DR DRULLINSKY: This patient first presented in 1989 with an infiltrating lobular carcinoma and 21 positive lymph nodes. She was treated at a local hospital with CMF and etoposide in the adjuvant setting and placed on tamoxifen for five years.

Then she was watched for several months and developed bone metastases. At this point, she was switched to an aromatase inhibitor, anastrozole. Then she quickly developed aggressive disease, mostly extending to the bones, and she had mild ascites.

At this point, 11 years after presentation, she has been through all the hormones, all the aromatase inhibitors, and fulvestrant. She has had a number of chemotherapy agents, including capecitabine, gemcitabine, vinorelbine, and every three-week docetaxel.

At the end of last year, she developed extensive bone marrow involvement, complicated by anemia and thrombocytopenia requiring transfusions. Her baseline platelet count last year was nine, and her hemoglobin was five.

The only treatment she hadn’t received was an anthracycline. So I gave her liposomal doxorubicin, and she had a one-year response. She became transfusion- free from both red blood cells and platelets. Now I’m faced with the fact that she’s progressed on liposomal doxorubicin, and she’s again thrombocytopenic, anemic and dependent on transfusions.

DR LOVE: What about her symptomatology and performance status?

DR DRULLINSKY: She is completely asymptomatic. She does not take any narcotics at all, and her performance status is 90 percent.

DR LOVE: Has she experienced any bleeding?

DR DRULLINSKY: No.

DR LOVE: Which taxanes has she received?

DR DRULLINSKY: She’s only had every three-week docetaxel. And with that, she actually had stable disease.

DR LOVE: What are you thinking about at this point?

DR DRULLINSKY: Well, she has not yet received the platinums and weekly taxanes. Given the data with bevacizumab, I was considering that. The problem is she’s very thrombocytopenic, with a platelet count under 10.

DR LOVE: Aman, any thoughts about her case?

DR BUZDAR: One thing you may consider is weekly paclitaxel or nab paclitaxel. With weekly paclitaxel, myelosuppression is not one of the side effects. She may benefit, even though she has been treated with docetaxel. There is a partial lack of cross-resistance between these two agents, and the lack of myelotoxicity might be worthwhile. The same is true with nab paclitaxel, which may be another option for you to consider.

DR LOVE: You mentioned that she had a good response to liposomal doxorubicin. Along the way, as she’s gotten these various therapies, is there anything else that she had a good response to?

DR DRULLINSKY: Every therapy she has had has worked.

DR LOVE: How did she do on capecitabine?

DR DRULLINSKY: Capecitabine worked for one year. Every treatment regimen worked for approximately nine months to one year.

DR LOVE: John, what are your thoughts?

DR MACKEY: Perhaps this is heresy, but at some point you have to have a conversation with the patient about what realistically she can expect from further chemotherapy. You could kill this woman with your next cycle, potentially. She has to be aware of that. In our center in Edmonton, we have a world-class palliative care team. At this point, we would hand over this woman’s care to the palliative care team.

DR SEIDMAN: Having just completed a two-week stint as the inpatient attending at Memorial Sloan-Kettering, I wish I were in Canada right now with Dr Mackey. Obviously, no further chemotherapy and best supportive care certainly should be part of a discussion with someone when they’re facing their sixth line of therapy. Despite the dangerously low platelet count that Pam described, I did get a sense that this patient has a high functional status and is living a good quality of life. She has repeatedly had at least transient responses to every chemotherapy regimen she’s been exposed to. I think an overall difference in orientation exists toward breast cancer and the utility and futility of chemotherapy between Canada and the US.

DR LOVE: What, specifically, would you recommend, Andy?

DR SEIDMAN: I would include in a discussion the possibility that chemotherapy could lead to life-threatening hemorrhagic complications. If the patient still wanted to proceed, the regimens that would likely not contribute further to thrombocytopenia — weekly paclitaxel or weekly nab paclitaxel — are reasonable options. Other drugs I would consider, if she had a healthier bone marrow, include agents like irinotecan, for which we have Phase II data in the anthracycline/ taxane-refractory population (Perez 2004). Even agents such as pemetrexed, for which there are Phase II data (O’Shaughnessy 2005).

DR RAVDIN: I would largely agree with what has already been said. I think that weekly taxane therapy would be my first pick in this patient. The one thing I would also keep in the back of my mind is the possibility, when her platelets are back at 100,000, of rebiopsying her tumor. There are times, particularly over long periods, where the biology of the tumor can drift. Maybe she’s actually HER2-positive at this point.

DR DRULLINSKY: I do have the bone marrow from a year and a half ago, and it was completely packed, so maybe we could test that.

DR LOVE: Do we know what the incidence is of switching from HER2- negative to HER2-positive, or an original false negative that you would now identify as positive? Andy?

DR SEIDMAN: Lindsey Harris and others have reported on this. Dr Luftner from Germany recently reported that the incidence is in the range of 10 to 15 percent discordance (Luftner 2004). More commonly, the direction tends to be negative to positive, rather than positive to negative. This probably does warrant rebiopsying patients, specifically when you’re running out of options and when a biopsy doesn’t represent a major ordeal for the patient.

DR LOVE: Let’s talk about the typical case of a patient who doesn’t have rapidly progressive, visceral, symptomatic metastatic disease that requires an immediate response — the patient who’s had AC/paclitaxel, a very common adjuvant regimen in patients who relapse. Starting with John, in patients with ER-negative, HER2- negative disease, how have you thought through the decision at that point? And did your thought process change after you saw the bevacizumab data (Miller 2005a)?

