• Biopsy of the upper inner quadrant of her right breast 12 years ago revealed a 4x3x3-centimeter infiltrating lobular carcinoma
• ER-positive, PR-negative tumor
• Node-positive (1/9)
• Underwent breast-conserving surgery with clear margins and radiation therapy
• Received CMF x 6 and tamoxifen x two years, discontinued due to macular degeneration
• Follow-up 12 years later revealed anemia, elevated CA27-29
• Bone scan and X-ray revealed skeletal and liver metastases
• HER2-negative by IHC and FISH

Key discussion points:
	Sequencing endocrine therapy in the metastatic setting
	Treatment of the patient with ER-positive asymptomatic metastatic disease
	Potential benefits of parenteral therapies
	Combining hormonal therapy with biologic agents

DR LEVINE: I first saw this patient in 1988 when she was 56 years old. She was a recovery room nurse who noted a lump in the upper inner quadrant of her right breast. A biopsy revealed infiltrating lobular carcinoma. It was 4x3x3 centimeters, and one of nine nodes were positive. She underwent breast-conserving surgery and her tumor margins were negative. Her tumor was ER-positive at 9.5 and PR-negative. She was treated with six courses of CMF, breast irradiation and tamoxifen.

She discontinued the tamoxifen after two years because she had macular degeneration and was concerned that this was the result of the tamoxifen.

The patient remained disease-free and returned for follow-up once a year. She took a bicycle trip around the world for 12 months in 2000. When she came back, which was about a year and a half after her last visit in February 2001, she was anemic, with hemoglobin of 10 and an elevated CA27-29. I did a metastatic work-up and everything was negative other than her bone scan and a subcentimeter lesion in her liver. X-rays were also compatible with metastatic disease of the skeletal system. Mammogram was negative. Bone marrow biopsy revealed extensive involvement of metastatic adenocarcinoma consistent with lobular carcinoma of the breast. HER2 was negative by IHC and FISH.

DR LOVE: Can you talk about what her clinical status was at that point? What was her attitude, her family support, et cetera?

DR LEVINE: She is a very active, otherwise healthy person. She had no history of smoking or alcohol use. Her performance status was 100 percent. She bicycled around the world with her husband and had a very good support system and a very athletic family.

DR LOVE: Richard, this woman is presenting with anemia, bone and bone marrow metastases and a liver lesion, but she is completely asymptomatic and very active. She has had two years of tamoxifen and then an ophthalmic problem. With that said, how would you approach her systemic therapy at that point?

DR ELLEDGE: She has a long disease-free interval and we're not sure but she probably has bone-only disease. She has few, if any, symptoms, and estrogen receptor-positive disease, so she is an ideal candidate for hormonal therapy. In this case, I would start with an aromatase inhibitor, but you could start with tamoxifen or fulvestrant.

DR LOVE: In a situation like this one, how would you select hormonal therapy? Any thoughts about the increased duration of response with fulvestrant?

DR ELLEDGE: That was seen in one study. It's an interesting observation but I wouldn't use it to make a therapeutic decision. I consider the side-effect profile, ease of administration and therapeutic efficacy. The aromatase inhibitors have demonstrated a small response and progression-free survival advantage to tamoxifen, so I would pick an aromatase inhibitor because they are easy to take, have few side effects and are probably the best in terms of therapeutic efficacy.

DR LOVE: I'm certain this woman was receiving bisphosphonates. Kevin, does the fact that the woman is coming into the office every month and could easily get an intramuscular (IM) injection at that time affect your choice between an aromatase inhibitor and fulvestrant?

DR FOX: The reasons to use fulvestrant in this situation would be economic or if there were a question about compliance. It doesn't sound like either would be an issue in this case. She happened to be coming in on a monthly basis, but that alone wouldn't provoke me to choose fulvestrant.

DR FAVIS: Wasn't there a study comparing tamoxifen to fulvestrant in the first-line setting that showed tamoxifen to be better?

DR ELLEDGE: No, that perception is not true. If you look at the data recently published in the Journal of Clinical Oncology in the ER-positive subset, fulvestrant and tamoxifen were basically equivalent. If you evaluate all the patients, there was some numerical inferiority for fulvestrant.

One factor you might consider in selecting a hormonal agent is that some patients actually like IM monthly as opposed to daily oral therapy. If you asked most oncologists, they would say, "Patients prefer an oral treatment." However, there is a substantial minority that would prefer to get a shot every month.

DR LOVE: Dr Grabelsky, have you seen patients who feel a parenteral treatment is better or stronger than a pill?

DR GRABELSKY: Yes. I've had several patients express that they felt the injection was somehow stronger and that it was going to be more effective. Patients choose fulvestrant over an oral aromatase inhibitor for several reasons, including a desire to not have to worry about forgetting their medicine.

DR LOVE: One of the clinical trial concepts being evaluated is combining an aromatase inhibitor with fulvestrant. I recently interviewed John Robertson, who has done a lot of the sentinel research in this area, and I didn't realize there is this competitive inhibition between fulvestrant and estrogen that makes it rational to use an aromatase inhibitor and fulvestrant together. Richard, what are your thoughts on that?

DR ELLEDGE: Combining these nontoxic agents that impinge on growth factor pathways is an exciting therapeutic opportunity for the future. By using single agents, I think we may have wrung just about everything we can out of the estrogen receptor. When we start combining these agents and destroying the receptor and inhibiting communication between other growth pathways, it is very exciting.

DR LOVE: Richard, at the NSABP meeting in June 2003 we were talking about a trial evaluating anastrozole, fulvestrant and gefitinib together. What is the biologic rationale for evaluating a drug like gefitinib in combination with hormonal therapy, and what is the status of that study?

DR ELLEDGE: To make a long story short, we are preparing to open that study at a couple of sites as a neoadjuvant option for older patients. Biologically, the cell has a lot of interconnecting molecular pathways that communicate with each other. Many of these are redundant and reinforce the others. Thus, if you can knock out several pathways at once, you have a better chance of potentially getting a therapeutic response as opposed to simply targeting one pathway.

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