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MS GROGAN: This was a 50-year-old premenopausal woman who is a wife and mother of four. She initially presented to our office in July 2004 with an eight-month history of a fungating, ulcerated breast mass. The mass had almost completely replaced the entire left breast and had a purulent discharge. The patient was admitted to the hospital for debridement of the mass and a biopsy.

To no one’s surprise, the biopsy revealed extensive, poorly differentiated, infiltrating ductal carcinoma, which was noted to be ER- and PR-positive but HER2-negative.

An extent-of-disease workup revealed, unfortunately, widely metastatic disease to the bones, liver and lungs. At the time of presentation, the patient also complained of right-sided hip pain and had difficulty ambulating without assistance.

DR LOVE: This is a dramatic, unusual presentation. Women presenting with metastases constitute five percent or less of breast cancer cases. Would you talk more about the woman, her lifestyle and her thoughts as she saw this disease developing in her breast?

MS GROGAN: We call this woman the “Martha Stewart” of our practice. She is your average suburban, stay-at-home mom. She loves being a mother, being a wife and taking care of her house. She excels in crafts and is very creative.

Her mother and maternal aunt both had breast cancer. I don’t know the details of their treatment, but I believe her mother passed away from the disease when she was in her sixties.

It was hard to imagine a 50-year-old woman presenting like this. Her husband was with her at presentation. He is active in her care and supportive.

You wonder how neither of them sought medical attention. If she was in denial, how did her husband not notice something? Unfortunately, by the time they presented, she already had Stage IV disease.

DR LOVE: This is a tricky situation. Were you able to tease out a little bit more about what she was thinking?

MS GROGAN: In retrospect, she clearly knew what was going on. She was just afraid to find out, which I think is true for a lot of patients, although it’s hard to imagine ignoring this evidence.

This isn’t just a lump under your breast that, if you don’t touch it, is not there. This was objective, visible evidence, but she said she was fearful. She knew, with her family history and the symptoms, what she was dealing with and she was just trying to avoid dealing with it for as long as possible.

DR LOVE: Did she keep up with her other healthcare?

MS GROGAN: Yes. She had mild hypertension that was controlled with antihypertensive medication.

DR VOGEL: Did she have a previous mammogram?

MS GROGAN: No, she had not had a mammogram.

DR LOVE: Chuck, this situation in which you have someone who’s taking care of a family, accepting all kinds of responsibility and has this isolated denial in the breast, how often do you see patients present like this, and what do you think is going on?

DR VOGEL: We probably see two or three women a year in our practice, which is limited to breast cancer, with about 400 new breast cancer consults a year. Every year, we see a few patients like this, and you just sit back and wonder how on Earth they could do this. I have no explanation. There’s just a lot of denial, and there’s nothing one can say about it.

DR LOVE: Gary, what’s your experience been with this? Is there a lot of self-recrimination?

DR LYMAN: It’s hard for us to put ourselves in their situation, particularly as male oncologists. Chuck and I have been around long enough, and we both used to see this a bit more frequently in the past, but we still do see it.

I often feel that I’m able to distinguish two categories here. One is a slow-growing tumor that was just ignored, often in a postmenopausal woman with a lot of denial who doesn’t want to bother the family or be a burden and is ignoring the fact that eventually she will be a burden, maybe even more so than if the condition was addressed early.

The other category, which I believe does happen, is an inflammatory-type tumor that has grown rapidly. This patient doesn’t seem to fall into that category, or maybe she’s somewhere in between. Obviously, this tumor was present for some time and should have been noticed by the husband and the wife.

The denial must have been enormous, or maybe paralyzing fear prevented them from seeking treatment. They knew what the answer would be, but if they didn’t go in, perhaps they could pretend it wasn’t true.

It’s hard, psychologically, to know what they’ve gone through, but if you think of yourself in paralyzingly fearful situations, you can get a little bit of a feel for what they’ve gone through. It doesn’t change the situation, but it may allow you to empathize a bit more with what they’re facing and what they’ve gone through over the last few months or even a year or more.

DR LOVE: Chuck, how would you think through management at this point?

DR VOGEL: A lot of what she has is probably reversible, and my gut feeling would be that she has a hormonally sensitive tumor, but she’s gone beyond where you could just put her on a hormone and observe. You have to shrink the tumor. I think you have to quickly show her that you can make a tangible difference.

This would be one of those situations in which I would probably go with chemotherapy up front to get a maximum response and then switch over to a hormone and try to maintain that response.

DR LOVE: Was she having symptoms from the metastases?

MS GROGAN: She had right-sided hip pain and difficulty ambulating.

