Detection of genomic mutations in blood and urine free circulating tumour DNA in patients with inoperable and metastatic lung adenocarcinoma harbouring an EGFR mutation in tissue: a UK pilot study

The development of methodologies to analyse circulating tumour DNA (ctDNA) in the blood or urine of cancer patients provides an invaluable resource that can be used for diagnosis and prognosis and to evaluate response to treatments. Lung cancer has seen in the last years a revolution in treatment strategy with the use of several classes of EGFR inhibitors. However, almost invariably, resistance to such therapies appears. In this paper, we describe a pilot, longitudinal study with 20 patients with confirmed EGFR mutations in tissue biopsy for lung cancer. The objective of the study was to determine whether ctDNA from plasma and/or urine could be used to monitor the EGFR mutational status of patients with confirmed EGFR mutation-positive non-small cell lung cancer (NSCLC) during treatment with EGFR inhibitors. Blood and urine were collected monthly over periods ranging from 6 to 16 months. CtDNA was analysed in each patient for the presence of several known mutations that predispose to resistance to EGFR inhibitors. We have proven that serial monitoring of ctDNA from both plasma and urine is feasible and that patients are willing to participate in this process. We have also shown that longitudinal ctDNA monitoring may detect resistance mutations before the development of radiological and clinical disease progression

Protocol for a prospective observational cohort study collecting data on demographics, symptoms and biomarkers in people with mesothelioma (ASSESS-meso)

Introduction: Mesothelioma is a heterogeneous disease that can be challenging to monitor and prognosticate. ASSESS-meso is a multicentre, prospective, longitudinal observational cohort study of patients with mesothelioma. The primary aim is to describe different clinical phenotypes and investigate predictive and prognostic factors, including biomarkers from blood and pleural fluid. The secondary aim is to provide a resource for future trials and substudies. Methods and analysis: We aim to recruit 700 patients with a histological, cytological or clinicopathological diagnosis of mesothelioma, at any anatomical site (pleural, peritoneal, pericardial, etc). Longitudinal data will be collected, including clinical information, radiological investigations, blood tests and patient-reported outcome measures for breathlessness, chest pain and sweats. Preplanned analyses will use Cox proportional hazards method to evaluate factors associated with survival, linear and logistic regression models to investigate associations with symptoms, and analysis of variance modelling to explore changes in symptoms over time. Ethics and dissemination: Ethical approval has been granted by the Research Ethics Committee South West—Central Bristol (17-SW-0019) and Health Research Authority (IRAS ID 220360). A study steering committee has been established and results will be published OpenAccess in peer-reviewed journals. Trial registration number ISRCTN: 61861764

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial):Study protocol for a randomised controlled trial

Abstract Background Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). Methods Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. Discussion The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. Trial registration ISRCTN Registry, ISRCTN45536692. Registered on 9 August 2016. EudraCT no. 2015–004433-26

Immunotherapy-related adverse events in real-world patients with advanced non-small cell lung cancer on chemoimmunotherapy: a Spinnaker study sub-analysis

BackgroundThe Spinnaker study evaluated survival outcomes and prognostic factors in patients with advanced non-small-cell lung cancer receiving first-line chemoimmunotherapy in the real world. This sub-analysis assessed the immunotherapy-related adverse effects (irAEs) seen in this cohort, their impact on overall survival (OS) and progression-free survival (PFS), and related clinical factors.MethodsThe Spinnaker study was a retrospective multicentre observational cohort study of patients treated with first-line pembrolizumab plus platinum-based chemotherapy in six United Kingdom and one Swiss oncology centres. Data were collected on patient characteristics, survival outcomes, frequency and severity of irAEs, and peripheral immune-inflammatory blood markers, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII).ResultsA total of 308 patients were included; 132 (43%) experienced any grade irAE, 100 (32%) Grade 1–2, and 49 (16%) Grade 3–4 irAEs. The median OS in patients with any grade irAES was significantly longer (17.5 months [95% CI, 13.4–21.6 months]) than those without (10.1 months [95% CI, 8.3–12.0 months]) (p<0.001), either if Grade 1–2 (p=0.003) or Grade 3–4 irAEs (p=0.042). The median PFS in patients with any grade irAEs was significantly longer (10.1 months [95% CI, 9.0–11.2 months]) than those without (6.1 months [95% CI, 5.2–7.1 months]) (p<0.001), either if Grade 1–2 (p=0.011) or Grade 3–4 irAEs (p=0.036). A higher rate of irAEs of any grade and specifically Grade 1–2 irAEs correlated with NLR <4 (p=0.013 and p=0.018), SII <1,440 (p=0.029 ad p=0.039), response to treatment (p=0.001 and p=0.034), a higher rate of treatment discontinuation (p<0.00001 and p=0.041), and the NHS-Lung prognostic classes (p=0.002 and p=0.008).ConclusionsThese results confirm survival outcome benefits in patients with irAEs and suggest a higher likelihood of Grade 1–2 irAEs in patients with lower NLR or SII values or according to the NHS-Lung score

Synergistic antitumour effects of rapamycin and oncolytic reovirus.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Targeting cancer with reovirus.

