Silent theatre 1 – Tuesday 5 November

12:40 pm-2:00 pm

Room: Hall 4


Programme session type(s): Silent theatre

Survival and ‘Cure’ of Acute Myeloid Leukaemia (AML) in Children, Adolescents and Young Adults in England
Speaker: Mae-Yen Tan
Affiliation: University of Glasgow

Abstract:

Acute Myeloid Leukaemia (AML) is one of the most common malignancies among children and young adults. In England, five-year net survival of patients with AML aged 15-24 years increased from 7% to 53% during 1971-2006. The ‘cured’ proportion of these patients also increased substantially during this time period. This study aims to investigate the trends in survival and ‘proportion cured’ for children (aged 0-14), adolescents (aged 15-19) and young adults (aged 20-39) diagnosed with AML in England between 2006 and 2014. 

Method

We report 1- and 5-year net survival using the Pohar-Perme estimator for children, adolescents and young adults between 2006 and 2014. Cure modelling was used to estimate the proportion of patients “cured” during 2006-2014. This is the proportion of patients with no excess mortality compared to the general population.

Results

Between 2006 and 2014, 2216 patients aged 0-39 were diagnosed with AML in England and 855 deaths occurred. Young adults (aged 20-39) had the most dramatic increase in five-year net survival; 10% from the period 2006-2010 to 2011-2014. Adolescents’ (aged 15-19) 1- and 5-year net survival decreased by 6% and 3% respectively. Young adults had the highest increase in proportion ‘cured’ (13.6%) and the largest improvement in median survival of the ‘uncured’ proportion (0.34 years) between 2006 and 2014. Children (aged 0-14) had the highest proportion ‘cured’, and the highest 1- and 5-year net survival in both time periods.

Conclusion

AML in children, adolescents and young adults still remains an elusive disease with hardly any improvement in the last decade. What is of concern is the decrease in net survival among adolescents over the last decade. More research on paediatric AML is needed to discover risk factors and novel treatments to improve outcomes for the children, adolescents and young adults.

Exposure to ionizing radiation elicits significant lung tissue perturbations and creates a tumour-supportive microenvironment
Speaker: Emma Nolan
Affiliation: Francis Crick Institute

Abstract:

Radiation therapy is a treatment modality used for many types of cancer, with almost half of all cancer patients undergoing radiotherapy as part of their treatment plan in the UK. Off-target exposure of healthy tissue to ionizing radiation remains a significant challenge for the treatment of cancer, since it can lead to severe side effects such as lung fibrosis. Importantly, it is also thought to play a role in promoting tumour recurrence and resistance. The aim of this work is to understand how healthy lung tissue responds to radiation-induced injury, and to uncover the mechanisms by which these perturbations can influence fibrosis development and cancer cell behaviour.

Method

Female mice aged 8-12 weeks received targeted lung irradiation at a dose of 13Gy using a collimator attached to the radiation source. Lungs were harvested 7 days after irradiation to assess tissue perturbations. To determine the impact of radiation exposure on metastatic colonization, cancer cells were seeded in sham or pre-irradiated lungs via tail-vein injections or subcutaneous mammary fat-pad injections, and lungs analyzed 7 days later.

Results

Radiation exposure led to significant alterations in the endothelial, epithelial and mesenchymal compartments of the lung, as well as perturbations in the composition of the extracellular matrix. These alterations resulted in a tissue microenvironment that was favourable for cancer cell growth, since a striking increase in metastatic colonization was observed in irradiated lungs. Notably, the induction of the tissue response and the subsequent tumour-supportive microenvironment appears to be partly mediated by inflammatory components, with the inhibition of these components reducing metastatic burden in irradiated lungs.

Conclusion

The striking perturbations detected in radiation-exposed lungs could have implications for patient response, particularly the formation of a tumour-supportive environment. Importantly, the influence of inflammatory components on this process raises the possibility of a therapeutic intervention for off-target effects.

Best supportive care (BSC) with or without low-dose chemotherapy (chemo) in frail elderly patients with advanced gastroesophageal cancer (aGOAC): The uncertain randomization of the GO2 phase III trial
Speaker: Daniel Swinson
Affiliation: St James’s University Hospital, Leeds, UK

Abstract:

Trials comparing BSC +/- chemo for aGOAC show overall survival (OS) benefit in predominantly fit patients (pts). We have revisited this question using low-dose chemo in a frail population, with comprehensive baseline health and frailty assessment.

