SAN ANTONIOThe bisphosphonate zoledronic acid (Zometa)
effectively counteracts bone loss associated with combination endocrine
treatment in premenopausal women with hormone-responsive breast cancer, Michael
Gnant, MD, University of Vienna, said at the 27th Annual San Antonio Breast
Cancer Symposium (abstract 6) on behalf of the Austrian Breast and Colorectal
Cancer Study Group (ABCSG).
Combination endocrine therapy for ovarian suppression using
an LHRH analogue with tamoxifen yields benefits similar to chemotherapy in
these patients, but treatment-induced bone loss is common and increases with
treatment duration, he said. Aromatase inhibitors have generally superior
toxicity profiles to tamoxifen but stronger adverse effects on bone. "Aromatase
inhibitors are on the verge of replacing tamoxifen as adjuvant therapy for
hormone-responsive breast cancer," Dr. Gnant noted.
In ABCSG-12, with a planned enrollment of 1,800,
premenopausal patients with stage I-II hormone-receptor-positive breast cancer
are treated for 3 years with the LHRH analogue goserelin (Zoladex), 3.6 mg
subcutaneously every 28 days, and randomized to one of four treatment groups:
tamoxifen 20 mg/d plus placebo or IV zoledronic acid (4 mg every 6 months), or
the aromatase inhibitor anastrozole (Arimidex), 1 mg/d, plus placebo or
zoledronic acid. The trial design mirrors that of the ATAC trial for the premenopausal population.
Dr. Gnant and his colleagues conducted a substudy of 401
patients from ABCSG-12, to determine whether there is significant
cancer-treatment-induced bone loss in patients treated with combination
endocrine therapy. Their further question was whether zoledronic acid would
counteract the bone loss. The 401 patients all had bone mineral density (BMD)
measurements at baseline, 6 months, 1 year, and 3 years.
Analysis showed that most bone loss occurred in the first
year. By 3 years, lumbar spine BMD in those patients receiving tamoxifen or
anastrozole, but not zoledronic acid, was reduced by 14.4% (P < .0001):
11.6% in the tamoxifen/placebo group and 17.4% in the anastrozole/placebo
group. BMD remained constant in those receiving zoledronic acid.
In addition, T-scores were significantly worse compared with
baseline (P < .0001) in the anastrozole/placebo group (-1.7) than in the
tamoxifen/placebo group (-1.1). For zoledronic acid, however, T-scores did not
decline significantly. [A T-score is the number of standard deviations the BMD
measurement is above or below the normal peak value for young adults.
Osteoporosis is defined as a T-score of -2.5 or lower.]
The researchers also evaluated potential interactions with
age or baseline BMD, and found no significant relationships. Furthermore, renal
function was not affected by zoledronic acid, and no fractures have been
reported to date.
The findings suggest, he said, that patients receiving
combination endocrine therapy who have T-scores worse than
-2.5 or who lose a total of 10% of BMD within 12 months of treatment should
receive a bisphosphonate. The trial’s further implication is that all such
patients should have annual BMD measurements.
Responding to a question about news reports of mandibular
necrosis in metastatic breast cancer patients receiving zoledronic acid, Dr.
Gnant said that to date there have been no cases of mandibular necrosis
reported in ABCSG-12, with 1,315 patients enrolled. He noted, however, that the
trial involves younger patients "in a country where oral hygiene is not a