An update to a joint guideline from Cancer Care Ontario (now a division of Ontario Health) and ASCO provides revised recommendations for the use of adjuvant bone-modifying agents for patients with nonmetastatic breast cancer, with the overarching goal of improving relapse and survival rates.1,2
Catherine H. Van Poznak, MD
“This update was focused on answering three important questions,” said Expert Panel Co-Chair Catherine H. Van Poznak, MD, of the University of Michigan. “Who should be considered for treatment with an adjuvant bone-modifying agent? Which bisphosphonate regimens are favored? What is the role of adjuvant denosumab?”
New Data on Adjuvant Bone-Modifying Agents in Breast Cancer Spur Update
The need for updated guidance on using bone-modifying agents in the adjuvant setting resulted from the publication of findings from four recent randomized clinical trials: ABCSG-18, D-CARE, SWOG S0307, and SUCCESS A.3-6 These trials offer new data on the use of adjuvant denosumab and bisphosphonates and were all ongoing at the time the original guideline was released in 2017. The panel thought the studies had the potential to impact clinical decision-making.
Andrea Eisen, MD
“The previous version of the guideline also relied heavily on the conclusions of the Early Breast Cancer Trialists’ Collaborative Group meta-analysis, whereas updated and new data were available for this version,” added Expert Panel Co-Chair Andrea Eisen, MD, of Sunnybrook Odette Cancer Centre, Toronto. “In addition, it was evident from our review that access to adjuvant bisphosphonates is variable. For example, oral formulations are not available in all jurisdictions, and in the United States, intravenous bisphosphonates are not widely covered by insurance plans. This provided another rationale for updating the original guideline.”
The panel, comprising an international, interdisciplinary team, conducted a targeted systematic literature review, which yielded pertinent and potentially practice-changing data leading to the guideline revision. The panel concentrated on the use of bone-modifying agents for nonmetastatic breast cancer. In this disease site, bone-modifying agents typically consist of bisphosphonates (oral or intravenous) and denosumab.
Data also revealed that postmenopausal women—the most appropriate patient population for these agents—of any hormone receptor status and HER2 status are most likely to benefit, with clinical trials indicating modest improvements in survival. As such, the updated guideline recommends oncologists discuss bisphosphonate therapy with all postmenopausal patients but notes these agents should be used only in conjunction with, and not in place of, standard anticancer treatments.
The panel suggests oncologists use a risk-stratified approach, such as the National Health System’s PREDICT tool, to identify the most appropriate candidates and help clinicians weigh the potential benefits vs harms for adjuvant bisphosphonate therapy among women with nonmetastatic invasive disease.7
Regarding which bisphosphonates to use, the updated guideline identifies three therapeutic options—oral clodronate, oral ibandronate, and zoledronic acid—and emphasizes the importance of patient input when selecting a treatment, as the agents’ availability and toxicity profiles vary.
Finally, the panel recommends against the use of adjuvant denosumab, as evidence is conflicting from the two largest randomized trials of its impact on survival outcomes (ABCSG-18 and D-CARE).3,4
Building the Evidence Base for Future Recommendations
To help build a more robust foundation of evidence for future guidelines and updates, the panel also highlighted areas of needed research. They include studies to ascertain whether particular biomarkers might identify patient populations that could most likely derive benefit from bone-modifying agents, as well as whether some patients are more likely to benefit from a particular bone-modifying agent regimen.
“Research is needed to identify patient subgroups that are most likely to benefit from adjuvant bisphosphonate therapy. Similarly, treatment toxicities need further study, as does the financial burden of these treatments,” Dr. Van Poznak said. “Additionally, most of the bisphosphonate studies to date have used high-dose therapy for 2 to 5 years. There is now an interest in studying regimens of lower intensity.”
Despite the current knowledge gaps in this area, both Dr. Van Poznak and Dr. Eisen expressed cautious optimism that the guideline could help more patients benefit from bone-modifying agents as a safe and effective adjunctive treatment option in the adjuvant setting.
“We hope this updated guidance will enable wider access to intravenous bisphosphonates,” Dr. Eisen said. “But the degree to which they are practice changing depends on the jurisdiction. In Ontario, where intravenous zoledronic acid is publicly funded and available, there has been uptake across the province, even though it is not extremely high. So, we hope this new guideline might influence uptake and outcomes elsewhere as well, and we plan to study that in the future.”
1. Eisen A, Somerfield MR, Accordino MK, et al: Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: ASCO-OH (CCO) guideline update. J Clin Oncol. January 18, 2022 (early release online).
2. 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.
3. Gnant M, Pfeiler G, Steger GG, et al; Austrian Breast and Colorectal Cancer Study Group: Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): Disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:339-351, 2019.
4. Coleman R, Finkelstein DM, Barrios C, et al: Adjuvant denosumab in early breast cancer (D-CARE): An international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 21:60-72, 2020.
5. Gralow JR, Barlow WE, Paterson AHG, et al: Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307. J Natl Cancer Inst 112:698-707, 2020.
6. Friedl TWP, Fehm T, Müller V, et al: Prognosis of patients with early breast cancer receiving 5 years vs 2 years of adjuvant bisphosphonate treatment: A phase 3 randomized clinical trial. JAMA Oncol 7:1149-1157, 2021.
7. National Health System: Predict Breast Cancer. Available at https://breast.predict.nhs.uk/. Accessed February 15, 2022.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, December 23, 2021. All rights reserved.