Dr Krill: This 58-year-old postmenopausal woman has a history of bilateral breast cancer. She was diagnosed with her first breast cancer 12 years ago and her second breast cancer seven years ago.

The tumor recurred four years ago with bony metastases. She then developed carcinomatous meningitis, which, after treatment, appears miraculously gone and has not recurred since then. She was stable, had stable tumor markers and was on anastrozole for about two years when she developed liver metastases and rising tumor markers.

Dr Love: Did she have an objective response to anastrozole?

Dr Krill: Not really. She had bone-only metastases and it was very hard to measure. She also had a mildly elevated tumor marker, which remained stable on anastrozole, so I would say she had stable disease on anastrozole.

Dr Love: What was her general condition at that point?

Dr Krill: Outside of some memory deficit because of intrathecal chemotherapy, she was fine physically.

Dr Love: Asymptomatic?

Dr Krill: Completely.

Dr Love: In addition to anastrozole, what therapy did she have in the past?

Dr Krill: The only therapy she ever had was CMF adjuvant therapy 10 years before, followed by tamoxifen. She also received radiation to the brain and methotrexate intrathecally.

Dr Love: How extensive were the liver metastases?

Dr Krill: There were multiple liver metastases, some of which were sizable. Her liver function was normal.

Dr Love: Lisa, what are your thoughts about management at that point?

Dr Carey: Extensive liver metastases makes me a little bit nervous in a patient who's progressed on an aromatase inhibitor, having previously received adjuvant tamoxifen. You can watch her carefully and try another hormonal agent, like fulvestrant, but this is a patient in whom I would also think about using chemotherapy. You have the option of trying to cytoreduce the tumor with chemotherapy. Some patients with large liver metastases have normal liver function and are asymptomatic. The problem with liver metastases is that a lot of times the patient does not become symptomatic until there is liver failure, and that's a real problem. You can use chemotherapy to try to cytoreduce the disease, and then try to maintain control with a hormonal agent.

Dr Love: What were her thoughts about treatment?

Dr Krill: This was two years ago. She was very nervous about any sort of chemotherapy. She did not want to lose her hair, and she had a very active lifestyle (Figure 6.1).

Dr Carey: The story about carcinomatous meningitis that resolves is a very unusual one. I don't think I've ever seen that happen as you described it.

Dr Krill: I agree. I was not taking care of her at that point in time, but we reviewed the pathology.

Dr Love: Lisa, very specifically, what do you think you would have done?

Dr Carey: Given her story, I would probably use weekly paclitaxel and then, if she's doing well and she's cytoreduced, I would try fulvestrant (Figure 6.2).

Dr Love: It's interesting how often you see that strategy of chemotherapy induction followed by hormonal therapy maintainance. Bob, what research evidence do we have on this?

Dr Carlson: There is relatively minimal or no supporting data, although it's a commonly utilized strategy.

This woman has relatively minimal liver disease and stable to slightly progressed bony disease. She's asymptomatic. She's fearful of chemotherapy. I would just use another hormone.

Dr Love: Which one?

Dr Carlson: Fulvestrant.

Dr Love: Peter, what do you think you would have done for this patient? A lot of people get nervous with liver metastases and hormone therapy.

Figure 6.1

Figure 6.2

Dr Ravdin: Actually, as long as we're talking about evidence-based medicine, we did a large 300-patient study in the Southwest Oncology Group, evaluating response rates for tamoxifen and predictors of response. Patients with visceral disease -specifically hepatic disease - had just as good a response rate as patients with cancer in any other site, indicating that the site of the disease does not predict failure of therapy. If this patient had one or two liver metastases, I might try hormonal therapy again. But if she had, say, 10 small liver metastases and the markers had increased rapidly, I would probably treat such a patient with chemotherapy.

Dr Love: What type?

Dr Ravdin: I would treat this patient with an intensive chemotherapy -something that I expected to have about a 40- or 50-percent response rate - something like one of the taxane combinations. This case illustrates an interesting point that I find troubling. This is a patient who was picked up from someone else, who has a remote diagnosis of breast cancer and complicated events. If I'd been thinking about it de novo, it might have made me think about genetics. Here's a woman with a premenopausal, bilateral breast cancer. I find it fruitful and sometimes a little bit humbling to go back and look at the history and realize that, if I'd seen that patient de novo today, I would be recommending that they see a genetics counselor.

From the floor: Do we really have any evidence-based medicine supporting the role of sequential hormonal therapy beyond tamoxifen for either an aromatase inhibitor or fulvestrant?

Dr Carlson: In the randomized trials of fulvestrant versus anastrozole, the investigators who accrued patients were asked to report on patients who had failed and crossed over to the other regimen. It was not a planned analysis. It was questionnaire-collected data - what I would call low-level evidence - but that low-level evidence indicated that responses were seen (Figure 6.3).

One of the difficulties here is that nobody is doing hormonal therapy trials as third-line, so everyone's trying to get first-line and second-line indications. We certainly know from experience that third- and fourth-line

hormonal therapy responses certainly are observed, although they become less frequent with each generation of hormonal therapy. We'll probably never have high-level evidence about what to do with fourth- or fifth-line hormonal therapy.

Dr Love: If you have a patient who's progressed through a nonsteroidal aromatase inhibitor, who's had tamoxifen in the past, would you tend to use exemestane or fulvestrant in that situation?

Dr Grana: I don't know that either one is better, and that's exactly the question now being asked by an ongoing trial (Figure 6.4). This study is randomly assigning patients who failed on a nonsteroidal aromatase inhibitor to either exemestane or fulvestrant which include a loading program of 500 mg initially, and then 250 mg on day 14, and, 250 mg on day 28.

The idea is that you may need to load the drug to obtain better efficacy. I don't know what the right answer is, but I agree that I would ask the patient about their preference between injections and pills. Cost issues also come into play.

A small amount of data suggests that switching from a nonsteroidal to a steroidal aromatase inhibitor will lead to some responses.

Figure 6.3

Figure 6.4

Dr Carlson: The response rate was about 13 percent, but a substantial group of about another 20 percent had stable disease.

Dr Grana: It's not an earth-shattering number, but it is a response, and I think there's no right answer.

Dr Love: What happened to the patient? What did you end up doing?

Dr Krill: This was about a year and a half ago, before fulvestrant was easily available to us. She was very hesitant to receive intravenous chemotherapy.

She's a very anxious person. And I prescribed capecitabine, which she's tolerated incredibly well. It's like she's not taking anything.

She's now been on capecitabine for a year and half, and her liver metastases nearly disappeared on CAT scan. Her tumor markers have stabilized, and they've been there for approximately a year now. I'm fearful to take her off, and yet I keep asking myself, "Should I take her off the capecitabine and observe her?

Should I take her off and put her on fulvestrant?" She has a performance status of zero, and she has no side effects from the capecitabine, whatsoever. So the question is: Do I just keep going on this or do I change tactics? Clinically, she's incredibly well.

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