Method

Elderly and/or frail aGOAC pts were randomised between 3 chemo doses. In this substudy, pts with an “uncertain” indication for chemo were instead randomised to BSC ± the lowest dose chemo. Both pt and clinician considered the indication for chemo uncertain, eGFR ≥30 and bili < 2xULN were required. Baseline assessment included globalQL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d1-21 (modified if eGFR 30-50 ml/min or bili 1.5-2.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not pre-set.

 

Results

558 pts entered GO2 at 61 centres 2014-17, 45 pts (8%) at 21 centres entered this uncertain randomisation providing 80% power at p = 0.05 (2-tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p<0.01) or distant mets (p<0.05). OS was not significantly improved with chemo although survival rates were higher after 3 months. QL and fatigue deteriorated less with BSC+chemo than with BSC alone. 

BSC alone BSC + chemo
Pts (deaths) 22(20) 23(17).
Median age 78.5 79
%PS ≥2 68 57
%frail; %very frail 96; 68 91; 70
Mean baseline EQ5D QL (scale 0-1) 0.64 0.61
Median OS mo unadjusted 3.0 6.1
OS adjusted Cox model HR= 0.69 [95%CI: 0.32-1.48], p=0.34
Mean QL@9wks 0.37 0.45

Conclusion

We observed a small non-significant survival benefit with chemo. Clinicians should consider BSC alone a valid treatment option for aGOAC pts with a limited life expectancy. 

CD99 regulation of cancer cell dynamics and tumour formation
Speaker: Adam Odell
Affiliation: York St. John University

Abstract:

Secondary breast cancer carriers the greatest risk to patient life and therapeutic targeting of metastasis remains a prominent novel anti-cancer strategy. During metastasis, tumour cells cross endothelial cell barriers via mechanisms akin to extravasating leukocytes, utilising numerous cell surface molecules in the process. CD99 is one such molecule capable of modifying leukocyte transendothelial migration (TEM). However, CD99 is also expressed by tumour cells, suggesting a potential role for this molecule in tumour progression and cancer TEM.

Method

We used RNA interference to deplete CD99 protein from human breast cancer (MDA-MB-231) and primary endothelial (HUVECs) cells. Tumour-endothelial cell interactions and cytoskeletal dynamics were analysed in vitro, using fluorescence microscopy, live cell imaging and impedance-based analyses. CDC42 activity was determined using pull down assays with PAK1 coated beads and immunoblotting. Angiogenesis assays were performed in vitro using co-cultures models. For tumour progression studies, we used a mouse tail vein injection xenograft model with luciferase-expressing MDA-MB-231 cells, complemented by expression analysis of publicly available breast cancer databases.

Results

Breast cancer cell lines expressed moderate to high levels of CD99 protein and tumour cell CD99 was required for cancer cell adhesion to the endothelium. However, the presence of tumour cell CD99 impeded the subsequent TEM of breast cancer cells. Depletion of tumour cell CD99 was associated with cytoskeletal remodelling and increased activity of the Rho family GTPase, CDC42. For endothelial cells, loss of CD99 also increased activity of CDC42, while enhancing endothelial barrier function and reducing tumour cell TEM. Importantly, normal CD99 expression inhibited metastatic breast cancer progression to the lungs in vivo. Furthermore, in patients, we found reduced CD99 expression was associated with metastasis.

Conclusion

Cell surface CD99 negatively regulates the activity of the Rho family GTPase CDC42 in both breast cancer and endothelial cells. For tumour cells, loss of CD99 favours CDC42 activity, TEM and tumour progression. In endothelial cells, CD99 loss strengthened endothelial junctions while reducing tumour cell adhesion and TEM. As a key signal transduction hub, CDC42 activity influences numerous hallmarks of cancer. The functional link between CD99 and CDC42 implicates CD99 in regulating these diverse pathways through alterations in cytoskeletal remodelling.

Mapping Cellular Subpopulations within Triple Negative Breast Tumors Provides a Tool for Cancer Sensitization to Radiotherapy
Speaker: Ariel M. Rubinstein
Affiliation: Hebrew University of Jerusalem

Abstract:

Radiation therapy (RT), which emerged more than a century ago, continues to be a key modality in the treatment and management of various types of cancer. Recent studies have shown that irradiation not only kills the cancer cells but also promotes anti-apoptotic and pro-proliferative responses. Cancer researchers search for overexpression of oncogenic druggable targets that can sensitize a tumor response to RT. However certain cancer types, such as triple negative breast cancer (TNBC), did not allow for the development of targeted strategy due to tremendous inter- and intra-tumor heterogeneity. Not a single targeted therapy has been approved for the treatment of TNBC, thus chemotherapy (CT) and radiation (RT) remain the standard TNBC treatment over the past 20 years.

