JOHN F R ROBERTSON, MB, ChB, BSc, MD: This is a presurgical study examining two to three weeks of fulvestrant 500-mg therapy versus fulvestrant 500 mg in combination with anastrozole versus anastrozole one mg. We used 500 mg because there was already some evidence of a dose response, and we felt that there were ongoing studies evaluating strategies to improve clinical outcomes. We wanted to try the higher dose. We chose to include an arm with anastrozole by itself because in case the combination was better, we wanted to show that the benefit was greater than what you would see with an aromatase inhibitor alone. We also knew from the results from Mitch Dowsett and the IMPACT trial what the effects of anastrozole therapy should be and that arm served as a good control.
We found that ER levels were decreased in all three study arms. The basement levels were similar, and we saw a decrease that was highly significant in all three groups.
What we then saw was that when you did an overall treatment effect, there was a highly significant difference between the groups. The percent change in the downregulation was 41 percent for fulvestrant 500 mg, 39 percent for the combination and 13 percent for anastrozole alone. When you compared the groups, the two fulvestrant groups demonstrated significantly greater downregulation of ER than the anastrozole group did. The combination, however, was not better than fulvestrant alone. The combination did not add to the effects of fulvestrant alone, which is in keeping with the FACT trial.
The differences in levels of ER downregulation in our three study arms point to a difference in mechanism of action between fulvestrant and aromatase inhibitors. I believe that more downregulation of the ER occurs with the antiestrogen fulvestrant. With fulvestrant 500 mg, you have reduced the levels of ER further, whereas the reduction with the aromatase inhibitors is less. The decreased levels of ER would decrease the level of receptor autophosphorylation that occurs and the switching on of the estrogen pathway.
ROWAN T CHLEBOWSKI, MD, PhD: This was a negative study presented by John Robertson. It is a preclinical study that examined the combination of high-dose fulvestrant and anastrozole in the neoadjuvant setting. The study demonstrated that the combination of fulvestrant and anastrozole resulted in the same change in the Ki-67 proliferative index as did anastrozole by itself.
DR LOVE: What are your thoughts regarding the question of whether to bring high-dose fulvestrant into an adjuvant trial?
DR CHLEBOWSKI: I thought for a while that the National Institute of Canada had a slot and was waiting for the results from the FACT study. I don’t know if that’s still the case. Of course, now you run into the issue of patent life, funding and other similar issues, but it would seem like this would be a reasonable thing to put in an adjuvant setting. I know some clinicians would use it if they had a patient who couldn’t tolerate a standard postmenopausal hormone therapy. Obviously, there are no data to support that type of use.
Prof Robertson is Professor of Surgery and Head of the Academic Division of Breast Surgery at Nottingham City Hospital in Nottingham, United Kingdom.
Dr Chlebowski is Professor of Medicine at the David Geffen School of Medicine at UCLA and Chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center in Torrance, California.