There has been increasing interest in oncolytic virotherapy for the treatment of cancer over the past decade. Reovirus is a ubiquitous double-stranded RNA virus that is oncolytic. It has been shown to selectively kill cancer cells in murine, and human models. The mechanism by which reovirus selectively targets and kills cancer cells is slowly being elucidated. Activation of the Ras pathway in transformed cells plays a part in the permissivity of cancer cells to reovirus, in part through the inability of Ras-activated cells to phosphorylate cellular PKR. Our microarray analysis found increased expression of epidermal growth factor receptor (EGFR) in B16 mouse melanoma cells after exposure to reovirus. As EGFR is a component of the Ras pathway, we explored this increased expression and found that in certain cell lines there was an increase in EGFR expression after reovirus exposure both by PCR and western blot analysis. Data is presented looking at the effect of silencing EGFR on cell survival. Early human trials indicate that while reovirus is safe and capable of inducing cancer cell death, single agent activity is likely to be limited. Attention has now focused on combination strategies. We evaluated the combination of reovirus with rapamycin in the B16.F10 murine model of malignant melanoma based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. These include cell cycle arrest, targeting of alternative signalling pathways, and suppression of the antiviral immune response. Rapamycin attenuated viral replication if given prior to or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death. However, we found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. Rapamycin showed no systemic immunomodulation and cell cycle effects of reovirus (increased G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. We also conducted a multicentre, phase 1 dose escalation study designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Patients received 75mg/m2 of docetaxel, day 1, and escalating doses of reovirus up to 3 x 1010 TCID50, day 1-5, every 3 weeks. 25 patients were enrolled, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropaenia was seen in one patient but the maximum tolerated dose was not reached. Antitumour activity was seen with one complete response and 3 partial responses. A disease control rate of 88% was observed. The combination of reovirus and docetaxel was concluded to be safe, with evidence of objective disease responses, and warrants further evaluation in a phase II study at a recommended schedule of 75mg/m2 of docetaxel, 3 weekly and reovirus 3 x 1010 TCID50 day 1-5, every 3 weeks

Protocol for a mixed-method study to inform the feasibility of undertaking a large-scale multicentre study comparing the clinical and patient-reported outcomes of oncoplastic breast conservation as an alternative to mastectomy with or without immediate br

Introduction: Approximately 40% of the 55,000 women diagnosed with breast cancer each year in the UK undergo mastectomy because they are considered unsuitable for standard breast conserving surgery (BCS) due to tumour size or multiple tumour foci. Mastectomy can significantly impact women’s quality of life and only 1 in 4 women currently undergo immediate breast reconstruction (IBR). Level 2 oncoplastic breast conserving surgery (OPBCS) that combine removing the cancer with a range of plastic surgical volume replacement (e.g. local perforator flaps) and volume displacement techniques (e.g. therapeutic mammaplasty) that can extend the role of BCS and may allow some women not suitable for standard BCS to avoid mastectomy. High-quality research to determine whether OPBCS offers a safe and effective alternative to mastectomy +/- IBR is currently lacking. Preliminary work is needed to ensure a future large-scale study is feasible, well-designed and addresses questions important to patients and the NHS. Methods and analysis: Mixed methods will be used to inform feasibility and design of a future large-scale study comparing the clinical and cost-effectiveness of OPBCS and mastectomy +/- IBR. It will have four parts:1.A national practice questionnaire to determine current practice and provision of oncoplastic breast and reconstructive surgery in the UK2.A pilot multicentre prospective cohort study to explore the proportion of patients choosing OPBCS vs. mastectomy; the proportion in whom OPBCS is successful and clinical and patient-reported outcomes of different techniques at 3 and 12-months post-surgery.3.A qualitative interview study to explore patients’ attitudes to different procedures; rationale for decision-making and perceptions of outcomes. 4.Design of the future studyAll centres offering OPBCS and mastectomy in the UK will be invited to participate. Recruitment is planned to commence winter 2020 and continue for 12 months.Ethics and dissemination: The study has ethical approval from the Wales REC 6 National Research Ethics Service (REC Ref 20/WA/0225). Results will be presented at national and international meetings and published in peer-reviewed journals. We will work with patients to develop lay summaries and share these through patient groups and breast cancer charities.Trial registration number: ISRCTN18238549STRENGTHS AND LIMITATIONS OF THIS STUDY •This mixed methods study will determine whether it is possible to undertake a large prospective cohort study directly comparing the clinical and cost-effectiveness of oncoplastic breast conserving surgery and mastectomy with or without breast reconstruction in patients considered suitable for both procedures.•It will determine whether the BREAST-Q core breast cancer modules are an appropriate and meaningful patient-reported outcome measure for use in a future comparative study.•Qualitative interviews will explore patients’ attitudes to different procedures, rationale for decision making and perception of outcomes providing the opportunity to improve informed consent in this group.•Suitability for OPBCS will be assessed by individual surgeons or teams. It is multifactorial with subjective elements and is likely to vary between individuals and centres.•Patients will only be followed up for 12 months and the effects of radiotherapy and any revisional surgery are likely to occur at a later time point