Edited excerpts from the discussion:

DR MARCOM: This patient is a 45-year-old woman, who presented first in May 1999 with bilateral breast cancer. She had a right breast tumor that was a T2 lesion, about 2.4 centimeters, Grade II, ER 10 percent, PR 10 percent, HER2 1+. She also had a contralateral breast tumor that was 1.2 centimeters and was also node-negative, ER and PR also 10 percent and HER2-negative.

She underwent bilateral mastectomies, very much at her preference, and received four cycles of AC. She was premenopausal and was placed on tamoxifen for borderline hormone receptor-positive breast cancer.

She did well and stayed on tamoxifen for five full years, but then presented in May 2005 to her internist with severe right upper quadrant abdominal pain. She had the clinical appearances of metastatic disease that, in my opinion, was bordering on visceral crisis.

She had essentially complete replacement of her left hepatic lobe and significant disease in her right hepatic lobe also. Her baseline alkaline phosphatase was 205, SGOT was 166 and SGPT was 61, but she was in quite a bit of discomfort. She also had some retroperitoneal mediastinal lymph nodes.

We biopsied the liver lesions, which were ERand PR-negative and HER2-negative — 1+ by IHC and FISH negative. A PET scan also revealed a pericardiac mass that was not hemodynamically compromising, retroperitoneal nodes and a right adnexal mass.

DR LOVE: Can you talk about her lifestyle and family situation?

DR MARCOM: She’s a “salt-of-the-earth” person. She’s a stay-at-home mother. Her husband has a blue-collar job, and her children are nine and 12 years old. She’s just a very solid woman, one of these tragic cases that we all see in young women with aggressive metastatic breast cancer in the midst of trying to raise their families.

DR LOVE: Therapy was initiated on May 26th of 2005, which was just 10 days after the bevacizumab presentation at the ASCO meeting (Miller 2005a; [3.1]). With that in mind, Gersh, how would you treat this unusual case of a young patient in visceral crisis with metastatic disease?

DR LOCKER: It’s a good point, because in the average patient with metastatic disease that’s ER-negative, there is little advantage to using anything other than sequential single-agent chemotherapy. The only advantage to using combinations is a higher response rate and probably a quicker response rate. So in this case, a taxane is a given — it’s the most active drug that she hasn’t already received — and this would be a patient for whom I would add something to a taxane. One key issue is her liver function.

In a patient such as this, the liver enzymes are a good reason to use a low-dose weekly paclitaxel regimen, because you’re going to get into less trouble than giving either docetaxel or paclitaxel every three weeks. Now, what would I add to low-dose weekly paclitaxel? Data were presented at ASCO in favor of adding bevacizumab and that’s one alternative (Miller 2005a). The other would be to add something like a fluoropyrimidine, since there’s data on capecitabine (Susnjar 2005; Uhlmann 2004).

To be honest, I’m not certain what I would do. Even though I was there for the presentation of the bevacizumab data, I’d probably add a second chemotherapeutic agent, understanding it probably will not impact survival. It’s just going to allow you to treat her quicker and get a greater response. Fluoropyrimidines are attractive because they don’t need liver metabolism. Doxorubicin is perfectly reasonable to combine with docetaxel, but not in a patient with liver disease.

DR LOVE: Would you treat her any differently if she had not received any prior chemotherapy?

DR LOCKER: Again, the most active regimen probably is a combination of a taxane and doxorubicin, specifically docetaxel/doxorubicin in this case, but my big concern is the liver function. You are going to have problems with stomatitis and GI toxicity if you do that, even if you administer cytokines. I think I would use low-dose weekly paclitaxel and 5-FU or capecitabine, and less likely bevacizumab.

DR BUZDAR: For this lady I would discuss various options, but I would recommend combination chemotherapy. The other option I would discuss with this patient is paclitaxel with bevacizumab. This patient has extensive replacement of the liver and I think it would be appropriate to utilize combination therapy to get a quick response, such as capecitabine or gemcitabine with a taxane.

DR LOVE: What about combination chemotherapy and bevacizumab?

DR BUZDAR: We don’t have any safety or efficacy data on the combination of bevacizumab with two drugs. If we had even Phase I data indicating that you could combine the drugs, I would have gone with that (Miller 2005a, 2005b).

DR LOVE: Dr Marcom, what happened with this patient?

DR MARCOM: I would generally use singleagent therapy and I don’t think of myself as somebody who pushes the envelope too much, but I had just returned from ASCO and seen the bevacizumab data. In my opinion, this case was a kind of the basallike breast cancer subtype. I fully discounted her original ER and PR and saw her case as aggressive and I felt she needed combination chemotherapy.

With all that said, I gave her weekly paclitaxel along with capecitabine and bevacizumab. She actually has had quite a remarkable response and has tolerated therapy extremely well (3.2). I was part of Bill Gradishar’s capecitabine plus paclitaxel study and was impressed that it was a pretty well-tolerated regimen (Gradishar 2004; [3.3]), and we have safety data on the combination of capecitabine and bevacizumab in breast cancer (Miller 2005b), so I felt I had a leg to stand on.

DR LOVE: How many courses has she received?

DR MARCOM: She’s received four cycles altogether now. She had very quick symptomatic improvement about halfway through the second cycle. Her right upper quadrant pain decreased quite dramatically. My plan was that I would drop the capecitabine at some point once I had gotten a response.

DR LOVE: Have you considered stopping the paclitaxel or even both chemotherapy agents?

DR MARCOM: That’s a very good question. Looking at ECOG data on paclitaxel plus bevacizumab, I think I have the best justification for stopping the capecitabine, at least initially. I would be hesitant to stop all chemotherapy and have her on just singleagent bevacizumab, given the response that we have for that (Cobleigh 2003).

DR LOVE: Aman, if this patient came to you for a second opinion a few months from now and she’d had a great response, and she were stable, what would you recommend at that point?

DR BUZDAR: Our approach is that if she were not experiencing excessive toxicity, we would advise her to continue the therapy, unless she had a complete clinical response.

DR MARCOM: For what it’s worth, her CA15-3 started at 331 U/mL and has normalized now. Hopefully, her scans will fully catch up with that if this is necrotic tumor left in her left lobe.

DR LOVE: In talking to Bill Gradishar about the capecitabine/paclitaxel study and Joanne Blum from US Oncology who looked at a similar regimen, it seemed they felt the combination was not necessarily more effective than other combinations — for example, docetaxel combinations — but that it was better tolerated. What was your impression?

DR MARCOM: It’s been my general sense that that is the case.

DR LOVE: Aman, you’re evaluating capecitabine with docetaxel in your neoadjuvant/ adjuvant trial. Can you talk about that study and what you’ve observed in terms of tolerance and the dose?

DR BUZDAR: We started that study a couple of years ago with 1,000 mg/m² twice daily of capecitabine, but after we treated a few patients, we had to modify the dose due to toxicities. The current dose of capecitabine is 750 mg/m² twice a day for two of three weeks with docetaxel 75 mg/m² every three weeks. That regimen is fairly well tolerated and we have now treated a sizable number of patients. Also, this regimen can be given on an outpatient basis. I don’t think 1,250 mg/m², the package insert dose of capecitabine, can be tolerated by most patients (3.4).

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