Anti-tumour effects of bisphosphonates in breast cancer

Breast cancer very commonly metastasizes to bone, often with devastating consequences, including pain, pathological fractures, hypercalcaemia and nerve compression syndromes. Bisphosphonates are very effective in the management of bone secondaries from breast cancer. Recent clinical studies have also suggested that adjuvant oral clodronate in patients with primary breast cancer may confer a survival benefit thereby raising the possibility that bisphosphonates have an anti-tumour effect. The aim of this PhD was to determine whether bisphosphonates have an anti-tumour effect on human breast cancer cells. The potent third generation bisphosphonate, zoledronic acid, was found to reduce cell number and increase apoptosis, mediated by inhibition of the mevalonate pathway, in human breast cancer cells in vitro. The effects on cell apoptosis were shown to be synergistic when zoledronic acid was combined with a chemotherapeutic agent, paclitaxel. To extend the investigation to the in vivo setting, we developed a dual fluorescence labelling technique to isolate apoptotic breast cancer cells from the bone marrow of patients with breast cancer undergoing treatment with intravenous pamidronate or zoledronic acid. The technique was effective at detecting breast cancer cells but studies were inconclusive in determining the effect of intravenous bisphosphonate treatment on breast cancer cell apoptosis in vivo. These studies are ongoing. Bisphosphonates may also alter the bone microenvironment by inhibiting 1 osteoclast-mediated bone resorption and interfering with the release of cytokines and growth factors. To complete these studies, we measured the levels of a panel of cytokines and growth factors in patient serum and bone marrow before and three days after intravenous bisphosphonate treatment and also compared pretreatment levels with those in a baseline group with primary breast cancer. TGFj3-1 was significantly elevated in bone marrow plasma from patients with advanced breast cancer than in patients with primary breast cancer, along with serum IL-6 and sIL-6R. In the advanced breast cancer group, bisphosphonate treatment resulted in significantly lowered levels of serum FGF-2 and bone marrow VEGF. The work presented in this thesis demonstrates that the bisphosphonate zoledronic acid does have anti-tumour effects on breast cancer cells in vitro, both alone and in synergy with paclitaxel, to induce apoptosis. This raises the possibility of in vivo anti-tumour effects in breast cancer. The dual fluorescence labelling technique made it possible to detect breast cancer cells in human bone marrow but the studies regarding the in vivo induction of apoptosis in breast cancer cells following intravenous bisphosphonate treatment were inconclusive. There were significant differences in bone-derived growth factors between patients with primary breast cancer and secondary bone metastases. There was also a significant reduction in certain cytokines and growth factors in the bone marrow and serum after intravenous bisphosphonate treatment, suggesting that bisphosphonates may also exert an indirect effect on the bone marrow microenvironment. Further in vivo studies in patients with breast cancer are required to confirm both the direct anti-tumour effects and indirect effects

Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin

ObjectivesTo assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first‐line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.Patients and methodsFrom 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double‐blind, placebo‐controlled randomised Phase II trial, receiving six 21‐day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m2 days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression‐free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention‐to‐treat and per‐protocol analyses were used to analyse the primary endpoint.ResultsThe 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65–1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79–2.52; P = 0.88); and radiological response rates were 50% and 55%.ConclusionThere is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first‐line treatment in patients with UC who were unfit for cisplatin

Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID)

Purpose: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. Patients and Methods: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. Results: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. Conclusion: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias

Anti-tumour effects of bisphosphonates in breast cancer

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Improved Disease Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer.: Final Results of the POUT Trial

POUT was a phase III, randomised, open-label trial, including 261 patients with muscle-invasive or lymph-node positive, non-metastatic upper tract urothelial cancer (UTUC) randomly assigned following radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups respectively, at median follow-up 65 months. Five-year DFS was 62% vs 45%, univariable HR=0.55 (95% CI 0.38-0.80, p=0.001). Restricted mean survival time (RMST) was 18 months longer (95% CI 6-30m) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms respectively. Five-year OS was 66% vs 57%, univariable HR=0.68 (0.46-1.00, p=0.049) and RMST difference 11m (1-21m). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Small Renal Cell Carcinomas after Image-Guided Cryoablation or Radio-Frequency Ablation

There is a lack of cheap and effective biomarkers for the prediction of renal cancer outcomes post-image-guided ablation. This is a retrospective study of patients with localised small renal cell cancer (T1a or T1b) undergoing cryoablation or radiofrequency ablation (RFA) at our institution from 2003 to 2016. A total of 203 patients were included in the analysis. In the multivariable analysis, patients with raised neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) pre-operatively, post-operatively and peri-operatively are associated with significantly worsened cancer-specific survival, overall survival and metastasis-free survival. Furthermore, an increased PLR pre-operatively is also associated with increased odds of a larger than 25% drop in renal function post-operatively. In conclusion, NLR and PLR are effective prognostic factors in predicting oncological outcomes and peri-operative outcomes; however, larger external datasets should be used to validate the findings prior to clinical application