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Bisphosphonates improve breast cancer survival in postmenopausal women
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Adjuvant treatment with bisphosphonates reduced the rate of breast cancer recurrence in the bone and improved breast-cancer survival among women who were postmenopausal at treatment initiation, according to the results of a meta-analysis.
“Currently, bisphosphonates are mainly used to reduce bone loss and fractures in postmenopausal women and to reduce bone complications in advanced cancer patients,” Robert Coleman, MBBS, MD, FRCP, professor of medical oncology at University of Sheffield, said in a press release.
Since bisphosphonates affect bone physiology, they may also affect bone metastases, according to study background.
Coleman and colleagues of the Early Breast Cancer Trialists’ Collaborative Group conducted a meta-analysis of individual patient data from all unconfounded randomized, controlled early breast cancer trials that evaluated bisphosphonates to clarify the risks and benefits of adjuvant bisphosphonate treatment for breast cancer.
The meta-analysis included data from 18,766 women who participated in 32 completed trials that recorded recurrence data. Ninety-seven percent of women (n = 18,206) participated in trials that evaluated 2 to 5 years of bisphosphonates.
Recurrence, distant recurrence and breast cancer mortality served as the primary endpoints. The researchers also conducted primary subgroup analyses for site of first distance recurrence (bone or other), menopausal status (premenopausal or postmenopausal) and bisphosphonate class (aminobisphosphonate or other).
After a median follow-up of 5.6 woman-years, the researchers observed 3,453 first recurrences and 2,106 deaths from breast cancer.
A statistically significant reduction in bone recurrence occurred among women assigned bisphosphonates (RR = 0.83; 95% CI, 0.73-0.94).
Further, researchers observed borderline significant reductions in recurrence (RR = 0.94; 95% CI, 0.87-1.01), distant recurrence (RR = 0.92; 95% CI, 0.85-0.99) and breast cancer mortality (RR = 0.91; 95% CI, 0.83-0.99) with bisphosphonates.
When researchers stratified women according to menopausal status, the benefits associated with bisphosphonates did not persist among premenopausal women. However, postmenopausal women (n = 11,767) treated with bisphosphonates appeared at a significantly reduced risk for recurrence (RR = 0.86; 95% CI, 0.78-0.94), distant recurrence (RR = 0.82; 95% CI, 0.74-0.92), bone recurrence (RR = 0.72; 95% CI, 0.6-0.86) and breast cancer mortality (RR = 0.82; 95% CI, 0.73-0.93).
However, even for bone recurrence, the heterogeneity of benefit barely reached significance by age (P = .03) and did not reach significance by menopausal status (P = .06 for trend), bisphosphonate class, treatment schedule, ER status, nodes, tumor grade or concomitant chemotherapy.
Non–breast cancer mortality did not differ among women who did and did not receive bisphosphonates; however, women who received bisphosphonates experienced fewer bone fractures (RR = 0.85; 95% CI, 0.75-0.97).
“Our results show that adjuvant bisphosphonates in postmenopausal women prevent around a quarter of bone recurrences and one in six of all breast cancer deaths in the first decade of treatment,” Coleman said. “These simple, well-tolerated treatments should now be considered for routine use in the treatment of early breast cancer in women with either a natural or medically induced menopause to both extend survival and reduce the adverse effects of cancer treatments such as the aromatase inhibitors on bone health.”
These data may support the widespread use of bisphosphonates for postmenopausal women with breast cancer, Adam M. Brufsky, MD, PhD, professor of medicine and associate chief of hematology and oncology at University of Pittsburgh Medical Center and Cancer Institute and a HemOnc Today Editorial Board member, and Aju Mathew, MD, MPhil, hematology and medical oncology fellow at University of Pittsburgh Medical Center and Cancer Institute, wrote in an accompanying editorial.
Adam M. Brufsky
“This landmark report on breast cancer treatment should lead to widespread adoption of bisphosphonates as a standard of care for the adjuvant therapy of early-stage breast cancer in postmenopausal women,” Brufsky and Mathew wrote. “Bisphosphonates, in one form or another, are generic and relatively inexpensive in most parts of the world. The toxic effects of these agents are relatively mild (ie, gastrointestinal upset, arthralgias and very uncommon osteonecrosis of the jaw). All bisphosphonates appear to be effective, as long as they are given for at least 2 years. Given their low cost, relatively low toxicity and OS benefit, widespread use of adjuvant bisphosphonates for postmenopausal breast cancer has great potential to reduce mortality from this disease further.”
