• Treated with surgical oophorectomy plus tamoxifen and radiation therapy to the spine
• Patient developed back pain and her tumor markers were rising
• Switched to anastrozole and had tumor control for three years

Key discussion points:
	Selection and sequencing of endocrine therapy in the metastatic setting
	Use of bisphosphonates in patients with metastatic bone lesions

DR STEINECKER: This is a woman I followed for almost 10 years. I first saw her in 1995, at which time she came into the emergency room complaining of severe back pain.

The emergency room staff observed a fungating tumor in the right breast with literally an automastectomy. It was reddened, raised and ulcerated, and her studies at that time showed bone metastases.

DR LOVE: Can you talk more about this woman and her history in terms of the evolution of this breast lesion?

DR STEINECKER: Where I practice we see one patient every year or two who presents with neglected tumors. She told me she had something in her breast for three to four months, but her records indicate she told her surgeon that she had changes in her breast for four to five years. I’m uncertain about the psychodynamics involved.

DR LOVE: I’ve often heard physicians describe cases like this in which the woman is responsible and takes care of herself in all aspects except this one isolated area of denial. Would that describe this woman?

DR STEINECKER: I think so. She had a family with children, and she was living with her husband and working regularly.

DR LOVE: What did you do at that point?

DR STEINECKER: Clinically, she had Stage IV breast cancer and was still menstruating at the age of 48. Her biopsies revealed ER/ PR-positive infiltrating ductal carcinoma. I recommended a surgical oophorectomy and tamoxifen.

She did well. Her automastectomy healed, the breast shriveled and the tumor disappeared. Her bone lesions seemed to regress and her pain went away.

She became quite active. She underwent radiation therapy to her spine and did well for about five years before having a relapse in the bone.

DR LOVE: At that point, what was her situation?

DR STEINECKER: She had more back pain, and her CA 27.29 tumor marker had risen. We thought her disease was progressing. She switched to anastrozole and did well for about three years, and her pain was under control.

Case follow-up:
	Developed severe pain and received radiation therapy; developed osteoporosis, vertebrae collapse and rising tumor markers Switched to fulvestrant and zoledronic acid

Gradually, her disease began to relapse and ended up in the hospital with really severe pain. She had significant osteoporosis and collapse of vertebrae. In retrospect, before the ATAC trials we probably didn’t realize the amount of osteoporosis caused by aromatase inhibitors. Bone scans clearly revealed bone progression and lytic disease, and she had elevated tumor markers.

She received radiation therapy to the painful areas. Her lytic lesions in the acetabulum and the femurs were such that the orthopedic physicians did not think they could perform prophylactic surgery. She avoided weight-bearing activity for almost six months and responded to a change in her hormone treatment to fulvestrant and zoledronic acid.

After six months, she has gradually resumed weight-bearing activity. It’s been about a year now, and she’s doing well. She comes to the office with her husband and is continuing on monthly fulvestrant and zoledronic acid.

DR LOVE: It has now been about 10 years since she presented with automastectomy?

DR STEINECKER: Yes.

DR LOVE: She has metastatic disease and has never been treated with chemotherapy?

DR STEINECKER: She never had chemotherapy and has disease isolated to the bones.

DR LOVE: What does her breast look like right now?

DR STEINECKER: It hasn’t changed much in the last couple of months. I thought I noticed a slight red raised area, which I’m keeping an eye on, but her automastectomy area is the same as it’s been for 10 years, which is basically scar tissue.

DR LOVE: So she has gone from oophorectomy/ tamoxifen to anastrozole to fulvestrant over a period of 10 years?

DR STEINECKER: Yes.

DR LOVE: How has she functioned over that entire time period?

DR STEINECKER: She’s been functioning well, working regularly up until the last couple of years when her pain started becoming worse. Now, she stays at home and her husband is very supportive. He took time off work to be with her for six months.

DR LOVE: Dan, what are your thoughts about this case?

DR BUDMAN: This is fairly classical ERpositive disease, which is mainly bone dominant. It’s gratifying to see the initial response was rather good. If you evaluate hormonal therapy in the neoadjuvant setting, the actual complete response rate is not particularly high. To achieve a complete response rate in the chest and a good response in the bones, obviously, makes everyone happy.