Method

We propose a novel concept according to which TNBC sensitization to RT can be rationally-designed based on resolution of patient-specific intra-tumor subpopulations that emerge in response to RT treatment. The computational strategy we developed resolves the intra-tumor protein expression heterogeneity, measured by flow cytometry at the single cell level, and allows to break down a tumor into distinct subpopulations and the altered protein networks associated with each subpopulation. More specifically, a set of altered protein-protein correlation subnetworks is computed in each cell, namely cell specific signaling signature, which is used to divide the tumor mass into intra-tumor subpopulations.

Using mice models and patient derived TNBC tumors we show that two distinct subpopulations expanded in response to RT.  We demonstrate that simultaneous targeting of central proteins representing those subpopulations, Her2 and cMet, was essential in order to sensitize TNBC to RT and stop its growth. The presented strategy can be broadly applicable.

Results

Conclusion

Addressing the variation in adjuvant chemotherapy treatment for colorectal cancer (CRC): can a regional intervention promote national change?
Speaker: Daniel Swinson
Affiliation: St James’s University Hospital, Leeds, UK

Abstract:

Analysis of routine population-based data has previously shown that surgery for patients with rectal cancer can vary widely. Through access to the Systemic Anti-Cancer Treatment (SACT) database we have quantified variation in adjuvant chemotherapy across England and in detail across a large representative region (Yorkshire and Humber).

Method

National Cancer Registry and Analysis Service (NCRAS) provided data on individuals aged ≥18 years with stage II and III CRC who underwent major resection from 01/01/14 – 31/03/16. Chemotherapy data was obtained from the SACT dataset. Rates of chemotherapy were calculated from multilevel mixed logistic regression and adjusted for age, sex, socioeconomic status, Charlson comorbidity index score and stratified by tumour stage and site. A questionnaire addressing different clinical scenarios was sent to oncologists across the region.

Results

The national adjusted chemotherapy treatment rate ranged from 2% to 43% & from 19% to 80% for patients with stage II and stage III cancers. Larger variation was seen for rectal than colon cancer, 10% to 70% vs 14% to 60%. Similar variation was seen in region and across subgroups.

 

Percentage received chemotherapy

Percentage of treated received combination-chemotherapy

Stage

Stage II

Stage III

5% – 28%

41% – 73%

0% – 63%

45% – 79%

Site

Colon

Rectal

27% – 47%

17% – 59%

31% – 72%

30% – 87%

Age

Age<70

Age≥70

33% – 68%

12% – 38%

48% – 91%

9% – 63%

Prior radiotherapy

No

Yes

20% – 58%

14% – 80%

29% – 100%

0% – 85%

A regional questionnaire obtained responses from 15 of 16 MDTs. Widest variation in opinions were observed for high risk stage II patients both with deficient and proficient mismatch repair tumours and stage IIIB patients over the age of 70.

Conclusion

Variation is seen across England in the use of adjuvant chemotherapy. Open discussion in our region has enabled consensus agreement on an algorithm for colon cancer, with one pending for rectal cancer.

High-content Profiling in Oesophageal Adenocarcinoma Identified Selectively Active Compounds for Repurposing and Novel Drug Discovery
Speaker: Rebecca Hughes
Affiliation: University of Edinburgh

Abstract:

Oesophageal adenocarcinoma (OAC) is a highly heterogeneous disease, driven by copy number alterations and large-scale genomic rearrangements. Such characteristics have hampered both therapeutic target discovery and success of targeted therapies in the clinic. We describe a phenotypic-led drug discovery platform using a multiparametric high-content profiling assay to identify active compounds and classify drug mechanism-of-action (MoA) across a panel of OAC cell lines as a novel strategy for discovery of new therapeutic targets and repurposing existing drug classes for OAC.

Method

We prioritized a panel of six OAC lines that represent the genetic diversity of OAC, a pre-neoplastic Barret’s oesophagus line, and a non-transformed squamous oesophageal line. We applied Cell Painting, a multiplexed fluorescent dye assay to profile the phenotypic response of the cell lines to 20,000 small molecules and approved drugs. We trained a machine-learning (ML) model to predict MoA using phenotypic fingerprints from a library of reference compounds covering distinct mechanistic classes.

