Edited excerpt from the discussion:

DR HART: This patient is in her late forties and was diagnosed in 1998 with a small, node-negative breast tumor. It was less than a centimeter in size, ER/PR-positive and HER2-negative. She underwent a mastectomy, radiation therapy and reconstruction and was placed on tamoxifen.

She did well for approximately two and a half years and then developed sternal pain. Following an abnormal bone scan and a biopsy positive for breast cancer, she went to a major university center in another state and had her sternum resected and then reconstructed.

Interestingly, the metastasis was very minimally ER-positive and strongly HER2-positive by immunohistochemistry and amplified approximately seven or eight times on FISH, so it was a much different phenotype than the initial cancer. She was treated with trastuzumab plus a taxane. She later went to a cancer center in Texas for another opinion and was given FAC also.

At that point she had no evidence of disease and was maintained on single-agent trastuzumab for a very short period of time after the FAC was completed. Then she developed further bone pain and was found to have a low-level relapse on bone scan and in the lymph nodes.

She was placed on the trial of a new oral agent, GW-2016. She experienced a minor response and stability for approximately six months. She then progressed in lymph nodes and bones again and was placed on vinorelbine plus trastuzumab. She tolerated the vinorelbine rather poorly — myalgias and feeling poorly — and was switched to capecitabine plus trastuzumab.

DR LOVE: What is her situation right now?

DR HART: It’s now approximately a year and a half later, and she’s still on capecitabine and trastuzumab and tolerating this regimen quite well. She had to take a brief holiday from the capecitabine a few months ago, when she developed a significant hand-foot problem. We held off treatment for a few weeks until it diminished and then restarted capecitabine at a lower dose.

She appears quite stable clinically, and she’s quite active. She has had several scans that show an area that arguably might be a little bit hotter, but overall, it’s been a very stable picture. Since she has minimal, if any, symptoms and has tolerated the capecitabine quite well, I’ve just maintained her on that regimen.

DR LOVE: It was interesting that there was a relapse even though she had a small nodenegative tumor and that she underwent surgical resection of the sternum.

The other thing that I thought was really interesting was what happened with the Oncotype DX assay. Can you tell us about that?

DR HART: When she was originally diagnosed, some physicians had recommended that she did not need adjuvant therapy, but this woman did receive adjuvant tamoxifen. When the Oncotype DX assay became available, we examined her original tumor retrospectively — out of interest and at no cost to the patient — and found she was at very high risk according to the assay.

DR LOVE: Any thoughts on that, Kathy?

DR MILLER: Even with the Oncotype DX, we’re still stuck with probabilities. This assay just gives us greater accuracy in predicting those probabilities. We need to remember that a few patients with low-risk scores do relapse. Even if a patient’s risk is only three percent, if they relapse then that information was not helpful to them. In addition, not every patient at high risk will relapse. It is reassuring that the assay was able to retrospectively identify this patient as high risk even though she had a small tumor that looked well behaved, but still, it just gives us probabilities.

DR LOVE: Another interesting thing about this case is that she had her sternum resected. Nancy, what are your thoughts about surgical resection of isolated breast cancer metastasis in the liver, sternum, lung, etc?

DR DAVIDSON: I do it occasionally, but usually in patients with a different clinical course. I would consider it in a patient with a really long disease-free interval, and two and a half years — as in this case — would not have impressed me. Rather, in this case I would have given more thought to radiating the metastasis and then some type of systemic therapy, as was done.

The other situation where I would consider surgical resection would be when the diagnosis is uncertain and the surgery would accomplish two things — determine what the lesion is and possibly treat it in the case of a second primary.

DR LOVE: Kathy, what are your thoughts about capecitabine and trastuzumab? There’s been debate about that combination in terms of synergy or additivity, etc.

DR MILLER: I believe the debate is more founded in misunderstanding than in real data. The data were predominantly with 5-FU, not capecitabine, which I believe behaves more like a different drug than just an oral form of 5-FU. Antagonism in those models doesn’t mean that you actually counterbalance the effect or you get less than you would expect, you just don’t get the same as one plus one.

It’s certainly a reasonable regimen, and we now have Phase II data with very respectable response rates in the high 50 to 60 percent range (5.1). In terms of the trastuzumab at this point, who knows whether this patient is still benefiting from it after this many progressions, but she’s not experiencing significant toxicity and receives it once every three weeks, so I assume it’s not terribly cumbersome and she’s happy with it. While I suspect trastuzumab is probably not adding much at this point, I don’t see any reason to mess with it.

DR LOVE: Nancy, we’ve seen a real shift towards single-agent chemotherapy in the metastatic setting over the last few years, whether treating HER2-positive or HER2-negative disease. What’s your usual sequence of single agents in patients with HER2-positive and HER2-negative disease?

DR DAVIDSON: I’m not certain we know one absolutely correct order, so much of that decision is driven by the patient, including what adjuvant therapy they received.

In the HER2-negative setting, I usually talk to the patient about single–agent taxanes, vinorelbine, capecitabine and gemcitabine. I explain that they’ll probably receive all of these agents sooner or later, so it’s really a question of order.

Many women are very keen to begin with capecitabine because they like the idea of an oral chemotherapy, not too much hair loss, and it’s an easier transition from a chemotherapy-free state to a chronic chemotherapy state.

For women with HER2-positive disease, I’ve been a little more supportive of the taxanes, just because that’s what our pivotal trial supports. However, I’ve had several patients who are not keen on that treatment, and I’ve been perfectly comfortable using capecitabine and trastuzumab as first-line chemotherapy and have had some wonderful anecdotal responses.