DR LOVE: How bad was it?

MS GROGAN: She was using a cane when I first saw her.

DR LOVE: What did her hip look like on x-ray? Did anything look as if it were ready to break?

MS GROGAN: A note of a possible impending fracture was made on the MRI.

DR LOVE: Gary, how would you think this through, both in terms of the question of radiation therapy or even prophylactic surgery in the hip, and what are your thoughts about Chuck’s comments regarding chemotherapy?

DR LYMAN: I agree with him completely. When you have liver and pulmonary disease, you have to get this controlled in addition to local control. That will require an aggressive approach. I would also approach the hip aggressively because the last thing that you want is a clean-through fracture and to have this patient laid up and end up with PEs, DVTs and so forth. So you want to address the hip quickly: If you don’t see a pending fracture, just radiation therapy can be utilized, or if it looks as if it’s about to break, surgical pinning along with some radiation therapy can be done, which will result in pain relief and prevent the dire consequences of a break. Then move on promptly with chemotherapy. I think hormonal therapy is also in her future, but it’s not the first step.

DR LOVE: What was her state of mind at that point? Was she depressed? Did she feel guilty? I’m sure she was scared. How did she come across to you?

MS GROGAN: As Dr Lyman was saying, she was ready for treatment at that point. She was aware of the diagnosis, and we put the treatment plan out to her and said, “Look, this is advanced. However, we have effective treatments.”

We tried to approach it as a chronic disease. We have a lot of treatments. We can go through them until we find something that is effective. It may be difficult in the beginning, because we’re going to be a little more aggressive with our treatments, but hope remains for good quality of life and for extension of her survival.

DR LOVE: How do you approach the issue of the curability or lack of curability of metastatic breast cancer? Do you bring it up to the patient?

MS GROGAN: In general and in this situation, I usually wait to play off what patients ask. If they ask, “Is this curable?” I’m generally honest and blunt with them and say, “This is not curable, but it’s treatable.”

I try to avoid questions about life expectancy and things like that because I don’t feel that any of us have the specific answer for each patient. For this patient, we were honest with her and said this is not curable.

DR LOVE: Chuck, if she wanted to pin you down in terms of what to expect for the next few years or five years, how would you have responded?

DR VOGEL: I would just say that nobody can predict what’s going to happen. I would take the same approach that Ms Grogan took and say that this has now become a chronic disease process, like diabetes or congestive heart failure. There will be times when the disease will be in remission and times when it will come out of remission.

I’d give her anecdotes about patients who have had metastatic disease in our practice for 10, 12, 14 years, and I would try to avoid precise statistics unless she’s one of those who’s going to pin me to the wall. I would try to parry that off.

Even now, we do have one study from MD Anderson Cancer Center on survival from first relapse that has shown sequential improvements over time, up to a 40 percent five-year survival. We usually have quoted two years median survival from first relapse.

In the study that we did at the University of Miami when I was there, we saw a tremendous heterogeneity. Basically, if you were hormone receptor-positive, the median survival was four years, and if you were hormone receptor-negative, the median survival was less than two years. I try to avoid getting into those discouraging statistics and, instead, leave the patient with encouraging anecdotes.

DR LOVE: This woman presented in the summer of 2004, and now in 2006 we have an additional issue on the table in terms of chemotherapy for metastatic disease, which is bevacizumab (2.1). Gary, right now, how would you think through chemotherapy for this woman and, assuming it was reimbursed, would you include bevacizumab?

DR LYMAN: At our institution, bevacizumab is not front-line therapy for metastatic disease for the oncologists, but it sometimes is to the patients. They come in having read and heard about bevacizumab and wanting to know a lot more about it, and we have those discussions.

Generally, in a chemotherapy-naïve patient such as this, although our treatment intent or long-term goal is a bit different, we often will turn to an anthracycline-based regimen to try to put the disease into remission. I think a taxane-based regimen and any of the regimens we’ve talked about in the adjuvant setting are equally viable options.

Again, the treatment intention’s a bit different, so it’s a little hard to talk about pushing the doses and forcing patients to experience a lot of toxicity. So you find the proper dose and schedule that they can tolerate but still try to get them into remission.

I agree with Chuck about proving to this woman that you can help her. The first thing you want to do is get her hip under control and then get this tumor regressed and show her that we can, in fact, relieve her symptoms and reduce her burden of disease. Then I think you’ll have a buy-in from her to continue with therapy.

DR LOVE: This woman’s tumor is ER/PR-positive, so you have hormonal therapy on the table. How would you integrate that into the initial plan?

