Edited excerpts from the discussion:

DR ALLISON: This is a 43-year-old premenopausal radiology technician who presented to her gynecologist’s office when she noted an inverted nipple. The gynecologist could palpate a five to six centimeter mass under her nipple. She underwent a mammogram, which confirmed the mass. Biopsy showed infiltrating ductal carcinoma. Upon examination, her axilla was a little full, but no discrete nodes were palpable.

MRI showed multifocal disease in the breast, with five lesions, and four axillary lesions were noted on a PET scan. Further information from the core biopsy showed that it was a poorly differentiated, high grade, and ER/PR-positive tumor. KI-67 was greater than 20 percent and HER2 was negative by FISH.

The surgeon requested preoperative chemotherapy, and the patient received four cycles of AC, but unfortunately, she showed minimal, if any, improvement in the palpable mass. At that time, I sent her back to the surgeon, who was more comfortable proceeding with surgery at that time, but she was not pleased about the response.

The patient underwent a modified radical mastectomy and axillary dissection in January 2005. The pathology showed a 14.4 x 8.5-centimeter infiltrating ductal carcinoma. Four of seven lymph nodes were positive for metastatic disease, and perinodal soft tissue extension was also evident.

DR LOVE: How concerned was she about the side effects of therapy?

DR ALLISON: She was not concerned about the chemotherapy because she was very, very concerned about the cancer. She was ready to do whatever it took.

DR LOVE: Vicente, for this premenopausal woman whose tumor was ER-positive and PR-positive, can you talk about what you would be thinking in terms of both immediate and long-term treatment strategy?

DR VALERO: Obviously she has a chemotherapy-resistant breast cancer. I want to make a couple of points. First, you’ve got to confirm that she really has negative HER2 disease. I know it was done once, but in such a young woman with an aggressive tumor with a high nuclear grade and proliferative rate, I would revisit that.

Secondly, if she’s truly HER2-negative and ER-positive, she hasn’t received her best therapy yet, which is hormonal therapy. In terms of chemotherapy, in this circumstance, we would administer a taxanebased therapy after the surgery, and our preference is something like in the Intergroup study.

When we use paclitaxel, we use it weekly. We administer 12 doses of 80 mg/m2. When we use docetaxel, we administer 100 mg/m2 every three weeks.

For now, I would administer three months’ worth of taxane-based therapy, and after that, we like to optimize the hormonal therapy. She may remain premenopausal and may have ovarian function, or she may regain ovarian function. You need to be very cautious.

DR LOVE: Assuming she’s still actively menstruating at the end of the taxane, what hormonal therapy would you think about?

DR VALERO: We use tamoxifen for these patients. She would be eligible for the SOFT trial, which randomly assigns patients to tamoxifen versus LHRH agonist with tamoxifen versus LHRH agonist with exemestane (4.1). Europeans incorporate ovarian ablation with tamoxifen as a standard for these patients. Some Europeans may incorporate the more experimental arm of this trial, which is an aromatase inhibitor with an LHRH agonist.

It’s of concern that this patient has only seven nodes removed. So, obviously, she needs optimal radiation therapy. Our approach would be taxanes for three months, radiation therapy and then, if the patient is premenopausal or we’re concerned that she will regain ovarian function, we’ll start her on tamoxifen.

DR LOVE: Rowan, how would you think this through?

DR CHLEBOWSKI: The Europeans are the ones who like ovarian suppression, as in the small metastatic disease trial, which evaluated tamoxifen versus tamoxifen and ovarian suppression versus ovarian suppression alone, with a survival advantage with the combination in metastatic disease (Klijn 2000, 2001). So you might say that the question of whether an interaction occurs is asked and answered in advanced disease. The toxicity issues are straightforward, so why not do it?

We have been practicing ovarian suppression in women under the age of 40 pretty routinely. With somebody who is 43, this is a kind of extension case in both directions — this is a patient for whom I would think about ovarian suppression because of the aggressive disease.

The other thing I would think about is referral for genetic testing. It would certainly facilitate your case if you knew that she was BRCA-1/2-positive, because you would go for ovarian ablation right off the bat. Then you would really have a clear course to the aromatase inhibitor.

DR LOVE: What specific hormonal therapy would you be likely to use and what adjuvant chemotherapy?

DR CHLEBOWSKI: For patients under 40 we have been using ovarian suppression and tamoxifen. I would probably use both for this patient because of her aggressive disease.

I agree with the weekly paclitaxel. The ECOG-E1199 trial was a little surprising to us in that every three-week docetaxel didn’t prove superior to the other regimens, but, if anything, a trend favored weekly paclitaxel. Another alternative to consider would be the carboplatin/docetaxel regimen if you wanted to use two drugs.