DR LOVE: Lowell, what have you observed in terms of the issue of alopecia in women with metastatic disease? For example, in this woman, how much of an issue was it?

DR HART: This patient leads a very active lifestyle, and it was something of an issue as far as reinforcing her illness to her. Alopecia is something that we — especially male oncologists — assume is a nonissue in patients with metastatic disease, but I don’t believe it’s a nonissue.

It’s been nice to have an oral agent for this patient that doesn’t cause alopecia, and the dose can be adjusted as needed. I would love to have her on a completely biologic regimen, but I think this is the next best thing.

DR LOVE: Susan, what are your thoughts about alopecia in metastatic breast cancer?

DR LUEDKE: It’s one of the first questions patients ask me when we talk about therapy at relapse, but very few refuse a therapy when they learn it causes some hair loss. I do have a number of professional women who have said that I can do anything to them, but they don’t want to wear their diagnosis, and they’re adamant about that. It’s not even so much hair loss, but feeling sick and looking puny and the like.

DR LOVE: Kathy, Nancy talked about her sequence of single agents in metastatic disease, and now we have a new choice on board — nanoparticle paclitaxel.

What’s your algorithm for sequential single agents and where does nanoparticle paclitaxel fit in at this point?

DR MILLER: My algorithm is fairly similar to Nancy’s. I discuss several options with the patient and I, too, believe the response rates in patients with newly diagnosed disease is roughly equivalent with all the available single agents, so it’s really a question of the order. For many patients with HER2-negative disease, capecitabine is often the first choice, and it’s a very nice option for them.

Nanoparticle paclitaxel has some advantages over the other taxanes that we currently use, and the biggest benefit is that the patients do not need steroid premedications (Blum 2004; O’Shaughnessy 2004; [5.2]). Many of my patients, especially the younger ones, find that the steroids are by far the most distasteful part of the whole process.

In addition, being able to administer nanoparticle paclitaxel over 30 minutes, rather than an hour — or three hours or four hours, if you add in the premedication — is a big difference in someone who’s working or taking care of children. These visits can frequently take an entire day with travel and registration and four hours in the infusion center. Being able to cut down the amount of time in the center is worthwhile.

DR WERTHEIM: In this patient, we had the advantage of using trastuzumab because she had HER2-positive disease at relapse, but what is the standard of care for systemic treatment after resection of metastatic disease?

DR MILLER: The Stage IV NED setting is a challenge because we don’t know how to treat those patients. It’s easy if they have ER-positive disease, because we can put them on another hormone therapy and they may derive some benefit. Even if they don’t, at least they’re not experiencing toxicities.

However, I struggle with the idea of administering chemotherapy when the response rates are significantly less than 50 percent, the disease is incurable and I have no disease to follow. I have done so in patients who had no or very limited adjuvant therapy — we consider this quasi-adjuvant therapy, and perhaps there will be long-term survivors, because their disease hasn’t seen systemic therapy before.

If they received only an anthracycline in the adjuvant setting, I’m comfortable giving them four cycles of a taxane assuming they may experience some benefit. In someone who’s had both of those agents in an adjuvant setting, my preference is to not give them any chemotherapy, because I don’t know if I’m helping them, and chances are that I’m probably not.

Withholding chemotherapy is unacceptable to some patients, and for those I try to select the agent with the least toxicity. This may be the last period of time that they are truly well and symptom free and I don’t want to change that.

My other recommendation to them is that they see me immediately the next time they develop a lump or bump, rather than a surgeon, because unfortunately, I have a couple of patients who’ve been through Stage IV NED two, three, four times, because people keep chopping things out.

DR ZELKOWITZ: The initial tumor was estrogen receptor-positive, and the metastasis in the sternum was ER-negative. I’ve heard from the pathologists that in bone specimens you can get false negatives if it’s not prepared appropriately. If nothing else had been biopsied at some point, would you rechallenge with a hormone, especially in this person who has limited active disease?

DR MILLER: Actually, I would and have when faced with that sort of situation before. You really don’t have anything to lose, with very minimal toxicity, especially if you have a patient who doesn’t have any disease that you can assess. However, in this situation, it really may be ER-negative, since the other features have shifted.

DR DAVIDSON: Your clinical acumen is important. If she had a six-year diseasefree interval, one might say, “Maybe this really is still fundamentally hormone responsive.” The fact that she only had a couple of years would lead me to believe this might be a true reading, but it wouldn’t necessarily dissuade me from using hormones somewhere along the way.

DR LOVE: What do we know about shifts that you referred to, Kathy, in terms of changes in ER status and HER2 status with metastatic disease?

DR MILLER: We know some but not a lot, and what we do know is complicated by the false negatives and positives that are inherent in the assays we use. It’s difficult to know whether the reports of these seeming shifts are true shifts or whether one or both of the assays were wrong. With the best information we have on the HER2 status, there probably is a shift from negative in the initial tumor to positive in the metastatic site in approximately 15 percent of patients.

I’m a firm believer that if we’re going to tell a patient she has metastatic disease from which she will most likely die, we ought to have cancer cells on a slide from somewhere else in her body before saying that. The advantage is that we can retest and determine whether there has been a shift that will be important when deciding on treatment.

DR LOVE: Nancy, we’ve had a lot of questions about false negatives in ER testing, particularly in a community setting. When you see a negative ER that was performed in the community, do you have your lab or other labs retest that?

DR DAVIDSON: I do, if there appears to be a disconnect. If it makes sense — say a highgrade lesion with negative receptors — then I don’t know that I would feel compelled to repeat it.

However, if there are other features that don’t add up biologically, I might consider getting the block and repeating the test.

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