Edited excerpt from the discussion:

DR DEUTSCH: This is a 55-year-old Ethiopian woman whom I initially saw in 1997. She presented with a large breast tumor and skin involvement. She underwent a mastectomy and had six of six lymph nodes positive, and her tumor was found to be ER/PR-positive and HER2-negative. At that time, she was treated on the Bonadonna protocol with four cycles of doxorubicin followed by six cycles of CMF.

She then had chest wall radiation therapy and received tamoxifen for five years. After five years of tamoxifen, we then stopped treatment. She did well until 2003, when she presented with multiple skin nodules over the left chest wall and extensive osseous metastatic disease without any visceral involvement.

At the time, her performance status was good, and she continued to work as a nurse’s aide. Her main complaint was that she had back pain, and it was interfering with her bending over and lifting when she was taking care of patients. She also had obvious skin nodules on her chest wall, which were disconcerting to her because she knew they were probably cancer.

DR LOVE: Tom, can you talk about how you would sort through the treatment algorithm at this point?

DR BUDD: In terms of systemic treatment, the choice is fairly easy. I assume she is postmenopausal, and it sounds like she has no absolute indication for chemotherapy, so I would probably elect to treat her with an aromatase inhibitor.

The other issue is whether or not she should receive radiation therapy to palliate her back pain. I think we’ve learned that one of the first symptoms of cord compression is pain, so I have a pretty low threshold to order an MRI just to make sure there is no epidural extension, which would mandate radiation therapy.

I would probably consider that and then recommend radiation therapy if it looked like it was necessary. For me, this decision is a matter of evaluating the imaging and getting an idea of how much pain the patient is having.

DR LOVE: Bob, Tom said he thought he would use an aromatase inhibitor. Would you have brought up the possibility of fulvestrant to this woman also?

DR CARLSON: Yes, I would have, and I also would have recommended hormonal therapy as the initial intervention for all the reasons Tom outlined. We do have randomized data comparing anastrozole and fulvestrant in women who were previously treated with tamoxifen, demonstrating that fulvestrant is at least as good as anastrozole and perhaps slightly superior in terms of disease-free survival and duration of response in those women who do respond (Mauriac 2003). So an AI or fulvestrant in this situation would both be perfectly appropriate therapies.

Like Tom, I would also be worried about this patient’s bone pain and would include a bisphosphonate in the treatment program, especially with such extensive skeletal involvement.

DR JAIN: If a patient presents with minimal bony disease and the lesion is difficult to biopsy, how aggressive are you in trying to get tissue?

DR BUDD: I will generally try to obtain a tissue diagnosis of metastatic disease. When you are telling a patient that she has an incurable situation, you ought to be as certain as possible.

On the other hand, if the biopsy is negative, it doesn’t mean the patient is off the hook. We may well be back in the situation in which we will have to make a decision to initiate treatment despite having a negative biopsy. So it’s best to present that to the patient up front.

For a patient with bone-only disease, I often order a bone marrow aspirate and biopsy. This will provide a diagnosis in approximately 60 percent of cases. If that is not diagnostic, I’ll try to do a bone biopsy.

Obviously, you need to think about other possibilities, multiple myeloma for one, in the situation described.

I’d probably do protein studies to consider the possibility of multiple myeloma because an isolated metastasis actually increases the likelihood that it’s something else.

This type of situation would warrant a more aggressive approach in terms of going after a diagnosis, but this is a difficult situation that we all deal with every day. I believe it is best to share your thought processes with the patient and try to get a diagnosis, but at the end of the day, recognize that you might end up making a decision based on radiographic evidence.

DR LOVE: This is another issue relevant to our Patterns of Care work because in general, what we have seen with cases like this postmenopausal woman is that most physicians do exactly as Tom suggested and generally use an AI.

However, as Bob talked about, we do have data on fulvestrant in this situation. A couple of studies, including one that our group conducted, document that approximately one third of women with metastatic breast cancer in this situation, particularly if they’re on a bisphosphonate, would actually prefer a monthly intramuscular injection.

DR CREWS: One of the questions in my mind about fulvestrant is: Are physicians using it appropriately? Some of the newer studies are considering higher initial doses or more frequent doses to obtain a steady state earlier, and this might make a difference where we use this drug.

DR LOVE: Tom, what about the issue of fulvestrant dosing?

DR BUDD: Pharmacokinetic studies (Robertson 2004a, b) indicate that therapeutic levels won’t be reached for three to six months after the initiation of treatment using only a monthly dose.

Patients may progress in that interval due to inadequate dosing rather than true endocrine resistance. So these loading dose schedules have been described, and I have used this approach in some patients.

For instance, we have a Southwest Oncology Group trial looking at anastrozole versus anastrozole plus fulvestrant, which uses a loading schedule (5.1). We don’t have randomized data to justify this approach, but we do have pharmacokinetic data to say that would be a better way to go. So I believe it’s a perfectly reasonable thing to do.

DR LOVE: Can you follow up with this patient, Dr Deutsch?

DR DEUTSCH: In July of 2003, the patient came in and we discussed her options. I personally have had no difficulty disscussing the option of a fulvestrant injection once a month, and she began taking that drug and zoledronic acid once every four weeks.

Her initial CA27-29 was 2,823, and over the course of two years, it dropped down to 94 but never any lower than that. All of her bone pain and the skin nodules on her chest wall completely went away.

