Zometa Stops Bone Loss During Endocrine Rx for Breast Cancer

SAN ANTONIO—Treatment with a bisphosphonate can counteract bone mineral density (BMD) deterioration in hormone-receptor-positive premenopausal breast cancer patients undergoing combined endocrine treatment, according to preliminary study results of a large, prospective, controlled multicen-ter trial presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 12).

In the trial, which is designed to compare the effect of two combined endocrine therapy regimens—the GnRH analogue goserelin (Zoladex) plus tamoxifen (Nolvadex) vs goserelin plus the aroma-tase inhibitor anastrozole (Arimidex)—patients who also received zoledronic acid (Zometa) avoided the reduction in bone mineral density seen up to 6 months after treatment began. "Longer-term monitoring will be necessary to determine whether these effects are prolonged," said Michael Gnant, MD, professor of surgery, University of Vienna, Austria.

The study is Trial 12 of the Austrian Breast & Colorectal Cancer Study Group (ABCSG). It follows up on already published results suggesting that combined goserelin and tamoxifen treatment is at least as effective as standard CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy as adjuvant treatment of hormone-responsive breast cancer in premenopausal women.

The ABCSG Trial 12 will show whether goserelin/anastrozole can improve upon the results already observed for goserelin/tamoxifen. "There are some data that the estradiol suppression is even more effective with goserelin/anastro-zole," Dr. Gnant said.

Investigators have enrolled 1,250 women with stage I-II estrogen- or pro-gesterone-receptor-positive disease and randomized them to goserelin (3.6 mg subcutaneously every 28 days) plus oral tamoxifen (20 mg/d) or oral anastrozole (1 mg/d) for a total of 3 years.

As a secondary goal, investigators want to determine whether bisphosphonate support can inhibit the detrimental effects of combination therapy on bone mineral density; furthermore, adding a bisphosphonate may improve relapse-free survival, Dr. Gnant said. Accordingly, half of each group received zoledronic acid as an IV infusion every 6 months. "Initially we used a higher dose (6 mg) of zoledronic acid," Dr. Gnant said. "However, due to safety concerns with respect to renal function, the dose was reduced to 4 mg after the first 100 patients."

As of the San Antonio report, 278 out of a planned 667 patients had been subjected to bone mineral density measurements of the lumbar spine and trochanter femoris by standard densitometry. However, the preplanned interim analysis reported by Dr. Gnant focused on the 172 women for whom three separate measurements had been taken (baseline, 6 and 12 months after treatment).

Study Results

After 12 months of treatment, lumbar spine bone density was significantly higher (P > .0001) for patients who received the bisphosphonate vs patients who did not. Regression analysis revealed a significant reduction in bone mineral density over time for the two arms that received no bisphosphonate. "In both groups receiving zoledronic acid, this effect is diminished," Dr. Gnant said. In addition, zoledronic acid counteracted bone mineral density deterioration to a similar degree at both the initial and reduced doses.

With regard to the primary endpoint, it is not yet clear whether one endocrine regimen will be superior to the other in this population of relatively low-risk patients. However, investigators have observed a nonsignificant trend toward more pronounced bone mineral density deterioration when anastrozole is used in combination with goserelin, compared with tamoxifen.

The ABCSG Trial 12 should have finalized data by the second quarter of 2004, with survival data available in 2005, Dr. Gnant said.