Are adjuvant bisphosphonates now standard of care of women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New Updates meeting.
ABSTRACT: The 9th Bone and the Oncologist New Updates conference was held in Ottawa, Canada during 2014. This annual meeting focuses on innovative research into the mechanisms and consequences of treatment-induced and metastatic bone disease. Given the recent presentation of the Oxford overview's "Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials" at the San Antonio Breast Cancer Symposium, a debate as to the pro's and con's of adjuvant bisphosphonate use in early stage breast cancer was undertaken. As bisphosphonate treatment in post-menopausal women appeared to demonstrate a similar magnitude of benefit to that of other commonly used adjuvant strategies the debate assessed whether or not there was sufficient data to incorporate adjuvant bisphosphonates into standard practice and if so, in which patient populations.
Project description:Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory responses to bisphosphonates and Toll-like receptor (TLR) agonists, we hypothesized that TLR9 expression may affect bisphosphonate responses in cells. We compared bisphosphonate effects in breast cancer cell lines with low or high TLR9 expression. We discovered that cells with decreased TLR9 expression are significantly more sensitive to the growth-inhibitory effects of bisphosphonates in vitro and in vivo. Furthermore, cancer growth-promoting effects seen with some bisphosphonates in some control shRNA cells were not detected in TLR9 shRNA cells. These differences were not associated with inhibition of Rap1A prenylation or p38 phosphorylation, which are known markers for bisphosphonate activity. However, TLR9 shRNA cells exhibited increased sensitivity to ApppI, a metabolite that accumulates in cells after bisphosphonate treatment. We conclude that decreased TLR9-expression sensitizes breast cancer cells to the growth inhibitory effects of bisphosphonates. Our results suggest that TLR9 should be studied as a potential biomarker for adjuvant bisphosphonate sensitivity among breast cancer patients.
Project description:Bisphosphonates are the gold standard for preventing skeletal-related events in patients with bone-metastatic cancer and have been investigated for reducing cancer treatment-induced bone loss. Evidence suggests bisphosphonates also offer anticancer benefits in adjuvant and advanced cancer settings. We conducted a retrospective analysis of data from a single-center, unselected cohort of women with early breast cancer (N=1646: 962 received adjuvant bisphosphonates, 684 did not) to assess the impact of bisphosphonates on disease-free and overall survival. The bisphosphonate group comprised all women who started bisphosphonate treatment within 1 year of breast cancer diagnosis and received ?3 months of bisphosphonate treatment (zoledronic acid, clodronate, ibandronate, or alendronate; majority received zoledronic acid). Disease-free survival was defined as the time from breast cancer diagnosis until first disease recurrence or death. Treatment groups were balanced for cancer stage, hormone receptor expression, and human epidermal growth factor receptor-2 expression. Patients in the no-bisphosphonate group were more likely to be ?75 years of age, node-negative, and have histologic grade 3 tumors. In patients treated with adjuvant bisphosphonates, disease-free survival was significantly longer than in those who did not receive bisphosphonates (P=0.0017). Both disease-free and overall survival were significantly longer in patients with hormone receptor-positive disease irrespective of lymph node status (disease-free survival: P=0.0038; overall survival: P<0.0026). No significant disease-free survival difference was detected in patients with hormone receptor-negative disease. This large, retrospective study demonstrates a significant survival benefit with adjuvant bisphosphonates in patients with early breast cancer, particularly in patients with node-positive and hormone receptor-positive disease.
