zoledronic acid, a bisphosphonate used for bone metastases and osteoporosis, has shown a significant benefit in early breast cancer in an Austrian trial of 1803 premenopausal women.
Results presented here at the American Society of Clinical Oncology 44th Annual Meeting show that women taking zoledronic acid had a 36% lower risk for breast cancer recurrence than those not taking the drug. They showed fewer events on all cancer measures — they had fewer locoregional recurrences, fewer distant recurrences, fewer bone and nonbone metastases, and less contralateral breast cancer.
Although bisphosphonates have shown anticancer effects in preclinical models, clinical studies with older compounds have yielded inconsistent results. “This is the first study to translate these effects into a clinical benefit,” said lead investigator Michael Gnant, MD, professor of surgery at the Medical University of Vienna and president of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).
zoledronic acid is already marketed (as Zometa) by Novartis for use in the treatment of bone metastases and was recently approved for use in postmenopausal osteoporosis (as Reclast).
This trial explored a new use for the drug — the adjuvant treatment of early breast cancer in premenopausal women with endocrine-responsive tumors (i.e., estrogen-receptor and/or progesterone-receptor positive). The women in the ABCSG-12 trial had all undergone surgery for the primary tumor, and about 5% had received preoperative chemotherapy to shrink the tumor; none of the woman received chemotherapy afterward, Dr. Gnant emphasized. Instead, they were treated with the lutenizing hormone-releasing hormone (LHRH) agonist goserelin for ovarian suppression, combined with either the antiestrogen drug tamoxifen or the aromatase inhibitor anastrozole (Arimidex, AstraZeneca). In addition, 1 group of women also received zoledronic acid (4 mg intravenously every 6 months). Treatment was continued for 3 years.
Significant Effects on Disease- and Relapse-Free Survival
A significant difference was seen in the primary end point of disease-free survival between women who were taking zoledronic acid and those who were not. After a median follow-up of 5 years, there were 54 events in the zoledronic acid group and 83 events in the 2 goserelin groups (hazard ratio, 0.64; P = .015). This translates into a 36% reduction in the risk for disease progression, Dr. Gnant added. There was a significant reduction in locoregional disease progression (10 events in the zoledronic acid group vs 20 events in the 2 goserelin groups) and distant metastases, both bone and nonbone (29 events in the zoledronic acid group vs 41 events in the 2 goserelin groups).
The secondary end point of relapse-free survival was also statistically significant: there were 54 events in the zoledronic acid group and 82 events in the 2 goserelin groups, which is a 35% reduction in risk for relapse (hazard ratio, 0.653; P = 0.014). There was also a trend in overall survival, although this was not statistically significant (16 deaths in the zoledronic acid group vs 26 deaths in the 2 goserelin groups; hazard ratio, 0.595).
The adverse effects of zoledronic acid were acceptable and were as expected, Dr. Gnant said. In particular, there were no confirmed cases of jaw osteonecrosis and no cases of renal failure or any signal of renal toxicity, despite monitoring of creatinine clearance.
“Adjuvant treatment with zoledronic acid should be considered in order to improve the standard of care in premenopausal breast cancer patients,” Dr. Gnant concluded.
Breast cancer expert Eric Winer, MD, from Harvard Medical School, in Boston, Massachusetts, who moderated the press conference at which the results were presented, agreed that zoledronic acid should now be considered an appropriate therapy. He emphasized, however, that the results apply only to the patient population in this trial — premenopausal women with endocrine-responsive early breast cancer who have undergone ovarian suppression with goserelin and who are receiving endocrine treatment. This is the standard of care (with tamoxifen) in about one third of premenopausal breast cancer patients, he explained to journalists. Another third are treated with endocrine therapy without goserelin, and the last third are treated with chemotherapy and tamoxifen.
The benefit of zoledronic acid was seen only in the first third of these patients, and in this group it is appropriate therapy, Dr. Winer said. He said he would be prepared to discuss the option of zoledronic acid with patients in the other 2 groups, “but at this moment I would discourage it.” When pressed, however, he added that he would “not refuse to give it.”
However, when discussing the study in a plenary session, internationally renown breast cancer expert Martine Piccart-Gebhart, MD, PhD, from the Institut Jules Bordet, in Paris, said: “This is not a practice-changing trial — yet!” There are still several questions that need to be answered, and there is a need for confirmation from other trials “before we can recommend widespread use of zoledronic acid in routine care,” she said. “I am convinced that we have to wait.”
This is not a practice-changing trial — yet!
However, it is an important trial, Dr. Piccart-Gebhart commented, because it is causing a paradigm shift in our approach, showing us that we need to target both “the seed and the soil.”
The magnitude of the benefit seen with zoledronic acid was “substantial,” she commented. However, this benefit was seen mainly in women who were taking the aromatase inhibitor, not the tamoxifen. She also pointed out that after 5 years, fewer than 10% of the enrolled women (137 of the 1803 participants) had experienced an event, so results from a longer follow-up are still needed. More results with zoledronic acid in breast cancer could be available soon; an interim analysis from the ongoing BIG 1-04 AZURE trial of 3349 women is due to be released this summer.
However, another expert, Linda Vahdat, MD, from Weill Cornell Medical College, in New York, New York, commented that the data on zoledronic acid are “compelling and are potentially practice-changing.” Discussing the trial at a “Highlights of the Day” session, Dr. Vahdat agreed that further data from ongoing trials are needed, but, she said: “If you have a patient with early breast cancer at high risk of relapse, then I would consider adding a bisphosphonate sooner rather than later.”
No Difference Between Anastrozole and Tamoxifen
The other main finding from the ABCSG-12 trial was that there was no significant difference in disease-free survival between the anastrozole and the tamoxifen groups. “This is an important finding,” commented Dr. Winer, because it shows that tamoxifen is an appropriate standard of care in premenopausal women with early breast cancer. The advantage of aromatase inhibitors over tamoxifen that has been seen in postmenopausal women does not appear to carry over into premenopausal women, he said. However, there were fewer potentially life-threatening adverse events with anastrozole; in particular, there were fewer cases of uterine polyps and thromboembolic events, Dr. Gnant pointed out.
But the way to compare aromatase inhibitors with tamoxifen in premenopausal women is still unclear, said Dr. Piccart-Gebhart. The ABCSG-12 trial was underpowered to answer this question. Results are needed from ongoing studies, such as the BIG 2-02 SOFT trial, which is comparing tamoxifen alone with an LHRH agonist and tamoxifen and with an LHRH agonist and another aromatase inhibitor, exemestane (Aromasin, Pfizer), and the BIG 3-02 study, which is comparing an LHRH agonist plus tamoxifen with an LHRH agonist and exemestane.
One important take-home message from the ABCSG-12 study, Dr. Winer continued, is that premenopausal women with early breast cancer do very well without chemotherapy. In this trial, 98% of women were alive after 5 years. He emphasized that these women had a favorable prognosis and a favorable outcome. This shows a change in practice; not too many years ago, all premenopausal women with breast cancer were treated with chemotherapy, he said.
The reassuring outcome from this trial adds to ongoing evidence that premenopausal women with early breast cancer who are at low or intermediate risk can be treated without chemotherapy, Dr. Gnant commented.
The ABCSG trial was an academic trial, and was investigator initiated, but it received support from AstraZeneca and Novartis, Dr. Gnant explained.
American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstract LBA4. Presented June 1, 2008.
Reviewed by Ramaz Mitaishvili, MD
