Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer

Strobl, Stephanie; Wimmer, Kerstin; Exner, Ruth; Devyatko, Yelena; Bolliger, Michael; Fitzal, Florian; Gnant, Michael

doi:10.1007/s11864-018-0535-z

Cited by 12 publications

(7 citation statements)

References 60 publications

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“…Both agents can be added to systemic therapy to prevent accelerated bone loss and reduce the risk of skeletal-related events in cases in which cancer treatment leads to decreased bone density and/or estrogen levels . Several clinical trials have shown that bisphosphonates maintain bone mass and prevent skeletal-related adverse events in women with breast cancer (BC) receiving adjuvant therapy …”

Section: Introductionmentioning

confidence: 99%

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

et al. 2021

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IMPORTANCEBisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear.OBJECTIVE To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer. DESIGN, SETTING, AND PARTICIPANTSThe SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014. Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size Ն pT2, histologic grade 3, negative hormone receptor status, or age Յ35 years) primary invasive breast cancer.INTERVENTIONS Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years). MAIN OUTCOMES AND MEASURESThe primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis).RESULTS Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P = .81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P = .90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%). CONCLUSIONS AND RELEVANCEThe results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced.

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Section: Introductionmentioning

confidence: 99%

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

et al. 2021

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“…15,24 Use of bisphosphonate showed a protective effect against bone loss in this cohort study, and it was consistent with the previous studies. [25][26][27] Menopausal status had a significance in only DBMD L1-L4 in this present study. Premenopausal women showed larger difference in DBMD L1-L4 than postmenopausal women.…”

Section: Discussionmentioning

confidence: 53%

Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history

Lee

Kim

et al. 2021

Science Progress

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As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. Bone health has become more compelling in care of breast cancer survivor than ever before. This retrospective study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up. Records of 164 women who underwent surgery for breast cancer were reviewed in this study. The basal characteristics included parity, menopausal state, medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), gonadotrophin releasing hormone agonist (GnRHa), chemotherapy, radiotherapy, cancer type including positivity of estrogen receptor, progesterone receptor and HER2, combined the other gynecologic disease or the other origin cancer. At initial and follow-up visit, all subjective were checked with BMD, endometrial thickness (EMT). The mean age was 52.1 ± 8.5 years old and overall interval between initial and follow-up visits were 17.6 ± 7.5 month in this study. The BMDs of L1–4 (1.040 ± 0.166 g/cm2 vs 1.070 ± 0.181 g/cm2, p < 0.001), femur neck (0.850 ± 0.121 g/cm2 vs 0.870 ± 0.136 g/cm2, p < 0.001), and femur total (0.902 ± 0.132 g/cm2 vs 0.915 ± 0.138 g/cm2, p < 0.001) at follow-up visit were significantly lower than those at initial visit. The change in BMDs of L1–4 ( ΔBMDL1–4, r = 0.353, p < 0.001, and r = 0.228, p = 0.003), femur neck ( ΔBMDNeck, r = 0.198, p = 0.011, and r = 0.282, p < 0.001), femur total ( ΔBMDTotal, r = 0.294, p < 0.001, and r = 0.327, p < 0.001) had positive correlation with age and the change in EMT ( ΔEMT). After age correction, ΔEMT had positive correlation with ΔBMDNeck ( r = 0.245, p = 0.002) and ΔBMDTotal ( r = 0.273, p < 0.001). ΔBMDL1–4 and ΔBMDNeck differed according to menopausal state ( p < 0.001 and p = 0.035), bisphosphonate ( p < 0.001 and p < 0.001), and GnRHa ( p < 0.001 and p < 0.001). In follow-up of women with history of breast cancer, ΔEMT could be an alternative screening marker for BMD decrease.

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“…Because we observed a significant increase in pro-osteolytic genes in breast cancer cells treated with entinostat, and bisphosphonates are FDA-approved for metastatic breast cancer and improve survival for postmenopausal patients with breast cancer, (27,28) we investigated whether combination of entinostat with bisphosphonate would prevent the progression of bone metastases and prevent bone loss caused by panobinostat in the bone metastatic setting. Mice were inoculated with MDA-MB-231b cells by intracardiac injection, given one dose of the bisphosphonate zoledronic acid the next day, and treated with entinostat or panobinostat for 4 weeks.…”

Section: Combination Treatment Of Entinostat or Panobinostat With Bis...mentioning

confidence: 99%

Select HDAC Inhibitors Enhance Osteolysis and Bone Metastasis Outgrowth but Can Be Mitigated With Bisphosphonate Therapy

et al. 2023

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Breast cancer has a high predilection for spreading to bone with approximately 70% of patients who succumb to disease harboring bone disseminated tumor cells. Despite this high prevalence, treatments for bone metastatic breast cancer predominantly manage morbidities, including pain and hypercalcemia, rather than reducing bone metastasis incidence or growth. Histone deacetylase inhibitors (HDACi), including panobinostat, entinostat, and valproic acid, typically slow primary tumor progression and are currently in clinical trials for the treatment of many cancers, including primary and metastatic breast cancer, but their effects on bone metastatic disease have not been examined in preclinical models. We report that treatment with the HDACi panobinostat, but not entinostat or valproic acid, significantly reduced trabecular bone volume in tumor-naïve mice, consistent with previous reports of HDACi-induced bone loss. Surprisingly, treatment with entinostat or panobinostat, but not valproic acid, increased tumor burden and incidence in an experimental model of breast cancer bone metastasis. In vitro, multiple HDACi stimulated expression of proosteolytic genes in breast tumor cells, suggesting this may be a mechanism by which HDACi fuel tumor growth. In support of this, combination therapy of panobinostat or entinostat with the antiresorptive bisphosphonate zoledronic acid prevented bone metastatic progression; however, the addition of zoledronic acid to panobinostat therapy failed to fully correct panobinostat-induced bone loss. Together these data demonstrate that select HDACi fuel bone metastatic growth and provide potential mechanistic and therapeutic avenues to offset these effects.

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Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer

Cited by 12 publications

References 60 publications

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment

Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history

Select HDAC Inhibitors Enhance Osteolysis and Bone Metastasis Outgrowth but Can Be Mitigated With Bisphosphonate Therapy

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