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Sheffield, United Kingdom

Yardley D.A.,Sarah Cannon Research Institute and the Tennessee Oncology PLLC | Brufsky A.,University of Pittsburgh | Coleman R.E.,Sheffield Cancer Research Center | Conte P.F.,University of Padua | And 8 more authors.
Trials | Year: 2015

Background: Triple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-paclitaxel-based regimens (with gemcitabine or carboplatin ± bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer. Trial design: In this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer. Methods: In the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment-naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year) to nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the "winner" of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently-assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1. Discussion: The tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer. Trial registration: ClinicalTrials.gov: NCT01881230. Date of registration: 17 June 2013. © 2015 Yardley et al. Source

Kroep J.R.,Leiden University | Charehbili A.,Leiden University | Coleman R.E.,Sheffield Cancer Research Center | Aft R.L.,University of Washington | And 9 more authors.
European Journal of Cancer | Year: 2016

Purpose The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. Methods Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (PCRb) and in the breast and lymph nodes (PCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. Results PCRb and PCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase PCRb or PCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the PCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the PCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. Conclusion This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on PCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC. © 2015 The Authors. Published by Elsevier Ltd. Source

Hofbauer L.C.,TU Dresden | Rachner T.D.,TU Dresden | Coleman R.E.,Sheffield Cancer Research Center | Jakob F.,Orthopaedic Center for Musculoskeletal Research
The Lancet Diabetes and Endocrinology | Year: 2014

Skeletal lesions are a frequent complication of breast and prostate cancer and a hallmark of multiple myeloma. Endocrine and paracrine factors modulate various aspects of bone metastases, including tumour proliferation, skeletal susceptibility to tumour homing, the microenvironment needed to support tumour persistence, and the initiation of a vicious cycle between tumour and bone-resident cells that further promotes tumour growth. Endocrine changes, such as oestrogen or vitamin D deficiency, contribute to a fertile bone microenvironment that might promote bone metastases. Bone health could be impaired further by existing cancer treatments, especially sex hormone deprivation. In this Review, we discuss the effect of hormones and associated local factors on cross-talk between bone metabolism and tumour biology. We review the biology of osteolytic and osteosclerotic lesions, with a focus on endocrine aspects, and outline potential therapeutic targets. We also summarise endocrine aspects of the pathogenesis and clinical presentation of bone metastases and provide an update on existing and future treatments. © 2014 Elsevier Ltd. Source

Brown J.E.,St Jamess Hospital | Coleman R.E.,Sheffield Cancer Research Center
Nature Reviews Clinical Oncology | Year: 2012

Elucidation of the molecular pathways underlying bone turnover has revealed potential therapeutic targets, including receptor activator of nuclear factor-κB ligand (RANKL), which is a mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL. This agent has been developed for use in patients with early-stage and advanced-stage cancer, as well as for the treatment of osteoporosis, and can prevent bone loss and reduce fragility fractures in both types of disease. In the bone metastasis setting, several large phase III studies have shown that denosumab is more effective than bisphosphonates, namely zoledronic acid, in reducing skeletal morbidity arising from a wide range of tumors. In addition, a remarkable activity of denosumab has been demonstrated in giant-cell tumors of the bone. Subsequent studies of denosumab have demonstrated that it can delay bone metastasis in patients with castration-resistant prostate cancer; adjuvant studies in patients with breast cancer are in progress. This Review critically explores the emerging role of denosumab in maintaining bone health in the oncology setting, and discusses the factors that are likely to influence the choice between bisphosphonates and denosumab in clinical practice. © 2012 Macmillan Publishers Limited. All rights reserved. Source

Gregory W.M.,University of Leeds | Twelves C.J.,University of Leeds | Bell R.,Deakin University | Smye S.W.,University of Leeds | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2016

We designed a mathematical model to describe and quantify the mechanisms and dynamics of tumor growth, cell-kill and resistance as they affect durations of benefit after cancer treatment. Our aim was to explore how treatment efficacy may be related to primary tumor characteristics, with the potential to guide future trial design and appropriate selection of therapy. Assuming a log-normal distribution of both resistant disease and tumor doubling times generates disease-free survival (DFS) or invasive DFS curves with specific shapes. Using a multivariate mathematical model, both treatment and tumor characteristics are related to quantified resistant disease and tumor regrowth rates by allowing different mean values for the influence of different treatments or clinical subtypes on these two log-normal distributions. Application of the model to the CALGB 9741 adjuvant breast cancer trial showed that dose-dense therapy was estimated to achieve an extra 3/4 log of cell-kill compared to standard therapy, but only in patients with more rapidly growing ER-negative tumors. Application of the model to the AZURE trial of adjuvant bisphosphonate treatment suggested that the 5-year duration of zoledronic acid was adequate for ER-negative tumors, but may not be so for ER-positive cases, with increased recurrences after ceasing the intervention. Mathematical models can identify different effects of treatment by subgroup and may aid in treatment design, trial analysis, and appropriate selection of therapy. They may provide a more appropriate and insightful tool than the conventional Cox model for the statistical analysis of response durations. © 2016, The Author(s). Source

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