Project description:Introduction: Bisphosphonates are well known above all for their use in the treatment of osteoporosis. They also play an important role as accompanying therapy for advanced tumour diseases with extensive spread into the skeletal system. Their adjuvant use in the treatment of breast cancer without bony metastases is currently a subject of controversial discussion. The objective of the present evaluation is to describe the use of bisphosphonates in the therapy for breast cancer. We will show how frequently bisphosphonates are used, which bisphosphonates are preferred and what specific features patients under bisphosphonate therapy exhibit. Methods and Materials: The pseudonymous data set from the biobank of the German PATH foundation was used for the evaluation. From the total collective, 2492 patients were selected after consideration of the inclusion and exclusion criteria. The selected patient collective was divided into two groups (with and without bisphosphonate therapy) and the two groups compared with one another with the help of descriptive statistics. Results: 17.5?% of the 2492 patients had prescriptions for a bisphosphonate as part of their therapy. The most frequently administered bisphosphonate was zoledronate. Pathological (induced by tumour therapy) osteoporosis was the most frequently stated indication among the bisphosphonate patients, followed by consumption starting prior to the breast cancer therapy and treatment of bony metastases. Patients under bisphosphonate and antihormonal therapy frequently received an aromatase inhibitor as the active principle in the antihormonal therapy whereas patients under antihormonal therapy but without bisphosphonates more frequently received tamoxifen as active principle. Ten of the 2492 patients reported receiving bisphosphonate therapy as prophylaxis for bony metastases without a documented and approved indication. Use of bisphosphonates in the course of the GAIN, ICE, SUCCESS or, respectively, NATAN trials was reported by 29 of the 2492 patients. Conclusions: In the PATH collective, bisphosphonates were employed above all for the treatment of (tumour therapy-induced) osteoporosis and bony metastases. Off-label use and participation in clinical trials played only a minor role in this patient collective. Against the background of the uncertain data status for the adjuvant use of bisphosphonates, the development (and use) of standardised, validated questionnaires to record the indications for and frequency of use of bisphosphonate therapy is recommended.
Project description:The 6th annual Bone and the Oncologist New Updates conference was held in Ottawa, Ontario, April 14–15, 2011. This meeting traditionally focuses on innovative research into the mechanisms and consequences of treatment-induced and metastatic bone disease. This year, the multidisciplinary audience was polled to produce “treatment recommendations for the use of bone-targeted agents.” In addition, the meeting report itself outlines some of the key topics presented on adjuvant bisphosphonate use and the role of bone-targeted agents in the settings of meta-static and cancer-therapy-induced bone loss.
Project description:Bisphosphonates are approved for treating malignant bone disease from advanced cancer because they are effective inhibitors of osteoclast-mediated bone resorption. However, there may be a greater role for the use of bisphosphonates than has previously been considered. There is a large body of preclinical evidence showing that bisphosphonates exert a variety of direct and indirect anticancer activities that affect both tumor cells and the surrounding microenvironment, and that stimulate immune reactions. Recent data from clinical trials have shown that adding the bisphosphonate zoledronate to endocrine therapy or chemotherapy improves disease-free survival of patients with endocrine-responsive early breast cancer in a low estrogen environment (that is, following ovarian suppression therapy or in women with established menopause at diagnosis). Adjuvant treatment with the bisphosphonate clodronate also improves disease-free survival in postmenopausal breast cancer. Additionally, zoledronate was found to prolong survival in patients with symptomatic multiple myeloma or other advanced cancers. Here, we present an overview of preclinical and clinical studies that demonstrate anticancer benefits of bisphosphonates, and we discuss potential mechanisms of action that might be responsible for the anticancer activity of bisphosphonates in the clinic.
Project description:PURPOSE:Bisphosphonates and denosumab prevent bone complications in patients with bone metastases from solid tumours. This retrospective, longitudinal, cohort study provides data on their real-world use in this setting in Germany. METHODS:Adults with bone metastases from breast, prostate or lung cancer who were newly initiated on a bisphosphonate or denosumab between 1 July 2011 and 31 December 2015 were identified from a German healthcare insurance claims database. Primary outcomes included persistence, compliance, discontinuation and switch rates at 12 months. RESULTS:This study included 1130 patients with bone metastases: 555 (49%) had breast cancer, 361 (32%) prostate cancer and 242 (21%) lung cancer. Mean age was 65 years for patients with breast or lung cancer and 74 years for those with prostate cancer. Across all tumour types, compared with any bisphosphonate, 12-month persistence was higher with denosumab (breast cancer 78% vs 54-58%, prostate cancer 58% vs 50%, lung cancer 68% vs 34-60%), median time to discontinuation was longer with denosumab and switch rates were lower for denosumab (breast cancer 5% vs 14-19%, prostate cancer 2% vs 11%, lung cancer 3% vs 7-12%). Compliance at 12 months was longer for denosumab than for any bisphosphonate in breast cancer (75% vs 42-48%) and in prostate cancer (47% vs 36%). CONCLUSIONS:Patients initiated on denosumab following a diagnosis of bone metastases from breast, prostate or lung cancer had greater medication persistence, longer time to discontinuation, improved compliance and lower switch rates than those initiated on a bisphosphonate.
