Ruth M. O’Regan, MD
Amye J. Tevaarwerk, MD
The oncology community has now conducted several prospectively designed, hypothesis-driven randomized clinical trials among women with breast cancer to address this question: Do adjuvant bisphosphonates decrease the risk of breast cancer bone metastases and other recurrence? A meta-analysis1 by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) pooling data from more than 18,000 women from ABCSG-12,2 AZURE,3 and 24 other trials demonstrated significant benefits for the use of adjuvant bisphosphonates in early-stage breast cancer. However, these benefits were confined to postmenopausal women, with significant reductions in recurrence (relative risk [RR] = 0.86, 95% confidence interval [CI] = 0.78–0.94, 2P = .002), distant recurrence (RR = 0.82, 95% CI = 0.74–0.92, 2P = .0003), and breast cancer mortality (RR = 0.82, 95% CI = 0.73–0.93, 2P = .002). These findings were independent of bisphosphonate class, treatment schedule, estrogen receptor status, nodes, tumor grade, or concomitant chemotherapy. No differences were seen in non–breast cancer mortality.
Given the EBCTCG meta-analysis combined with the known benefits to bone health (an important complication of endocrine therapy among postmenopausal breast cancer patients), the medical oncology community has faced the question of whether or not to routinely recommend bisphosphonates in the adjuvant setting. As reported by Dhesy-Thind and colleagues and reviewed in this issue of The ASCO Post, a Cancer Care Ontario and ASCO joint expert panel issued a clinical practice guideline to begin addressing this dilemma.4
Uncertain Benefits of Recommendation
The guideline applies to all postmenopausal women with stage I to III breast cancer who are otherwise candidates for adjuvant systemic therapy. This encompassing recommendation is regardless of risk, receptor status, and whether patients are postmenopausal for years at diagnosis or rendered postmenopausal by medical or surgical therapy. This guideline will mean discussing adjuvant bisphosphonates with a healthy 53-year-old postmenopausal woman with T2-N0 hormone receptor–positive breast cancer. Genomic assays can now inform us that such a woman has a low risk of distant recurrence at 10 years, provided she takes 5 years of endocrine therapy. The addition of adjuvant bisphosphonates for such patients might yield at most a further 1% to 2% absolute reduction in the risks of distant recurrence and cancer mortality. This raises the specter of overtreatment, given such small absolute benefits.
These benefits become even less certain when we consider we are operating based on post-hoc analyses of the primary trials. For instance, the primary endpoint of AZURE was not met, but further analyses suggested that benefit from adjuvant bisphosphonates might accrue to women who had been in menopause for more than 5 years. On the other hand, ABCSG-12 showed benefit for the addition of zoledronic acid to endocrine therapy but was conducted exclusively among premenopausal women rendered postmenopausal by ovarian function suppression. Most of the women (78.7%) included in the EBCTCG meta-analysis received adjuvant chemotherapy.
Given the time ranges for starting bisphosphonates in the included trials, chemotherapy would have largely overlapped the bisphosphonate. Receipt of chemotherapy may simply be a surrogate for higher- risk patients. However, an undefined interaction between adjuvant chemotherapy and bisphosphonates might drive benefit, given we lack a clear mechanism for adjuvant bisphosphonate benefit (although the EBCTCG meta-analysis indicates a similar degree of benefit regardless of chemotherapy receipt).
Choice of Agent, Safety, Dosing
Zoledronic acid and clodronate are deemed the recommended agents, with the authors noting the current limitations surrounding denosumab. Clodronate has not been studied specifically in patients receiving aromatase inhibitors (the most common endocrine therapy utilized in this postmenopausal population) and has not been approved by the U.S. Food and Drug Administration in the United States. For the United States, the guideline means choosing between zoledronic acid infusions vs no adjuvant bisphosphonate. Fortunately, zoledronic acid is now available generically and thus is potentially cost-effective5; nevertheless, it will be interesting to see how insurance coverage for adjuvant bisphosphonates plays out.
The guideline is unlikely to help busy clinicians and patients parse out the nuanced potential benefits and may contribute to an ‘all-or-nothing’ approach.— Ruth M. O’Regan, MD and Amye J. Tevaarwerk, MD
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The safety profile of zoledronic acid is well characterized and includes rare but serious complications such as osteonecrosis of the jaw, renal dysfunction, and atypical femoral fracture due to abnormal bone formation.6 Due to pushback against overuse of bisphosphonates for osteopenia, much of the readily available patient information regarding bisphosphonates prominently emphasizes these risks. It is worth noting the relative paucity of data with respect to the health consequences in the distant future (eg, 3 or 4 decades from now) for breast cancer patients who would receive adjuvant bisphosphonates in their 30s or 40s (if rendered postmenopausal as in SOFT/TEXT7 or ABCSG-12). Furthermore, prevention of osteonecrosis of the jaw relies on preventive dental health, but as many as one in five Americans may be unable to afford dental coverage.8
The guideline does provide a recommended dose, interval, and duration for treatment with zoledronic acid, based on the existing studies: 4 mg intravenously every 6 months for 3 to 5 years. It does not specifically state a time range for consideration of starting adjuvant bisphosphonates. However, ABCSG-12 enrolled patients within 8 weeks (56 days) of surgery,9 whereas AZURE allowed 60 days between the start of adjuvant bisphosphonate and definitive surgery.10 Thus, to adhere to the studies as closely as possible, the discussion of adjuvant bisphosphonates should occur early, when patients may be considering a potentially daunting array of treatment options including currently open clinical trials. This begs the following question: When is it too late to start bisphosphonates, if the primary purpose is to reduce the risk of recurrence rather than to promote bone health?
Practice Implications
More work clearly remains to be done in elucidating the mechanism by which adjuvant bisphosphonates may benefit postmenopausal woman. An assay that predicted benefit or lack thereof would allow tailoring of treatment for patients most likely to benefit. We applaud the efforts of the expert panel to direct us to some standardization with respect to practice surrounding adjuvant bisphosphonates. The guideline will serve to remind oncologists to consider adjuvant bisphosphonates. However, it is unlikely to help busy clinicians and patients parse out the nuanced potential benefits and may contribute to an “all-or-nothing” approach. ■
DISCLOSURE: Dr. O’Regan reported no conflicts of interest. Dr. Tevaarwerk reported a family member working for Epic Care Systems.
Dr. O’Regan is Division Head of Hematology and Oncology in the Department of Medicine, University of Wisconsin School of Medicine and Public Health, and Dr. Tevaarwerk is Associate Professor, Division of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health.
References:
1. Early Breast Cancer Trialists’ Collaborative Group: Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials. Lancet 386:1353-1361, 2015.
2. Gnant M, Mlineritsch B, Stoeger H, et al: Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: Final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 26:313-320, 2015.
3. Coleman R, Cameron D, Dodwell D, et al: Adjuvant zoledronic acid in patients with early breast cancer: Final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15:997-1006, 2014.
4. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al: Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: A Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 35:2062-2081, 2017.
5. Lamond NW, Skedgel C, Rayson D, et al: Cost-utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels. Curr Oncol 22:e246-e253, 2015.
7. Regan MM, Pagani O, Fleming GF, et al: Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: Design of the TEXT and SOFT trials. Breast 22:1094-1100, 2013.
8. Bloom B, Simile CM, Adams PF, et al: Oral health status and access to oral health care for U.S. adults aged 18-64: National Health Interview Survey, 2008. Vital Health Stat 10:1-22, 2012.
9. Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679-691, 2009.
10. Coleman RE, Marshall H, Cameron D, et al: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:1396-1405, 2011.
