Bisphosphonate (Zoledronic Acid=Zometa) Improves Adjuvant Endocrine Therapy for Pre-menopausal Breast Cancer Patients; Ongoing CORT Study Assesses Bisphosphonates in Adjuvant Therapy in Broader Groups of Patients

Here is the ASCO (American Society of Clinical Oncology) News Post regard the Zoledronic Acid (Zometa) study presented at the ASCO 2008 Annual Meeting, demonstrating improved outcomes for pre-menopausal breast cancer patients receiving adjuvant endocrine therapy:

Zoledronic Acid Added to Endocrine Therapy Improves Outcome for Premenopausal Patients with Early Breast Cancer

 

Zoledronic acid has been found to increase disease-free survival by 36% and relapse-free survival by 35% for premenopausal patients who received adjuvant endocrine therapy for early breast cancer (Abstract LBA4). Michael Gnant, MD, of the Medical University of Vienna, Austria, presented the data on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) during Sunday’s Plenary Session. Adjuvant endocrine therapy with ovarian suppression is used as an effective alternative to standard cytotoxic chemotherapy for premenopausal patients with endocrine-responsive breast cancer. ABCSG-12 is the first study to compare endocrine suppression with goserelin plus tamoxifen to goserelin plus an aromatase inhibitor (anastrozole). Adjuvant bisphosphonate therapy (zoledronic acid) was included in two of the four treatment arms both to mitigate the marked bone loss associated with complete ovarian suppression and to explore whether the antitumor effects demonstrated previously in preclinical and clinical settings might translate into a longer time to disease recurrence and improved survival. The study was a randomized, open-label, phase III, modified 2×2, four-arm trial of oral tamoxifen and goserelin with or without zoledronic acid compared with oral anastrozole and goserelin with or without zoledronic acid for 3 years. The primary endpoint of this trial was disease-free survival for the 903 patients who received anastrozole compared with the 900 patients who received tamoxifen. Secondary endpoints included overall survival and the effect of the treatments on local-regional relapse. The effect of treatment on bone metastasis-free survival was considered to be an exploratory endpoint. At a median follow-up of 60 months, overall 5-year disease-free survival was 94% and overall survival was 98.2%. No difference in disease-free survival was detected among patients who received tamoxifen and those patients who received anastrozole. There was no advantage in relapse-free or overall survival rates for anastrozole over tamoxifen. In the analysis of zoledronic acid, the bisphosphonate improved the primary endpoint of disease-free survival (hazard ratio [HR] = 0.643, p = 0.011). The incidences of contralateral breast cancer, distant metastases, and local-regional recurrence were all reduced by zoledronic acid (six vs. 10 cases, 29 vs. 41 cases, and 10 vs. 20 cases for the group treated with zoledronic acid compared with those patients who were not treated, respectively). Forest plots showed that the effect for all subgroups clustered around the main effect with no interaction. Treatment with zoledronic acid increased relapse-free survival (HR = 0.653, p = 0.014), with a trend toward improvement in overall survival (HR = 0.595, p = 0.101). Zoledronic acid treatment was well tolerated. No renal toxicity or confirmed cases of osteonecrosis of the jaw occurred. Differences in side effects among the tamoxifen and anastrazole groups were seen. Arthralgia, bone pain, and fever were more frequent (all, p < 0.0001) in the anastrozole groups, especially for those patients who received zoledronic acid. The only serious adverse events that reached statistical significance included an increased incidence of uterine polyps (p < 0.0001) and thrombosis (p = 0.012) in the tamoxifen groups. Dr. Gnant noted that differences in efficacy between tamoxifen and anastrozole may not have been detectable because of the effect of goserelin on suppression of ovarian function and that perhaps two large ongoing studies will provide better answers. The Suppression of Ovarian Function Trial (SOFT) has enrolled 3,000 patients, and the Tamoxifen and Exemestane Trial (TEXT) has enrolled 1,845. With regard to zoledronic acid, Dr. Gnant said, “Zoledronic acid significantly improves clinical outcomes beyond those achieved with endocrine therapy alone.” The benefit was seen in and outside of bone (reduction in contralateral breast cancers, local-regional recurrence, and distant nonbone metastases) with acceptable toxicity. Dr. Gnant concluded that adjuvant therapy with zoledronic acid should be considered in order to improve the standard of care for premenopausal women, although the optimal dose, schedule, and treatment duration are yet to be addressed. Discussant Martine J. Piccart-Gebhart, MD, PhD, of Jules Bordet Institute — Université Libre de Bruxelles, Belgium, referred to ABCSG-12 as elegant in design, but also noted some of its limitations: the study was not double-blind, the control arm (goserelin plus tamoxifen for 3 years) is not widely accepted, and there was no stratification for HER2. Another important observation was that the large confidence interval of the hazard ratio for disease-free survival comparing tamoxifen and anastrozole (HR = 1.096; 95% CI; 0.78, 1.53) suggests that this study was not adequately powered to detect a 20% difference between the two drugs. Dr. Piccart-Gebhart noted that the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (Howell A, et al. Lancet. 2005;365[9453]:60-62) and the Breast International Group (BIG) 1-98 (Thurlimann BJ, et al. Abstract 511. Presented at: 2005 ASCO Annual Meeting) were powered to detect a 20% difference in disease-free survival between tamoxifen and an aromatase inhibitor. ATAC required 6,241 patients and 900 events, and BIG1-98 required 4,922 women and 770 events. With regard to the zoledronic acid results, Dr. Piccart-Gebhart suggested that the data illustrate the 1889 “seed and soil” hypothesis of Paget (Paget S. Lancet. 1889;1:571-573), that is, zoledronic acid affects not only malignant cells (the “seed”), but also the tissues in which metastases grow (the “soil”). Dr. Piccart-Gebhart concluded that ABCSG-12 is not yet a practice-changing trial, but an important trial, “announcing a paradigm shift: targeting both seed and soil.” END OF ASCO POST

The SWOG (Southwest Oncology Group) S0307 Study open at CORT continues enrollment.  This study evaluates the addition of one of three bisphosphonate drugs (Zoledronic Acid, Clodronate, or Ibandronate) in adjuvant therapy of breast cancer.  Patients with Stage I-III resected breast cancer are eligible.  They may have received chemotherapy and/or hormonal therapy.   ER+ and ER- patients are eligible.  The study enrolls pre- and post-menopausal patients. 

For more information about this study, call 972-566-5588 (Dallas) or 972-981-4012 (Plano), and ask to speak with a research coordinator.  More information about CORT and CORT studies is available at www.CORTPA.com.

Tags: adjuvant therapy, Breast Cancer, Clodronate, ER+, Ibandronate, S0307, Stage I-III, SWOG, SWOG S0307, zoledronic acid, zometa