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The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

ABSTRACT: Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04-5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55-12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78-3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42-3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17-1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.

SUBMITTER: Ferreira A

PROVIDER: S-EPMC5173066 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

Ferreira Arlindo A Alho Irina I Vendrell Inês I Melo Marta M Brás Raquel R Costa Ana Lúcia AL Sousa Ana Rita AR Mansinho André A Abreu Catarina C Pulido Catarina C Macedo Daniela D Pacheco Teresa T Correia Lurdes L Costa Luis L Casimiro Sandra S

Oncotarget 20160701 27

Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequenc ...[more]

PMID: 27191503

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Project description:Skeletal metastases are an incurable complication afflicting the majority of patients who die from advanced breast cancer. They are most often osteolytic, characterized by net bone destruction and suppressed new bone formation. Life expectancy from first diagnosis of breast cancer bone metastases is several years, during which time skeletal-related events - including pain, fracture, hypercalcemia, and spinal cord compression - significantly degrade quality of life. The bone marrow niche can also confer hormonal and chemo-resistance. Most treatments for skeletal metastases target bone-destroying osteoclasts and are palliative. Recent results from the Breast cancer trials of Oral Everolimus-2 trial suggest that agents such as the mammalian target of rapamycin inhibitor everolimus may have efficacy against breast cancer bone metastases in part via stimulating osteoblasts as well as by inhibiting tumor growth. Selective estrogen receptor modulators similarly inhibit growth of estrogen receptor-positive breast cancers while having positive effects on the skeleton. This review discusses the future role of bone-anabolic agents for the specific treatment of osteolytic breast cancer metastases. Agents with both anti-tumor and bone-anabolic actions have been tested in the setting of multiple myeloma, a hematological malignancy that causes severe osteolytic bone loss and suppression of osteoblastic new bone formation. Stimulation of osteoblast activity inhibits multiple myeloma growth - a strategy that might decrease breast cancer burden in osteolytic bone metastases. Proteasome inhibitors (bortezomib and carfilzomib) inhibit the growth of myeloma directly and are anabolic for bone. Drugs with limited anti-tumor activity but which are anabolic for bone include intermittent parathyroid hormone and antibodies that neutralize the WNT inhibitors DKK1 and sclerostin, as well as the activin A blocker sotatercept and the osteoporosis drug strontium ranelate. Transforming growth factor-beta inhibitors have little tumor antiproliferative activity but block breast cancer production of osteolytic factors and are also anabolic for bone. Some of these treatments are already in clinical trials. This review provides an overview of agents with bone-anabolic properties, which may have utility in the treatment of breast cancer metastatic to the skeleton.

Project description:Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone.The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases.The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the potential of metabolomic profiles for risk assessment and early detection and the signalling pathways controlling the metastatic tumour microenvironment. There is substantial synergy between the four projects and it is hoped that this integrated program of research will advance our understanding of key aspects of bone metastases from breast cancer to improve the prevention, prediction, detection, and treatment of these lesions.

Project description:BackgroundTo assess prognostic and predictive effects of clinical and biochemical factors in our published randomized study of a weekly low dose (metronomic arm) versus a conventional dosage of zoledronic acid (conventional arm) in breast cancer patients with bone metastases.MethodsTreatment outcome of 60 patients with bone metastases were used to assess impacts of following potential prognostic factors, estrogen receptor status, lymph node status, 2 year-disease free interval (DFI), numbers of chemotherapy regimens administered, interventions, and serum levels of VEGF, N-telopeptide of type I collagen (NTx), CEA, and CA 15-3.ResultsIn univariate analyses, patients pretreated with 2 or fewer chemotherapy regimens, ER-positive tumors, 3 or fewer lymph nodes, DFI of more than 2 years, serum VEGF of less than 500 pg/mL after 3 months of intervention, serum CEA and CA 15-3 of less than ULN, and baseline serum NTx of less than 18 nM BCE had significantly longer progression free survival (PFS). The multivariate analysis showed that ER positivity (hazard ratio [HR], 0.295; 95% confidence interval [CI], 0.141-0.618; P = 0.001), serum VEGF of less than 500 pg/mL after 3 months of intervention (HR, 2.220; 95% CI, 1.136-4.338; P = 0.020), baseline serum NTx of less than 18 nM BCE (HR, 2.842; 95% CI, 1.458-5.539; P = 0.001), and 2 or fewer chemotherapy regimens received (HR, 7.803; 95% CI, 2.884-21.112; P = 0.000) were associated with a better PFS. When evaluating the predictive effect of the biochemical factors, an interaction between NTx and zoledronic acid intervention was shown (P = 0.005). The HR of weekly low dose versus a conventional dosage of zoledronic acid was estimated to be 2.309 (99% CI, 1.067-5.012) in patients with baseline serum NTx of more than 18 nM BCE, indicating a superiority of weekly low dose of zoledronic acid.ConclusionsER, serum VEGF level after intervention, and numbers of chemotherapy regimens administered are prognostic but not predictive factors in breast cancer patients with bone metastases. Patients with baseline serum NTx of more than 18 nM BCE might benefit more from weekly low-dose of zoledronic acid.Trial registrationClinicalTrials.gov unique identifier: ClinicalTrials.gov: NCT00524849.

Dataset Information

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

Publications

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

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