DR LOVE: Did you say that if this patient had her ovaries taken out surgically, you’d use an aromatase inhibitor, but if she were going to receive an LHRH agonist, you’d administer tamoxifen?

DR CHLEBOWSKI: Yes. At least in the ATAC trial, they can’t say exactly how many people with oophorectomy were eligible for the trial. So it’s a technical point. We have data from a couple of Phase II trials — one of them from Stanford — and it looks as though the clinical benefit is pretty good from a Phase II anastrozole/goserelin trial. We haven’t done that in practice. We’ve been sticking with ovarian suppression and tamoxifen.

DR LOVE: Vicente?

DR VALERO: I’m the coprincipal investigator for that particular trial, and we’re working with Stanford. We have put many patients on the trial in the metastatic setting. It’s a very well-tolerated therapy. We have almost completed accrual, preliminary data show a lot of activity and, biologically, it makes sense.

However, if you’re driven by the data, the Europeans published a meta-analysis a few years ago that showed the use of tamoxifen and an LHRH agonist was superior to an LHRH agonist alone (Klijn 2001). A very small study suggests that an LHRH agonist and tamoxifen might be superior to tamoxifen, but we don’t have enough data, and that’s why the SOFT trial is ongoing (4.1).

DR CHLEBOWSKI: One of the reasons for that dichotomy is that goserelin every month has an approved indication for breast cancer treatment. Goserelin every three months doesn’t because it couldn’t suppress estrogen levels. The effects on estrogen of the three- and four-month preparations of leuprolide have never been reported.

So I would be concerned about the data, asking, “Do I have enough evidence to say that I can really suppress estrogen enough with goserelin to combine it with an aromatase inhibitor?”

DR LOVE: Vicente, do you have any reason to think the LHRH agonist is not suppressing the ovaries enough and administering anastrozole is problematic?

DR VALERO: In the SOFT trial, we’re administering it monthly, and we were checking estradiol levels. As you know, menopause might be transient. You might start a patient on an aromatase inhibitor and all of a sudden, she is having cycles.

DR LOVE: For this 43-year-old woman with a 14-centimeter tumor, why not get a laparoscopic oophorectomy and start an aromatase inhibitor regardless of BRCA?

DR CHLEBOWSKI: At our institution, our gynecologists are not enthusiastic about ovarian ablation. They’re reluctant to remove the ovaries; you have to show them absolute “knock-your-socks-off” data. And here we’re really talking about “This’ll help me adminster this kind of therapy.” If you had gynecologists who were enthusiastic about it — that would be the easiest way.

DR LOVE: Dr Allison, what happened with this patient?

DR ALLISON: I treated her postoperatively with four cycles of docetaxel every three weeks. She also received radiation therapy to the chest wall and the axilla, then I placed her on tamoxifen. During that time, we discussed the available options. I talked to her about BRCA testing. Her comment was, “What’s that going to do for me? I’ve already had my mastectomy.”

We also talked about where we were going regarding her ovaries. She was 43 years old and didn’t want to have any more children. I have no trouble getting a gynecologist to take out ovaries, as long as I write a letter of medical necessity. Her gynecologist, in particular, has a mother with metastatic breast cancer, so she was very willing to do this and understood the issues.

The patient was anxious about ovarian cancer. So she underwent a total abdominal hysterectomy on December 28, 2005. On December 30, I got a call from her gynecologist, saying, “Her belly looked fine. I took out her ovaries and her uterus, and she has a 0.9-centimeter subcapsular nodule in the ovary, which the pathologist is calling breast cancer.”

So I called the pathologist and I said, “Are you sure this is breast cancer? You’re sure it’s not ovarian cancer?” If it was ovarian cancer, found incidentally, then I wouldn’t change much about the management.

They did special stains for me, the BRST-2 and the WT-1. The finding was consistent with breast cancer, and they told me that as far as they could tell from the special stains, it was not ovarian cancer.

On top of that, the ER and the PR were 3+ and the HER2 was repeated on this tumor and it was negative again. I ordered PET and bone scans, both of which were negative, so I have no evidence of disease. I have an incidentally found ovarian metastasis.

DR LOVE: What endocrine therapy is she receiving?

DR ALLISON: She’s now on an aromatase inhibitor, which I had planned on administering no matter what the hysterectomy showed.

DR LOVE: Rowan, Dr Allison had her patient’s ovaries taken out and put her on an aromatase inhibitor, which is a common strategy among community oncologists, yet when you talk to researchers, you get a lot more push-back. That’s an interesting dichotomy.

