Oral Bisphosphonates and Improved Survival of Breast Cancer

Rennert, Gad; Pinchev, Mila; Gronich, Naomi; Saliba, Walid; Flugelman, Anath; Lavi, Idit; Goldberg, Hadassah; Fried, Georgeta; Steiner, Mariana; Bitterman, Arie; Landsman, Keren

doi:10.1158/1078-0432.ccr-16-0547

Cited by 43 publications

(24 citation statements)

References 46 publications

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“…Several randomized clinical trials have investigated the efficacy of oral bisphosphonates for preventing AIBL (Table 2) [85], [86], [87], [88], [89], [90], [104], [105]. Because of the complex trial designs of some of these studies, the numbers of patients randomized to AI therapy alone versus AI therapy plus bisphosphonate is much smaller than the overall number of patients enrolled.…”

Section: Selecting a Treatment To Prevent Aiblmentioning

confidence: 99%

Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG

Hadji

Aapro

Body

et al. 2017

Journal of Bone Oncology

225

182

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BackgroundSeveral guidelines have been reported for bone-directed treatment in women with early breast cancer (EBC) for averting fractures, particularly during aromatase inhibitor (AI) therapy. Recently, a number of studies on additional fracture related risk factors, new treatment options as well as real world studies demonstrating a much higher fracture rate than suggested by randomized clinical controlled trials (RCTs). Therefore, this updated algorithm was developed to better assess fracture risk and direct treatment as a position statement of several interdisciplinary cancer and bone societies involved in the management of AI-associated bone loss (AIBL).Patients and methodsA systematic literature review identified recent advances in the management of AIBL. Results with individual agents were assessed based on trial design, size, follow-up, and safety.ResultsSeveral fracture related risk factors in patients with EBC were identified. Although, the FRAX algorithm includes fracture risk factors (RF) in addition to BMD, it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL.ConclusionsIn all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score<−2.0 or with a T-score of <–1.5 SD with one additional RF, or with ≥2 risk factors (without BMD) for the duration of AI treatment. Patients with T-score>−1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12 - 24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

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Section: Selecting a Treatment To Prevent Aiblmentioning

confidence: 99%

Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG

Hadji

Aapro

Body

et al. 2017

Journal of Bone Oncology

225

182

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“…The use of oral bisphosphonates (alendronate or risedronate) also improves survival of breast cancer patients 21 . The anti-tumor activity of bisphosphonates is likely mediated through several pathways; one possible pathway is by promoting the anti-tumor activity of γδ T cells.…”

Section: Introductionmentioning

confidence: 99%

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug

Tanaka

Iwasaki

Murata-Hirai

et al. 2017

Sci Rep

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Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.

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“…The EBCTCG meta-analysis on adjuvant use of bisphosphonates concluded there was insufficient evidence for the use of alendronate and risedronate in the adjuvant setting of breast cancer [7]. Nevertheless, non-prospective trials suggest this relationship also exists for these oral bisphosphonates [22,23]. Hopefully, future prospective trials will clarify this matter.…”

Section: Discussionmentioning

confidence: 99%

Breast cancer outcome in relation to bone mineral density and bisphosphonate use: a sub-study of the DATA trial

Hellemond

Smorenburg

Peer³

et al. 2020

Breast Cancer Res Treat

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Purpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. Methods We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan-Meier methods and Cox proportional hazards models were used for analyses. Results Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45-1.49), osteoporosis HR 1.10 (95% CI 0.26-4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40-1.42), osteoporosis HR 1.86 (95% CI 0.43-8.01)]. Moreover, bisphosphonate use did not impact DRFS.Conclusion No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS.Keywords Breast cancer · Tamoxifen · Aromatase inhibitor · Bone health · Osteoporosis · Bisphosphonates · Survival · Bone metastases · Distant recurrence-free survival Part of these results were presented at the poster session of the 2018 San Antonio Breast Cancer Symposium, abstract number 810.

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Oral Bisphosphonates and Improved Survival of Breast Cancer

Cited by 43 publications

References 46 publications

Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG

Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug

Breast cancer outcome in relation to bone mineral density and bisphosphonate use: a sub-study of the DATA trial

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