You are here: Home: BCU 3 | 2006: Professor John F R Robertson, MB, ChB, BSc, MD

Tracks 1-10

Track 1 Introduction Track 2 Distinction between sequencing and switching from tamoxifen to an aromatase inhibitor Track 3 Response to hormonal therapy in patients with ER-negative disease Track 4 Potential rationale for response to exemestane after a nonsteroidal aromatase inhibitor Track 5 Clinical trials of fulvestrant and aromatase inhibitors in the metastatic setting Track 6 Results of combining anastrozole and tamoxifen in the ATAC trial Track 7 Ongoing trials evaluating fulvestrant in combination with aromatase inhibitors Track 8 Combination endocrine therapy for premenopausal patients with ER-positive disease Track 9 Clinical trial results of high-dose fulvestrant in premenopausal patients Track 10 Delayed adjuvant fulvestrant after standard endocrine therapy

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Track 2

DR LOVE: In your opinion, should some postmenopausal patients be started on adjuvant tamoxifen up front and then switched to an aromatase inhibitor, or should postmenopausal women generally be started on an adjuvant aromatase inhibitor?

DR ROBERTSON: Until now, we regarded five years of tamoxifen as the gold standard for postmenopausal patients with ER-positive disease. Now we have data comparing five years of an aromatase inhibitor to tamoxifen. Two studies indicate that the aromatase inhibitors are clearly more effective and have different side-effect profiles (Howell 2005; Thürlimann 2005).

We currently have no data on sequencing studies, by which I mean trials that start tamoxifen up front and change to an aromatase inhibitor after two to three years, which is different from the switching trials. Sequencing trials are evaluating the concept of starting all patients on tamoxifen and switching them over to an aromatase inhibitor at two to three years.

The switching trials involved taking a group of people who had reached two to three years — among whom there’d been a number of recurrences — and switching over the people who were still disease free. So the sequencing and the switching strategies are entirely different.

DR LOVE: It sounds as though you may be splitting fine hairs, but this is an important concept.

DR ROBERTSON: I believe so, in that we know that in the adjuvant setting, the peak of recurrences occurs after approximately two years among patients with either ER-positive or ER-negative disease.

It’s likely that a disproportionate number of patients with ER-positive, hormone-resistant disease experience recurrence during the first two years, so afterwards a more hormone-sensitive group remains. Therefore, if a new drug is more efficacious, the hazard ratio for risk reduction will be larger in that population than in the initial population treated up front.

We conducted an interesting study in which we took approximately 1,000 patients who underwent surgery and radiation therapy but received no systemic therapy. Approximately 400 of those patients experienced recurrence.

For those who experienced recurrence, what happened with their metastatic disease informed us whether they were hormone-sensitive. So we had four groups of patients: ER-positive, hormone sensitive; ER-positive, hormone insensitive; ER-negative, hormone sensitive (a small group of patients) and ER-negative, hormone insensitive.

In a replotting of the disease-free survival curves for the 400 patients with hormone sensitivity data, the curves for patients with ER-positive and ER-negative disease overlap.

However, the ER-positive, hormone-insensitive group experienced recurrences earlier than the ER-positive, hormone-responsive group, although they had not received prior hormonal therapy (Figure 2, page 4).

This indicates that those populations — although we call them ER-positive — have another factor that makes their disease recur more quickly. That’s why they don’t respond as well to hormonal therapy.

That’s the point I’m making about the difference between using a sequencing policy up front and a switch policy at two to three years. In the switch strategy, a greater portion of the ER-positive, hormone-insensitive patients has been omitted. That is why a higher hazard ratio exists in the data from the switch studies.

For patients who are going to experience recurrence in the first couple of years, starting with an aromatase inhibitor instead of tamoxifen will reduce the risk of recurrence substantially.

Tracks 5, 7

DR LOVE: Would you discuss the trials comparing fulvestrant and aromatase inhibitors in the metastatic setting?

DR ROBERTSON: The SoFEA trial compares exemestane to fulvestrant following another aromatase inhibitor (3.1). The EFECT study is also testing the question of exemestane versus fulvestrant following another aromatase inhibitor. That study has finished recruiting and is now in the follow-up phase, so the results should be reported in the foreseeable future.

DR LOVE: What do you expect the SoFEA trial to demonstrate?

DR ROBERTSON: I hope we see an improvement by combining the two treatments, though I suspect we may have answers to that question before the SoFEA trial results are reported, in that metastatic studies often take a bit longer to run. A couple of ongoing studies are also combining therapies, and they may report sooner.

The SWOG-S0226 trial is comparing fulvestrant with anastrozole to anastrozole alone, so we may see whether the combination is better than a single-agent aromatase inhibitor, and that will be an interesting result.

We’re conducting a presurgical study in the United Kingdom evaluating fulvestrant versus anastrozole versus the combination. This trial will extend the previous presurgical study we performed with 50 mg, 125 mg and 250 mg of fulvestrant (Robertson 2001).

This time we’re using fulvestrant at 500 mg and anastrozole. We’re attempting to determine whether we can elicit a greater effect by increasing the dose and determining how that compares when we both increase the dose and decrease the estradiol level.

Track 9

DR LOVE: Would you discuss the data Mike Dixon presented at the 2005 San Antonio Breast Cancer Symposium evaluating higher doses of fulvestrant in premenopausal women?

DR ROBERTSON: Mike’s study followed from one that we conducted two or three years ago, in which we administered 250 mg of fulvestrant to premenopausal women. We did not see any effect on ER, PR or Ki-67 — the proliferation marker — when fulvestrant was administered two to three weeks before surgery (Robertson 2004).

So in our study we saw decreases in ER, PR and Ki-67 in postmenopausal patients, but we didn’t see the same effects in the premenopausal patients at a dose of 250 mg.

Mike Dixon treated premenopausal patients with a dose of 750 mg of fulvestrant, and his data indicated similar effects on ER, PR and Ki-67 in premenopausal women with 750 mg (Young 2005) as we had seen in postmenopausal women with 250 mg (Robertson 2001).

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