Edited excerpt from the discussion:

DR DRESDNER: This 72-year-old woman presented with a palpable breast mass on the right side. An excisional biopsy showed a 2.8-centimeter, Grade II, ER/PR-positive, HER-2-positive and FISH-positive ductal carcinoma. She decided to proceed to mastectomy, and there were two positive nodes.

Following the mastectomy, we sat down with the Adjuvant! online data and discussed options. She did not feel that chemotherapy offered her enough, and we discussed hormone options. I recommended anastrozole because the tumor was HER2-positive.

She came in for her first follow-up visit at three months and said she had stopped the anastrozole about two weeks earlier because she was lightheaded. We switched her to exemestane and one month later she said she was still lightheaded (6.1).

At that point, I sent her to a neurologist and no cause was found by MRI, halter monitoring or carotid ultrasound. She said she was finished with aromatase inhibitors, so I switched her to tamoxifen, somewhat reluctantly, and she actually did pretty well.

DR LOVE: In terms of her personality, was it your impression that the lightheadedness was related to the aromatase inhibitors?

DR DRESDNER: Initially, no. However, she’s a very active woman — plays golf three or four times a week — and this was really bothering her. She had never experienced lightheadedness before in her whole life. It was hard to deny the temporal relationship between starting the medication.

DR LOVE: And she had absolutely none of this on tamoxifen?

DR DRESDNER: Absolutely none.

DR LOVE: Any interpretation at this point? Kathy?

DR MILLER: I certainly can’t explain it on a physiologic basis. I actually have had a couple of patients ask about lightheadedness or a sense of wooziness or dizziness on an AI. It’s certainly not to the degree that you’re describing, for which they refused to take treatment. I’m not sure if in those patients it actually went away or they just stopped mentioning it to me, but it seemed a fairly minor thing.

DR DRESDNER: We strongly questioned the relationship to the AI and tried to disprove it, but she was rather insistent after trying the second agent.

Everything was fine until approximately two years from diagnosis, when she came into the office complaining of a painful skin nodule on the side of the mastectomy. It looked rather suspicious and a biopsy confirmed it was metastatic breast cancer, still ER- and HER2-positive.

The metastatic workup included a positive bone scan in two ribs but no extensive disease, and her CA-27 was elevated to 96. She was actually asymptomatic and had no bone pain.

DR LOVE: Kathy, at this point, how would you think through her therapy, particularly given this previous history with the AIs and tamoxifen?

DR MILLER: Well, I’d be thinking about a couple of things.

First, I’d probably chat with her about whether her thoughts of retrying an AI have changed. I’d like to use them, if she’s willing, and if she’s not, fulvestrant would be a very reasonable option for additional hormone manipulation. Her probability of responding to another hormone agent is probably somewhat less than the typical ER-positive patient, but it’s certainly not zero.

This isn’t someone who has galloping disease. The two-year or so disease-free interval is not long, but it’s respectable in someone who was on tamoxifen during that time, so I wouldn’t feel bad about giving additional hormones before moving on. Then I would probably move on to trastuzumab monotherapy at whatever point hormones either weren’t working or she wasn’t accepting of the hormones I had available.

DR LOVE: Nancy, what has your experience been with fulvestrant (Howell 2004; Robertson 2003)? In many patients, fulvestrant is considered when progression occurs on tamoxifen. In this case, she’s had an AI, although not really a therapeutic trial. How do you sort through that decision — AI versus fulvestrant — in a patient who’s relapsed on tamoxifen?

DR DAVIDSON: The randomized trial that led to the FDA approval of fulvestrant was that it compared fulvestrant to an AI, and I believe the two treatments had basically identical results, so I’d be comfortable with either one. A lot of that decision depends on the patient. Most patients will take the AI, because it’s oral, it’s not an injection and it’s easy; however, some patients won’t, for whatever reason.

Are you considering a bisphosphonate in her with the positive bone scan in the ribs or are you not convinced?

DR DRESDNER: Clinically, the bone scan was positive, but the rib x-rays were negative. We talked about it, and I decided not to start it at that point.

DR DAVIDSON: I must say, I’ve become a little more conservative with my bisphosphonates given the osteonecrosis issue.

DR LOVE: Would you use bisphosphonates in this situation?

DR DAVIDSON: I probably wouldn’t in this case, as it’s described.

DR LOVE: Did you use bisphosphonates, Dr Dresdner?

DR DRESDNER: No. We talked about it and, given the risks of the joint necrosis, I felt we should wait until we actually saw some significant bone disease.

DR DAVIDSON: I was asking because patients with more florid bone disease are already coming in monthly and a fulvestrant injection may not be such a big deal to them. I don’t have strong feelings here about which one you would start with — AI versus fulvestrant — but it sounds like your patient probably did.

DR DRESDNER: Yes. We radiated the area, because the nodule could not be completely resected. We discussed oral agents again, and she wanted no part of any aromatase inhibitor. Her golf game was going real well at that point. We decided to move ahead to fulvestrant, and she had a very nice response. Within 90 days, her CA-27 came down to normal and within six months, the bone scan showed improvement. It’s been eight and a half to nine months now and that’s where she is at this point.

DR LOVE: How is she tolerating the injection?

DR DRESDNER: Just fine. No complaints.

DR LOVE: Is that what you’d normally see in these patients?