Project description:BACKGROUND:Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS:Patients with stage I-III breast cancer were randomly assigned to 3?years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS:A total of 6097 patients enrolled. Median age was 52.7?years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P?=?.49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P?=?.50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P?=?.93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS:We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
Project description:Endo180 (CD280; MRC2; uPARAP)-dependent collagen remodelling is dysregulated in primary tumours and bone metastasis. Here, we confirm the release and diagnostic accuracy of soluble Endo180 for diagnosing metastasis in breast cancer (BCa).Endo180 was quantified in BCa cell conditioned medium and plasma from BCa patients stratified according to disease status and bisphosphonate treatment (n=88). All P-values are from two-sided tests.Endo180 is released by ectodomain shedding from the surface of MCF-7 and MDA-MB-231 BCa cell lines. Plasma Endo180 was significantly higher in recurrent/metastatic (1.71±0.87; n=59) vs early/localised (0.92±0.37; n=29) BCa (P<0.0001). True/false-positive rates for metastasis classification were: 85%/50% for the reference standard, CA 15-3 antigen (28 U ml(-1)); ?97%/?36% for Endo180; and ?97%/?32% for CA 15-3 antigen+Endo180. Bisphosphonate treatment was associated with reduced Endo180 levels in BCa patients with bone metastasis (P=0.011; n=42). True/false-positive rates in bisphosphonate-naive patients (n=57) were: 68%/45% for CA 15-3 antigen; ?95%/?20% for Endo180; and ?92%/?21% for CA 15-3 antigen+Endo180.Endo180 is a potential marker modulated by bisphosphonates in metastatic BCa.
Project description:Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.
Project description:Numerous observational studies suggest that bisphosphonates reduce mortality. This study showed that bisphosphonate use is associated with lower mortality within days of treatment, although the association was not significant until the second week. Such an early association is consistent with confounding, although an early treatment effect cannot be ruled out. INTRODUCTION:The purpose of this study was to examine whether confounding explains why numerous observational studies show that bisphosphonate use is associated with lower mortality. To this end, we examined how soon after treatment initiation a lower mortality rate can be observed. We hypothesized that, due to confounding, the association would be observed immediately. METHODS:This was a retrospective cohort study of hip fracture patients discharged from Swedish hospitals between 1 July 2006 and 31 December 2015. The data covered 260,574 hip fracture patients and were obtained from the Swedish Hip Fracture Register and national registers. Of the 260,574 patients, 49,765 met all eligibility criteria and 10,178 were pair matched (bisphosphonate users to controls) using time-dependent propensity scores. The matching variables were age, sex, diagnoses, prescription medications, type of hip fracture, type of surgical procedure, known or suspected dementia, and physical functioning status. RESULTS:Over a median follow-up of 2.8 years, 2922 of the 10,178 matched patients died. The mortality rate was 7.9 deaths per 100 person-years in bisphosphonate users and 9.4 deaths in controls, which corresponded to a 15% lower mortality rate in bisphosphonate users (hazard ratio 0.85, 95% confidence interval 0.79-0.91). The risk of death was lower in bisphosphonate users from day 6 of treatment, although the association was not significant until the second week. CONCLUSION:Bisphosphonate use was associated with lower mortality within days of treatment initiation. This finding is consistent with confounding, although an early treatment effect cannot be ruled out.