DR MACKEY: The reality is, we have a lot of patients treated with an anthracycline and a taxane in the adjuvant setting who relapse. At the time of relapse, it’s always nice to be able to offer them an option where they don’t lose their hair and they can have outpatient oral therapy. So we’ve made a major shift to first-line capecitabine. It’s a well-tolerated, often very effective option. Unlike the data we’re getting from the vinorelbine and the gemcitabine studies, some of these patients have a tremendous prolonged response. I’m not saying the median times to progression are substantially greater, but we are seeing at two and a half and three and four years people who are still on at cycle 70 of capecitabine.

DR LOVE: We know there are reimbursement and cost issues that enter into this, but looking at the pure science in terms of decision-making, John, what about bevacizumab? Would you combine it with capecitabine? Where, right now, would you utilize it in the metastatic setting?

DR MACKEY: There are two ways to look at the bevacizumab data. What makes it particularly exciting is that it’s a new therapeutic target. We’ve introduced antiangiogenic therapy. But if you look at ways of beating single-agent paclitaxel at 175 mg/m2 every three weeks, bevacizumab is number six on the list. The excitement is because of the possibility of a new mechanism, almost as much as the improved progression-free and overall survival (Miller 2005a). Until such time as we have bevacizumab available for breast cancer treatment in Canada, which it currently is not, we are stuck with looking at what provides optimal survival with the agents that we have. I apologize. We have a pragmatic barrier here.

DR LOVE: Andy, how do you approach patients like this, and where does bevacizumab fit in?

DR SEIDMAN: Clearly, there are patients who have minimal and sometimes no symptoms of disease for whom hormones are just not the right choice. Their disease is ER/PR-negative, or you’ve exhausted all of your reasonable hormonal options. In an effort not to make the treatment worse than the disease, oral capecitabine is a very attractive option. Patients live their lives at home, not in your oncology clinic.

We will have some data on this from a Mexican oncology group trial that was unfortunately presented way too prematurely at ASCO within the last couple of years (Soto 2003). This was a randomized study of capecitabine first, followed by taxane, a taxane first followed by capecitabine, or the combination of taxane and capecitabine. With mature results from that trial, maybe we’ll be more reassured that using capecitabine as monotherapy, as chapter one, is perfectly appropriate.

DR LOVE: Andy, you’re saying that in patients who’ve had prior dose-dense ACT, in general, you’re going to start with capecitabine. Is bevacizumab going to work its way into the algorithm of a patient like that?

DR SEIDMAN: When I think about what to use after adjuvant anthracycline/ taxane-based therapy, the thing I think mostly about is how long it has been since they’ve completed that therapy.

If it’s been a relatively short period of time — there’s nothing magic about one year, but we often use that as a benchmark — I’m not that enthusiastic about going back and using a taxane or an anthracycline again. At that particular moment in time, capecitabine is an obvious default option. Given the increased response rate seen with bevacizumab when added to capecitabine (Miller 2005b; [7.1]), as long as your insurance companies will recognize the benefits seen with this drug in combination with other agents, and in other diseases, and in combination with paclitaxel in the first-line setting for metastatic disease, it definitely seems to be a rational option.

DR LOVE: With bevacizumab, the cost and reimbursement issues obviously are out on the table. We don’t know how that’s going to play out. We’re focused on the science today, but I think, obviously, that’s a huge issue. Aman, same question: Patient has had prior AC/paclitaxel, asymptomatic metastatic disease. What’s your algorithm? And is bevacizumab going to fit into it?

DR BUZDAR: I discuss the data, which were presented by Kathy Miller, with these types of patients. I think the point that Andy made is very important: If the patient failed very shortly after receiving the taxane in the adjuvant setting, then I think capecitabine might be a better option, and the taxane might not be the appropriate option. But if the patient has a longer disease-free interval, I think we need to discuss that because of two points. There is substantial improvement in time to progression and early evidence to suggest that bevacizumab may have a favorable impact on survival (Miller 2005a).

DR LOVE: Again, cost aside, Aman, would you bring up the issue of bevacizumab plus capecitabine?

DR BUZDAR: With bevacizumab and capecitabine, I think the data, which were in a somewhat more heavily treated patient population, unfortunately, did not pan out into longer control of disease or any favorable impact on the survival. Although investigator-reported data and independently peer-reviewed data did show that women who received the combination of bevacizumab and capecitabine had a higher objective regression of their disease, it somehow did not translate into a time to progression or survival benefit (Miller 2005b; [7.1]).

DR LOVE: Peter, how do you approach the choice of chemotherapy in a patient who received prior AC/paclitaxel?

DR RAVDIN: Actually, capecitabine is my first choice because of all the reasons that have already been stated: low toxicity and the sometimes very long duration of responses. One thing I’ve been doing more is thinking about new agents in Phase I testing very early in those patients who don’t have threatening disease. I always used to give these as fifth- and sixth-line therapy, but by then, eligibility issues come up: central nervous system metastases, bone marrow problems.

I’ve recently become aware of how many people have been disappointed in the idea that they wanted to receive something new, but it was only thought of when they were so far down the road and had other comorbid problems that they were no longer eligible. So I often tell people who are two or three treatments in: If we’re going to try a wild card, now is the time to try it, when you’re in relatively good shape; let’s not wait until your eligibility might be in question.

Select publications