DR DRESDNER: Fulvestrant is probably the easiest hormonal therapy in terms of the least amount of hot flashes.

DR ZELKOWITZ: I’ve heard some concerns about the dose of fulvestrant.

DR MILLER: The concern is that it’s a depot injection and if you’re giving it monthly, it typically takes three to four months to actually reach steady state levels in the optimal therapeutic range, as best we understand that now.

I think this challenges us to not declare it a failure if after a month or two on fulvestrant we don’t see much response, particularly in patients who have more indolent, minimally, or asymptomatic disease. In such cases, we’ve got time to sit tight and give it a reasonable shot.

It’s led folks to examine in a research setting an induction schedule (6.2), giving the first three doses on an accelerated every two-week schedule to try and get to that steady state level a bit faster, to improve the efficacy of the agent. Using an induction schedule would also limit the number of patients who may have ultimately responded, but stopped the agent because of a lack of response in a very short follow-up period.

It might also help patients who have more symptoms from their disease and really need to get up to therapeutic levels more quickly.

DR ZELKOWITZ: Have you used this schedule, and is it reimbursable?

DR MILLER: I have done it in several folks. I’ve made that decision based on the pace of their disease and whether I think it will allow me three or four months on a monthly injection before I’m forced to either evaluate their response or make a change.

DR DAVIDSON: I don’t think Medicare will reimburse that schedule. You can’t even get them to do it every 28 days.

DR LOVE: Another somewhat related strategy that’s being evaluated, since fulvestrant competes with estrogen, is to lower the estrogen level.

The SoFEA study — an ongoing trial in Europe — is evaluating fulvestrant versus fulvestrant plus anastrozole versus exemestane in patients with advanced metastatic breast cancer who progress on anastrozole or letrozole. Of course, we don’t know if it’s going to work, but it kind of makes sense — rather than increasing the dose, you decrease the competitor, so to speak.

Any thoughts on that trial, Nancy?

DR DAVIDSON: Interesting trial, but I don’t think I’d try it off study without something to back it up.

DR LOVE: Lowell?

DR HART: If she eventually progresses on fulvestrant, would you add trastuzumab to perhaps restore hormonal sensitivity? Or would you just stop it completely and go to trastuzumab as a single agent? In this patient, if she still refuses to take AIs, what would you do next after that?

DR MILLER: You’re describing a woman who has hormone-sensitive disease, and she’s had a glorious response. She’s now eight months or so into this with no sign of progression, so I’m not sure her next progression is going to trigger me to go immediately to trastuzumab monotherapy. I doubt her opinions about AIs are ever going to change, but megestrol acetate is still a very reasonable therapy. I would think about another hormonal intervention before making that leap.

DR LOVE: Have you used a combination of trastuzumab and hormones, Nancy?

DR DAVIDSON: No, I haven’t. However, I think the preclinical modeling is very interesting on that. For example, if you’ve followed Kent Osborne’s work, he has a lot of nice data in nude mouse models, examining receptor tyrosine kinase inhibitors and steroid hormone-directed therapies. The models are showing some nice information about cross-talk between these pathways and inhibition of more than one pathway with good results, at least in the mice. That really gives us the fodder for a lot of the clinical trials that you’re talking about, so stay tuned.

I guess the combination of trastuzumab and fulvestrant would be a very expensive therapy, so I’d be thinking hard about what the gain would be right now without some kind of overt support for that in people.

DR LOVE: Dr Blaustein?

DR BLAUSTEIN: I didn’t quite understand why you didn’t want to use bisphosphonates in this situation. The patient had documented bone metastases. What would be the downside, understanding the small potential for osteonecrosis and so forth?

DR DAVIDSON: I’ve had a few patients who had limited bone disease in whom it was a really long time before something went wrong. In the meantime, I’m giving a bisphosphonate month after month and I’m wondering what we’re accomplishing. We do have these rare side effects.

Sometimes your creatinine can bump even with the conventional dosing. The patient could have osteonecrosis of the jaw. I don’t know if you’ve seen any — I’ve seen one or two and they’re actually pretty impressive.

For a patient who has a single site that I’m not too impressed with, I sometimes wait a little while and see what happens, because in my experience, some of them stay like that for a long period of time.

Now, if I were taking the medical oncologist boards, I’m not sure I would say that. It has partly to do with just how you interpret the bone disease and what you think you might accomplish in that circumstance. What was your reasoning, David?

DR DRESDNER: Well, the ribs are not weight-bearing bones. There really was no evidence of any impending fracture, and the zoledronic acid data is pretty strong in terms of prevention of pathological fractures. I didn’t think there was a high risk at this point. The patient was going to be followed up regularly and would have had follow-up bone scans. I think at an appropriate point I would add it, but I just felt at this point, it probably wouldn’t add much and the risk of the joint necrosis was probably greater than the risk of pathological fracture at this time.

DR MILLER: I believe osteonecrosis of the jaw is becoming more common as we and our oral surgery and dentistry colleagues have become aware of it. I particularly worry about it in these folks who have fairly indolent, oftentimes bone-only disease, who piddle along on hormones for years. In the meantime, they’re receiving their monthly bisphosphonates.

I’ve actually started shifting some of those patients who have been receiving monthly bisphosphonates for years to receiving them every two or three months to try and stave off renal toxicity and the osteonecrosis, though I have absolutely no data that do anything other than make me worry less.

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