocrine agent because her tumor markers are changing, because I can tell you that in some of these patients, if you continue with the same therapy, these markers continue to fluctuate. If they were consistently going up, I would say that it may be time to change therapy. I have some patients whose markers are about three to four times the normal value of our lab, and I have followed one lady more than six or eight years, and she has not yet developed any metastases.

DR LOVE: What dose and schedule of fulvestrant do you use?

DR BUZDAR: Data suggest that if you use the package insert dose, which is 250 milligrams every four weeks, it takes about two to three months to get a steady state therapeutic level. So we give a 500-milligram loading dose, and then in another two weeks we give another 250 milligrams, and then treat every four weeks. This is being evaluated in a prospective study because an important question is, are we losing some patients before we get to the therapeutic level and the disease is progressing because the patient does not have enough drug in their system?

DR LOVE: Gersh, one of the things that’s being evaluated in clinical trials is the concept of an AI plus fulvestrant — the idea being that fulvestrant competes with estrogen. One way would be to load up, get a higher dose up front, but another way might be to decrease the ligand through the AI. It’s being studied in clinical trials like SoFEA (7.1). A number of oncologists actually do that in their practices, particularly for a patient who’s on an AI and progresses. Some people will keep the AI going and add the fulvestrant. What are your thoughts?

DR LOCKER: A very elegant study in Cancer Research in June 2005 from Angela Brodie (Jelovac 2005) evaluated a preclinical model and found that if you combine an AI with fulvestrant, you get incredible suppression, destruction and disappearance of the estrogen receptor and great responses.

One of the things that stimulates the estrogen receptor is the presence of estrogen. If you take estrogen away, then destroy the receptor with fulvestrant, you don’t get replenishment. Some data from the group at Mass General show that with this combination, the receptor goes away for as long as fulvestrant is present.

Anecdotal data suggest that the combination works, and clinical trials are about to commence that will study the combination. I’ve administered it only once, and I’m almost embarrassed to say that, because I’m evidence-based. I think this is the wave of the future and may be the way to make fulvestrant more effective.

DR BUZDAR: I believe it may be the wave of the future, but at the present time, no data support doing that. Unless we have clinical data to support this wave of the future, I would discourage the utilization of two endocrine agents.

DR LOCKER: I’m in complete agreement with Dr Buzdar. Extenuating circumstances applied to the one patient with whom I used it. When the studies come out, I would strongly urge patient enrollment.

DR LOVE: I’ve got to challenge Aman a little bit about combined endocrine therapy. You’ve got a premenopausal patient who’s received adjuvant tamoxifen. She develops a relapse. She’s put on ovarian suppression, has a good response, and then progresses. Are you going to keep the suppression going and add in an AI?

DR BUZDAR: Yes. In a Phase II study published by John Robertson, an LHRH agonist with an AI showed high response rates in the metastatic setting (Forward 2004).

DR LOVE: Bob Carlson has also looked at that and found pretty much the same thing (Carslon 2004).

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