Henderson Offers ‘Take-Home Messages’ From Endocrine Studies

ATLANTA—Results of three studies on the use of adjuvant endocrine therapy in premenopausal breast cancer patients suggest several “take-home messages,” I. Craig Henderson, MD, of the University of California, San Francisco, said at the 35th annual meeting of the American Association of Clinical Oncology (ASCO). In his discussion of the three papers at a session on local-regional treatment of breast cancer, he noted the following.

Adjuvant endocrine therapy and chemotherapy appear to offer equivalent overall benefits, but these studies may have used suboptimal chemotherapy regimens. Indirect comparisons of adjuvant endocrine and chemotherapy have suggested equivalent overall benefit. Now, Dr. Henderson said, “we have three randomized direct comparisons.”

An earlier Scottish trial showed no difference in outcome with ovarian ablation or intravenous CMF (cyclophosphamide, methotrexate, fluorouracil), but two of the studies presented at the ASCO session “provide substantially more statistical power with a very similar design,” Dr. Henderon said. “The Austrian study [ABCSG Trial 5] suggests that endocrine therapy might even be superior to chemotherapy.”

Several previous studies have suggested that among women with receptor-positive breast tumors, the benefits of adjuvant endocrine therapy actually exceed those of adjuvant chemotherapy, Dr. Henderson noted, adding that these studies had a low statistical power to prove this point. The recent comparative studies offer further evidence of the benefits of endocrine therapy, compared with chemotherapy, in receptor-positive breast cancer patients.

Dr. Henderson cautioned, however, that all of the trials offering a direct comparison may have used suboptimal regimens in the chemotherapy arm—intravenous CMF rather than classic CMF or newer regimens incorporating an anthracycline or paclitaxel (Taxol).

“I believe this is an important confounding factor,” he said. The take-home point is that “we are now beginning to see differences among adjuvant chemotherapy regimens, and direct comparisons of endocrine therapy and chemotherapy need to take this into account.”

Adding tamoxifen (Nolvadex) to chemotherapy may be beneficial in “older” premenopausal women, ie, those who have a shorter time until their natural menopause. The new trial results suggest an inverse relationship between tamoxifen benefit and the time to menopause, particularly the ECOG study [Dr. Nancy Davidson’s presentation], Dr. Henderson said.

“It is quite plausible that the effects of adjuvant tamoxifen in a 48-year-old woman who has only 4 more years to natural menopause will be much greater than in, let’s say, a 42-year-old woman who might have a 10-year time to menopause,” he said.

There may be an advantage to combined endocrine therapy in some patients. Most randomized trials of patients with metastatic breast cancer have failed to show an advantage when different forms of endocrine therapy are combined, Dr. Henderson said. But if the effects of tamoxifen are greater among women who are close to or past menopause, “then any means of creating a menopausal state prior to tamoxifen administration (as with an LHRH analogue) will increase its effectiveness.”

He called this “the take-home point from these trials collectively and particularly from the trial presented by the ECOG Intergroup.”

There may be little additional benefit of adding chemotherapy to endocrine therapy in younger, ER-positive women. “It is increasingly clear that a large part of the benefit of chemotherapy in younger women is due to a chemical ovarian ablation,” Dr. Henderson said, “and this explains why chemotherapy is so much more effective in younger than in older women.”

Dr. Henderson commented that in the early 1980s, at European meetings, he was frequently invited to debate this point. “Americans tended to be on one side and the Europeans on the other, and I would regularly argue that the effects of chemotherapy were not due to chemical ovarian ablation.” But, he says now, “if you’re going to be data driven and use evidence-based medicine, I think you can no longer argue against this conclusion.”

This is not to say that chemotherapy has no role in the adjuvant setting, he stressed.

“We know that chemotherapy imparts a small survival benefit in women without ovarian function, including those with ER-positive tumors, so I don’t mean to dismiss chemotherapy,” he said, “but I think we now must ask, how much additional benefit is derived from adding optimal chemotherapy to endocrine ablation in younger women with ER-positive tumors?”