DR LYMAN: I don’t usually start hormones and chemotherapy together, but I have colleagues who do, saying, “What have you got to lose?” My thinking, which is entirely conjectural, is that, number one, if the patient responds, you don’t know which agent is working. Number two, maybe you’re putting some cells into G0 with the hormonal therapy, and maybe it won’t be quite as responsive to chemotherapy. These are issues that have never been fully resolved.

Some of my colleagues just go ahead with combined-modality therapy, and data exist to support that. I generally would go with chemotherapy initially, get the patient through if she’s responding, and exhaust the standard anthracycline cumulative dose.

If the patient were in a good remission at that point, I’d turn to hormonal therapy. If not, then I’d turn to one of the other agents, either a taxane or gemcitabine or some reasonably active second-phase agent.

DR LOVE: Can you bring us up to date with this woman’s situation?

MS GROGAN: She initially received radiation therapy to the hip. She also received aggressive anti-infective therapy to the mass with home care from a nurse. We started her on chemotherapy with a combination of doxorubicin and docetaxel with pegfilgrastim support. The patient received a total of eight cycles of therapy to reach her maximum lifetime dose of doxorubicin.

During the course of treatment, the hip pain resolved. She began to ambulate without any assistance, and strikingly, the breast mass slowly began to shrink.

By the time she completed the eight cycles of doxorubicin and docetaxel, approximately a 50 percent reduction had occurred in the breast mass and a 50 percent reduction in her hepatic and pulmonary metastases, with stabilization of her bone metastases.

At this point, we felt she still needed to receive chemotherapy because she still had substantial disease. We changed her to a combination of gemcitabine and paclitaxel; she continued to show improvement and the mass completely resolved.

Currently, she’s on single-agent gemcitabine. We stopped the paclitaxel because she started to develop some neuropathy and she was a seamstress, so it was beginning to affect her life. She has an active life with her children and is still ambulating without any trouble, and she just witnessed the birth of her first grandchild. She has a terrific attitude and realizes that we’ve come a long way, but there’s still a way to go.

DR LOVE: How about hormonal therapy?

MS GROGAN: She was initially premenopausal. After about four months, she stopped having her periods, and about eight months after that we started her on anastrozole in combination with the chemotherapy.

DR LOVE: Chuck, what about the issue of using an aromatase inhibitor in patients who start out premenopausal and then stop having their periods with chemotherapy?

DR VOGEL: She’s 50 years old, so the likelihood of her regaining menses is low, but you always have to be cautious, and we closely follow our patients who start out premenopausal and become postmenopausal. I’ve seen women who have been on an aromatase inhibitor regain menses after a year. I watch them closely with serum estradiol levels.

You can’t use LH and FSH if the patient is on tamoxifen because the pituitary views tamoxifen as an estrogen. You have this strange situation in which the estradiol level is low and LH and FSH levels continue to be low on tamoxifen.

DR LOVE: How did she tolerate the initial chemotherapy with the doxorubicin and docetaxel?

MS GROGAN: She tolerated it very well. As I said, once she was diagnosed, she went in with a positive attitude. She had some mild fatigue and hair loss but did not have any problems with nausea or vomiting.

DR LOVE: You said you used growth factor support with pegfilgrastim?

MS GROGAN: Yes. Doxorubicin and docetaxel are highly myelosuppressive.

DR LOVE: Gary, can you talk about the issue of growth factors in metastatic disease and what you do in your own practice?

DR LYMAN: As I’ve mentioned, it’s difficult to be too adamant about maintaining dose intensity when your treatment intention clearly is not cure. Nonetheless, as we discussed earlier, dose reductions and treatment delays will affect remission rates in the metastatic setting also.

You want to maintain some reasonable level of dose-intensity, and for the more aggressive regimens, like this one, use of growth factor support is reasonable. It enables the patient to receive enough drug to have a reasonably high chance of remission.

In fact, the pivotal studies comparing pegfilgrastim to filgrastim that led to pegfilgrastim approval involved the use of doxorubicin and docetaxel (Holmes 2002a, 2002b). These were noninferiority studies, designed to evaluate the duration of severe neutropenia.

What’s interesting, though, is that the pegfilgrastim arms of those studies showed a lower rate of febrile neutropenia than the filgrastim arms (Siena 2003).

This led to interest again in the issue of whether the pegfilgrastim was more active or more effective in preventing this particular outcome, although it was a secondary outcome in those studies. It clearly is the primary focus of concern about neutropenic complications. So growth factor support does work.

Pegfilgrastim may be more active. This regimen carries about a 40 percent risk of febrile neutropenia without growth factors and about a 20 percent risk of febrile neutropenia with filgrastim. In the pegfilgrastim arms, it’s down closer to a 10 to 12 percent risk. These clearly do work and enable delivery of most of the dose intensity, probably optimizing the chance for remission.