Results

From a subset of 3,000 approved drugs we have validated 46 compounds following dose-response confirmation. Clustering the phenotypic response to these molecules identified a number of phenotypic clusters enriched with similar pharmacological classes. We identified the drug Methotrexate and three other dihydrofolate reductase (DHFR) inhibitors as highly selective for the OAC lines compared to the Barrett’s and normal lines. In addition, the approved HDAC inhibitors, Belinostat, Panobinostat and Quisinostat demonstrate potent activity on OAC cell lines. Multiparametric phenotypic dose response profiles of the DHFR inhibitors cluster with DNA damaging agents and ML predicts them to be DNA damaging agents while the HDAC inhibitors cluster with several other HDAC inhibitors. We further identify a number of compound from our diverse chemical library which show potent and selective activity for OAC cells and which do not cluster with the reference library of known MoA, indicating they may be targeting novel oesopahageal cancer biology.

Conclusion

Integration of the phenotypic data with genetic data across our panel of diverse cell lines and proteomic and transcriptomic pathway analysis, pre- and post-treatment, are ongoing and may provide further insight into drug selectively and the basis for future biomarker-based clinical trials in OAC.

Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
Speaker: Emma Minihane
Affiliation: Babraham Institute

Abstract:

BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably leads to disease progression. Despite increasing the abundance of the pro-apoptotic BIM and BMF proteins, ERK1/2 pathway inhibition is predominantly cytostatic reflecting residual pro-survival BCL2 family activity.

Method

Results

Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the novel MCL1 inhibitor AZD5991, driving tumour cell death and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-XL inhibitors is typically stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL-XL/BCL2 inhibitors. Death induced by inhibition of ERK1/2-plus-MCL1 is BAK/BAX-dependent and requires BIM and BMF. Finally, AZD5991 delays acquired BRAFi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi-plus-MEKi resistance.

Conclusion

Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

Avoidable harm: making decisions about chemotherapy with advanced lung cancer patients
Speaker: Annamarie Nelson
Affiliation: Marie Curie Palliative Care Research Centre, Cardiff University, School of Medicine, Cardiff

Abstract:

Most non-small cell lung cancer (NSCL) patients that present with metastatic disease are unsuitable for curative treatment and many receive chemotherapy for symptom control. Some of these patients will die on, or within 30 days, of chemotherapy.

Method

The PACT study was a five stage, multi-site qualitative study (n=97) using multiple methodologies to observe how decisions around treatment in NSCLC are made. Observations of multidisciplinary team (MDT) meetings, patient consultations, and interviews with patients and oncologists tracked the treatment decision-making process. Mediated discourse, thematic, framework and narrative analysis were used to analyse the data.

Results

At MDT meetings, patients were not fully visible because patients’ social information were limited and varied between sites. MDT members constructed treatment recommendations mainly around patient pathology, clinical information and imaging. Information on the priorities and preferences of patients was not formally integrated into the oncology consultation. With a rapid disease trajectory, the health of the patient might change significantly. This placed additional stress on the oncologist, who had to re-evaluate the patients, with the potential need to consider a different treatment option to that suggested at the MDT.

Patients did not understand the decision-making purpose of the oncology consultation and focused on relationships, placing their disease in the context of everyday life. For the patient, the treatment context was focused on external priorities, such as being able to attend a special family event, prior understanding and experience of particular treatments, and existing relationships with health professionals, such as the chest physician.

Conclusion

The NHS seeks to place patients’ needs, wishes and preferences at the heart of clinical decision-making; however, the current pathway for NSCLC patients focuses on clinical management at the expense of patient-centred care. Future work will test the feasibility of applying a patient-held communication tool at the different stages of the patient pathway.

Socio-demographic variation in routes to diagnosis in head and neck cancer: a population-based analysis
Speaker: Jennifer Deane
Affiliation: Newcastle University

Abstract:

Patients with HNC are often diagnosed at a late stage. Some HNC symptoms can present in seemingly benign way and this may influence how and where patients present and progress through the health system. This study aimed to investigated which patient-related factors were associated with two distinct routes to diagnosis: (i) emergency presentation and (ii) for patients who presented through primary care, two week wait (2ww).

Method

Data was analysed for patients diagnosed with a primary invasive HNC (ICD10 C01-14, C31-32) during 2006 – 2014. Multivariable logistic modelling assessed factors influencing the route taken, comparing (i) emergency presentation with all other routes and (ii) 2WW with all other primary care initiated referrals.