DR CHLEBOWSKI: In terms of when to use an aromatase inhibitor, I think we have a little bit of difference. Menopause is defined as 12 months of no menstruation with nothing intervening. So if a 48year-old woman is treated with FAC and has ceased menstruation for eight months, she’s not postmenopausal.

Secondly, estradiol and age do not signify menopausal status. Basically, it just signifies whether you’re menstruating or not. You can go months and months and then start up again, and almost no data define the perimenopausal woman.

Those women can go years and years before somebody suddenly starts to menstruate again. We don’t have any idea of how many people do it, but we also don’t have any idea of how many estradiols, or generations, it takes in that setting of a short-term cessation of menstruation. We all know that aromatase inhibitors are egg stimulants. Case reports tell of women who are put on an aromatase inhibitor and become pregnant.

DR LOVE: I would say that this issue of the premenopausal woman with an ER-positive tumor who stops menstruating on chemotherapy is one of the most common scenarios I hear about from oncologists in practice. It’s a truly vexing situation. Particularly for a patient at higher risk, for whom you think an aromatase inhibitor will lower the relapse rate, you have to worry that maybe you’re administering something that’s going to be ineffective because she’s going to start to menstruate or produce estrogen again.

DR VALERO: I agree. That’s the reason we start those patients on tamoxifen, which is the standard of care — because we cannot really establish their ovarian function. That’s the reason for the SOFT trial, because we don’t know if something is better than tamoxifen in this setting.

The other day, I saw a patient who had undergone chemotherapy two and a half years earlier. She had been on tamoxifen for a year and relapsed. We put her on a trial with letrozole and then, when she failed, we enrolled her in the exemestane versus fulvestrant study (4.2). Now she’s responding.

DR LUNIN: I routinely recommend an oophorectomy for premenopausal women at high risk who remain potentially premenopausal after chemotherapy. For me, it seems straightforward. All of the data indicate that an aromatase inhibitor is superior to tamoxifen in postmenopausal women with ER-positive breast cancer. My understanding is that premenopausal women who are made postmenopausal with chemotherapy do better than premenopausal women who remain premenopausal after chemotherapy.

So in my mind, it’s absolutely clear that if I have a woman at high risk whom I ultimately want to get onto an aromatase inhibitor, then if menopause is not induced chemically, I will induce it surgically to try to improve her prognosis and ultimately get her on what I think is a better drug.

DR LOVE: There have been a lot of discussions — and the ASCO Technology Assessment addressed this in detail — about the optimal long-term strategy for hormonal therapy in postmenopausal patients. Can you talk about what’s gone into these types of discussions?

DR CHLEBOWSKI: Yes, the models that are available now take the existing adjuvant trials comparing aromatase inhibitors to tamoxifen or to placebo and take the hazard ratios at various times and do mathematical calculations to say which would be better or not for recurrence.

The difficulty with the models, for me, is with the switching trials. They’re assuming that you’d get the same result if, instead of doing the randomization after two to three years, you did the randomization at the start. In my view, we have no idea whether all the dropouts and patients who recurred would give you the same hazard ratios.

An equally plausible argument would be that the patients who aren’t going to respond to any hormone therapy are going to recur in those first two to three years. Then it would be easier to show a difference between the two trials. So you’re selecting out a nonresponsive population, and you would get a lower hazard if you really started right at the beginning.

DR LOVE: Putting aside side effects and toxicity, do you believe the long-term 10-, 15-, 20-year relapse rate would be lower starting with tamoxifen for some period of time, followed by an aromatase inhibitor? Is that a possibility or a likelihood?

DR CHLEBOWSKI: If you start with tamoxifen first, after two and a half or three years, or five years, there’ll be more people who have relapsed on the tamoxifen than the aromatase inhibitor, and a substantial number of those people will be irretrievable. They will have an incurable disease. So you’re banking on being able to capture more people later, but we don’t have any data for that. That’s just a speculation.

Sequencing therapy may be better, ultimately, but I still don’t see any reason not to start with the most effective therapy: an aromatase inhibitor followed by tamoxifen or followed by a steroidal aromatase inhibitor. We’ll get a signal from the BIGFEMTA trial.

DR LOVE: Clinically, you talked about using an aromatase inhibitor up front. Which one, in general, are you using?

DR CHLEBOWSKI: Until recently, we had anastrozole as our only agent. Since the St Galen meeting, we now have letrozole showing comparable efficacy. The issue to me is we have 68 months of follow-up with the anastrozole data, and we have 30-plus months of follow-up with letrozole.

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