Prior to placing her on the fulvestrant, we did an MRI of her spine. There was no evidence of cord compression, just lots of osseous metastatic disease. She was able to continue to work and did well for two years.

Lately, her CA27-29 is starting to creep upward, and she has been diagnosed by an ophthalmologist with a choroid metastasis in her right eye. So now we have to deal with that, but she did quite well on fulvestrant, had little in the way of hot flashes or side effects and was perfectly happy to come in once every four weeks to get her treatment and be done.

DR LOVE: What were the specific reasons why you decided to use fulvestrant rather than an AI with this woman?

DR DEUTSCH: There was a language barrier. She doesn’t speak English, and I have to do everything through her husband. It’s a cultural thing, but he’s in control. For him, there was an ease to bringing her in, getting her treatment once every four weeks and knowing it was getting done.

I also believe cost was an issue. Paying for an AI every month gets expensive. Here she was able to come and have her injection basically taken care of. I think there also was a compliance issue. From her standpoint and from his standpoint, it was easy to come in every four weeks and get her treatment without having to take a pill every day.

DR LOVE: Bob, because many people in practice generally use fulvestrant as thirdand fourth-line therapy, many of them haven’t actually seen what this case demonstrates, which is an objective response to fulvestrant. I thought the response this patient had was interesting.

DR CARLSON: That is an excellent point. If an agent is reserved for fourth- or fifthline therapy, the experience with it is going to be disappointing. Fulvestrant is clearly an active agent when it is used initially.

To get back to one of the other issues, I believe compliance is crucial. Study after study has shown that our patients take only a small fraction of the oral agents that we actually prescribe.

Everyone thinks that their patients are the compliers, but in fact, regardless of how you look at patient and physician demographics, compliance with oral agents, even for cancer therapy, is pretty awful.

With fulvestrant, if the nurse and patient say that they have taken the drug, they have taken it. So fulvestrant does have that as a distinct advantage, and this is probably most important in patients who are minimally symptomatic. Patients who have relatively limited disease are most likely not to take their medications because they don’t have symptoms to remind them on an ongoing basis about the need to take the drug.

Little high-level evidence exists evaluating sequencing endocrine therapies. The data we do have, at least as they relate to fulvestrant, are quite intriguing. Patients whose tumors respond to fulvestrant versus those patients whose tumors do not respond to fulvestrant seem to have similar rates of response to subsequent endocrine therapy (Vergote 2003).

This is intriguing because we have all been taught and believe that the best predictor of a hormonal response is that the last hormonal agent worked. However, that paradigm may not be true in patients who have been treated with fulvestrant.

DR BUDD: In general, I think an oral agent is a perfectly reasonable way to go, and I would tend to use aromatase inhibitors over fulvestrant just for ease of administration. Granted, you worry more about compliance or economic issues in some cases, and those are the situations in which I’ve tended to use fulvestrant. However, from a pure efficacy point of view, I think either one could be used.

In terms of optimal front-line chemotherapy in the metastatic setting, I believe it boils down to efficacy and toxicity. The route of administration is a tertiary consideration. We do have a big Phase II trial (Fumoleau 2004) and a lot of clinical experience saying that capecitabine is active in anthracycline/ taxane-resistant patients, and the toxicity is tolerable. I believe that is more important than the fact that it’s an oral drug.

DR LUSKEY: In a past issue of Breast Cancer Update, Steve Jones talked about his anecdotal experience with patients receiving fulvestrant on an early trial, and he believed that he had seen a number of “super responders” or patients with prolonged responses (Jones 2004; [5.2]). I was wondering if anyone else has a similar sense or has seen these long-term responders on fulvestrant over other endocrine agents?

DR CARLSON: I have also treated a handful of what you would call super responders. Actually, one comes immediately to mind. She has been on fulvestrant since it first became available and has had a wonderful and gratifying response with little toxicity.

The perception of the so-called super responder could happen for a whole variety of reasons, one of which could be compliance. The longer a woman takes a drug and the better she does with it, the more inclined she may be to not be as compliant with it.

It’s conceivable that the handful of long responders seen with fulvestrant is truly related to issues of compliance and may not relate specifically to issues of efficacy. One of the reasons we don’t see higher degrees of efficacy with some of the oral hormonal therapies is almost certainly compliance, and that is likely to be a substantial barrier to endocrine therapy efficacy.

DR LASSITER: With the choroidal metastasis that she now has, if she has otherwise ongoing evidence of systemic responsiveness, would you alter her hormonal therapy at this point or continue?

DR LOVE: That’s a great question. Bob, how would you view this choroidal metastasis? Is this a sanctuary site that maybe we should not overlook, and maybe we should not discount fulvestrant?

DR CARLSON: With a choroidal metastasis, she will need radiation therapy to that area. I would also order an MRI scan of her brain to be sure that she doesn’t have occult CNS metastases that you should try to irradiate at the same time as you radiate the choroid.

The choroid is a sanctuary site within the blood-brain barrier, so I would not necessarily consider her tumor systemically refractory to fulvestrant. I would have some concerns about her rising CA27-29 value, since that may be a harbinger that her bony disease is beginning to move out of control. I don’t routinely use CA27-29s in my practice because I often find them to be as misleading as they are helpful. However, I would not hesitate to continue her on fulvestrant until I had other convincing evidence of progressive disease.

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