DR LOVE: What other regimens utilized in the metastatic setting do you consider for preventive growth factors in healthier patients?

DR LYMAN: Growth factors are used in the metastatic setting with the TAC regimen. I don’t generally use dose-dense ACT in that setting, but I think with any combination of an anthracycline and a taxane, I would bring growth factors to bear.

What we’re seeing with agents such as gemcitabine — and some of those patients are receiving growth factor support — is more thrombocytopenia.

So alluding to comments that Chuck made earlier, as we minimize the major dose-limiting toxicity of many of the regimens, which is febrile neutropenia, we’re seeing more anemia, thrombocytopenia or nonhematologic toxicities become the focus of concern.

DR LOVE: We talked about Peter Ravdin’s Adjuvant! Online model that combines different factors. Do models or tools exist that will predict neutropenic fever?

DR LYMAN: They’re under development. At the last ASCO meeting, we presented a model based on some 4,500 patients followed prospectively — a cohort of patients from 120 practices in the United States — and were able to identify significant independent risk factors in a multivariate model that accurately discriminated high- from low-risk patients from the start of therapy (Lyman 2005a).

The goal was to identify who should be considered for primary prophylaxis from the beginning of therapy. We presented the breast cancer component, but the whole study includes multiple major disease categories.

We modeled the breast cancer patients — approximately 1,200 — separately and presented at San Antonio in December, again showing that we could accurately discriminate high- from low-risk patients for firstcycle neutropenic complications (Lyman 2005b; [2.2]). We’ve submitted the validation in an independent group of patients for this year’s ASCO meeting.

We’re also working with a larger group to package this in a computer-based, maybe Palm-based, Adjuvant! Online-like program that could be used in the clinic at the bedside to predict who is likely to develop these complications.

Approximately one quarter of our patients in that trial are in the metastatic setting and three quarters are in the adjuvant setting, at least among the breast cancer patients.

These models, though, as of today, are not ready for prime-time use. Clinicians already know about an increasing list of risk factors, but the hope would be that once validated, these models will put this all on a much more objective plane.

DR LOVE: What are the key factors, and how are they weighted?

DR LYMAN: Most of them won’t be any big surprise: First is the chemotherapy administered, particularly anthracycline-based therapies in breast cancer. Various comorbidities, including hyperglycemia and diabetes, increase risk.

Patients with low glomerular filtration rates bear increased risk, probably reflecting the impact on drug metabolism or drug excretion.

Prior chemotherapy is also a risk factor. Patients who receive primary prophylaxis with growth factors have a lower risk of febrile neutropenia.

DR LOVE: What about age?

DR LYMAN: When you adjust for other comorbid conditions, age is not a significant factor in the breast cancer data. It is still significant; that is, higher age equals higher risk in the risk model across disease categories, which includes lung, colon, ovarian, breast cancer and lymphoma.

DR LOVE: What’s the age break at which the risk increases?

DR LYMAN: It’s around age 70, although it is on a continuum. We don’t see much of a break, or increase in risk, until you get up to age 70, but much of the information contained in age is absorbed into the comorbidities. Once you include those in the model, age becomes a much weaker predictor.

DR LOVE: The last thing I want to ask about is the local therapy for this woman’s breast tumor. Currently, what does the breast look like, and is it causing symptoms?

MS GROGAN: It’s not causing any symptoms. Some scar tissue is visible but no obvious disease. It is essentially in complete remission.

DR LOVE: Chuck, how do you approach the issue of the primary tumor in a woman with metastatic disease? In what situations will you attempt surgery or radiation therapy? This woman has never had local therapy to her breast.

DR VOGEL: I believe the tumor is likely to come back, and the key at this juncture will probably be the hormonal therapy. I have seen women come in essentially with breast autoamputation, by which the tumor has grown and just completely destroyed the breast so that there is nothing left.

You might want to consider local therapy to the breast. After performing imaging, we’re doing mastectomies for people who have uncontrolled local problems, but this patient’s breast tumor seems to be nicely controlled.

At this juncture, if you’re down to a microscopic disease burden, you may be able to forestall that type of horrible complication by irradiating the breast.

MS GROGAN: That’s a viable option we should look into at this point. On her CAT scan, tumor is still visible beneath the skin surface. She may benefit from radiation therapy.

DR VOGEL: You might even want to remove the breast surgically. I don’t know that I’d be too concerned about margins, but fungating, ulcerating lesions are difficult to contend with, and that is in her future, unless she is very lucky.

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