Craig Henderson wrote a nice editorial in the Journal of Clinical Oncology approximately three years ago about the utility of being able to cycle hormones from one to the other, which is basically what we’ve done with this patient. An advantage in breast cancer is that it’s a chronic disease and is hormonally responsive at many levels, and hormonal therapy has minimal toxicity and potentially a lot of benefit.

One question that might be asked is whether the EGFR superfamily has become over expressed and the patent has developed endocrine resistance. Alternative methods exist to activate the estrogen receptor. Perhaps that’s why fulvestrant worked, because it destroyed the estrogen receptor. It might be worthwhile in this case to rebiopsy the lesion and evaluate it for both HER2 and EGFR expression. Ongoing studies are evaluating blocking both HER2 and EGFR expression to determine whether or not they are of value in patients who have failed primary endocrine therapy.

DR LOVE: Adam, what are your thoughts?

DR BRUFSKY: My thoughts were essentially the same. This woman has lived 10 years with endocrine-responsive disease, and you still have agents available after fulvestrant, including megestrol acetate, aminoglutethimide and even fluoxymesterone, if you could find it somewhere. Clearly, several other options are available for this woman before chemotherapy.

DR LOVE: Dan was talking about some of the new trial strategies evaluating hormonal therapy and biologic agents. Trastuzumab and fulvestrant is one that I’ve heard about. Adam, what are your thoughts about that clinical research strategy?

DR BRUFSKY: I think it’s a good one. Good preclinical data suggest that members of the EGFR superfamily have receptor crosstalk with members of the steroid receptor super-family.

Clinical trials with gefitinib and tamoxifen or trastuzumab and fulvestrant are ongoing. Newer agents, such as 2C4, actually inhibit some of the interaction between the HER1 and HER2, and HER2 and other members of the superfamily, HER3 and HER4. As soon as 2C4 can be evaluated as combination therapy, it will likely be combined with hormonal therapy.

DR LOVE: Adam, this woman had a good response to fulvestrant. What is your experience with this agent?

DR BRUFSKY: I’ve mostly used fulvestrant as third-line therapy. Occasionally, I’ve used it first-line in patients who cannot afford an aromatase inhibitor or in whom I have concerns about compliance.

In my experience with fulvestrant, I’ve probably seen more disease stabilization than clinical response. I’ve treated women who had nonprogression for three to four months, generally in the third-line setting. I’ve seen a few patients with disease stabilization for years, but in most patients it’s only been for months.

DR LOVE: When I ask research leaders and community-based physicians, they often report using fulvestrant third-line due to convenience. They agree that it seems to be at least equivalent to anastrozole. How often do you see patients in your practice who, if you offer either a once-a-month intramuscular injection or a daily pill, would prefer the injection?

DR BUDMAN: I think it varies throughout the country. We were involved in one of the initial studies of fulvestrant, and our major concern was that women wouldn’t like the injection. The toxicity was not an issue.

On the other hand, I use fulvestrant commonly now, although it’s mainly in patients who have failed primary endocrine therapy. Many physicians tell me their patients have no problems with the injection. In fact, women prefer it because they don’t have to worry about taking a pill. It varies throughout the country, and it may vary among the patient population you’re treating.

DR LOVE: We surveyed 239 women who had metastatic breast cancer, and we asked them, “If you were faced with the choice between a monthly intramuscular injection or a daily pill, assuming the same side effects, which would you prefer?” Thirtyfour percent preferred to have the injection. Does that surprise you, Dan?

DR BUDMAN: We know geographic differences exist in terms of whether patients prefer hormonal therapy or chemotherapy.

DR LOVE: I was surprised, because I don’t hear about physicians offering these as options. Typically, physicians will say, “Well, patients would rather have a pill,” yet, if a third of women would rather have an injection, why are we not presenting that as an option? Adam?

DR BRUFSKY: Fulvestrant is especially interesting because the patients are coming in monthly for zoledronic acid anyway. Why not just add in the fulvestrant?

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