These study findings also may further the biological understanding of cancer, Brufsky and Mathew wrote.
“This apparent success in altering the natural history of breast cancer by modifying the tumor microenvironment lends great credence to investigational efforts in breast cancer and other cancers attempting to understand and modify tumor–host microenvironmental interactions,” they wrote. – by Cameron Kelsall
Disclosure: The Early Breast Cancer Trialists’ Collaborative Group is funded by Cancer Research U.K. and U.K. Medical Research Council grants to the Clinical Trial Service Unit. Coleman reports personal fees for expert testimony from Novartis. Brufsky reports personal fees from Novartis and Thar Pharmaceuticals and stock ownership in Thar Pharmaceuticals. Mathew reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to TopKaren Lisa Smith, MD, MPH
Randomized studies evaluating adjuvant bisphosphonate therapy for early-stage breast cancer have yielded conflicting results. Interpretation is difficult due to different patient selection criteria, endpoints, types and schedules of bisphosphonate treatment, and inadequate power for subgroup analyses in trials to date. However, results from the AZURE and ABCSG-12 studies led to the hypothesis that anticancer benefit of adjuvant bisphosphonate therapy is limited to postmenopausal women. Although the mechanism is uncertain, data suggest that bisphosphonates may be beneficial in a low-estrogen environment.The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a meta-analysis of 26 trials evaluating adjuvant bisphosphonate therapy using individual patient data. For the study population as a whole, adjuvant bisphosphonate therapy was associated with borderline-significant small reductions in 10-year risks for distant recurrence (20.4% vs. 21.8%) and breast cancer mortality (16.6% vs. 18.4%), with the effect on distant recurrence largely explained by a statistically significant reduction in the 10-year risk for bone recurrence with bisphosphonate therapy (7.8% vs. 9%). A planned subgroup analysis by menopausal status revealed the benefit of adjuvant bisphosphonate therapy was limited to postmenopausal women. For this group, there was a 2.2% reduction in the 10-year risk for bone recurrence (6.6% vs. 8.8%) and a 3.3% reduction in the 10-year risk for breast cancer mortality (14.7% vs. 18%) with adjuvant bisphosphonate therapy. There were no differences in the effect of adjuvant bisphosphonate therapy according to other clinical features such as ER or nodal status, or according to type, duration or schedule of bisphosphonate therapy.
These data can be interpreted as evidence supporting the use of adjuvant bisphosphonate therapy for postmenopausal women with early-stage breast cancer. But, are these data truly practice changing?
The main limitation of this meta-analysis is that the key findings pertain only to a subgroup: postmenopausal women. Results of subgroup analyses have a higher risk for type I error (false-positive) in the setting of a true-negative trial and are usually not considered practice changing. An additional limitation of the currently available data is that the optimal bisphosphonate, schedule and duration of therapy are not defined. Data from the ongoing SWOG S0307 study comparing three adjuvant bisphosphonate therapies are expected to clarify the optimal regimen, however this study is limited by the lack of a control arm.
Despite its limitations, the magnitude of benefit observed with adjuvant bisphosphonate therapy in postmenopausal women in this meta-analysis is similar to that of other adjuvant breast cancer treatments. Moreover, adjuvant bisphosphonate therapy is relatively cheap, accessible and nontoxic.
Many questions remain about adjuvant bisphosphonate therapy, making clinical decisions challenging at this time. However, as more women pursue adjuvant ovarian function suppression given results of the SOFT and TEXT trials, physicians will likely face the decision of whether to offer adjuvant bisphosphonate therapy more frequently. Hopefully, future studies will better clarify the impact of adjuvant bisphosphonate therapy on breast cancer outcomes and identify biomarkers to guide patient selection.
But, we must make decisions using currently available data. I believe the current evidence is sufficient for physicians to consider having an informed discussion about the data supporting adjuvant bisphosphonate therapy and its limitations with appropriate postmenopausal patients. The potential benefit from this intervention needs to be placed within the context of each individual patient’s risk for recurrence, bone density, risk factors for loss of bone density (such as adjuvant aromatase inhibitor therapy), anticipated side effects and desires.
References:
Francis P, et al. N Engl J Med. 2015;doi:10.1056/NEJMc1502618.Gnant M, et al. Lancet Oncol. 2011;doi:10.1016/S1470-2045(11)70122-X.
Pagani O, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1404037.
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