Results

68,752 HNC were diagnosed 2006-2014, 8.3% of whom were diagnosed as an emergency and 38.1% through 2ww. Emergency admissions were significantly more likely to be older, non-white, be resident in a more deprived area, and have a cancer elsewhere than in the oral cavity. They were also significantly more likely to be diagnosed with a higher stage and grade cancer. Patients who came through a primary care initiated route were significantly more likely to be a 2WW referral if they were aged 55-64, male, white, more deprived and had an oropharyngeal or larynx cancer. There was a trend over time for an increase in 2WW referrals and a decrease in those diagnosed after an emergency admission.

Conclusion

The results suggest improvements over time in the way people with HNC are diagnosed (i.e. decline in emergency admission and increase in 2WW). However, differences in diagnostic route were found in relation to patients’ socio-demographic characteristics. Effective interventions are needed to change the stage distribution of HNC and outcomes improve. This findings help identify potential problems in the HNC diagnostic pathway and suggest areas for action for policy-makers.

PIK3CA and KRAS co-activation synergise to promote prostate cancer progression
Speaker: Helen Pearson
Affiliation: Cardiff University

Abstract:

Prostate cancer is the fifth cause of cancer­-related deaths in men globally, reflecting resistance to standard clinical regimens(1). Thus, there is an urgent need to improve our understanding of the molecular mechanisms underpinning prostate cancer, and to identify new therapeutic approaches to improve our management of this disease. The PI3K and RAS pathways regulate AKT/mTOR and MAPK signalling to mediate cell growth/survival/migration and are invariably activated in advanced prostate cancer, thus presenting attractive therapeutic targets(2,3). Although oncogenic PI3K/RAS signalling are common in prostate cancer, how these cascades synergise to promote prostate cancer growth remains unclear.

Method

To determine how PI3K/RAS signalling cooperate to accelerate prostate cancer growth in vivo, we employed a conditional transgenic approach to co-activate Pik3ca and KRas in murine prostate epithelium. We compared prostate histopathology/survival relative to single mutants and prostate tumours were comprehensively characterised using molecular assays and chemical inhibition studies performed to delineate the synergistic relationship between PI3K/RAS signalling.

Results

We show that simultaneous expression of oncogenic Pik3ca and KRas mutations in the murine prostate causes rapid formation of locally invasive prostate carcinoma compared to single mutants. We report that the observed synergy is associated with elevated proliferation and apoptosis evasion, which is not simply a consequence of augmented PI3K or MAPK signalling. Importantly, chemical inhibition of the PI3K and MAPK pathways indicates that targeting these cascades using pan-PI3K/mTORC1 and/or MEK inhibitors respectively only marginally reduces tumor burden in this setting.

Conclusion

Our findings indicate that Pik3ca activation and oncogenic KRas synergise in vivo to accelerate prostate cancer progression, and that pan-PI3K/mTORC1 and/or MEK inhibition shows limited therapeutic efficacy in this model. Establishing the molecular events that underpin the observed synergy and therapeutic resistance may present new therapeutic approaches to combat prostate cancer.


References:

  1. Bray,F et al, CA.2018;68:394-424.
  2. Taylor,BS et al. Cancer cell.2010;18(1):11-22.
  3. Mulholland,D et al. Cancer Res.2012;72(7):1876-89.

Assessment of systemic metabolic biomarkers to predict prostate cancer progression and mortality
Speaker: Meda R Sandu
Affiliation: University of Bristol

Abstract:

Overall survival for localised Prostate Cancer (PCa) is nearly 100% at 5 years, however a more reliable and less invasive predictor of PCa survival is needed to reduce unnecessary treatment in indolent cases. Recent evidence suggested that metabolic traits can predict the aggressiveness of PCa. We investigated the levels of metabolic traits in relation to the prospective development of metastases and PCa mortality, in the 10-year median follow-up of the Prostate Testing for Cancer Treatment (ProtecT) cohort of incident localised PCa.

 

Method

We analysed the baseline levels of 159 serum metabolic traits of 1,245 men diagnosed with localised PCa who were eligible for randomisation and were followed-up for a mean 10-year period in the ProtecT trial. We used Cox multivariable regression to assess survival and PCa progression for each metabolic trait, adjusting for clinical stage, BMI and age. We used bootstrapping to develop and test the performance of our multi-metabolic trait prediction model.

Results

Of the 1,245 patients, 12 died, 47 developed metastatic disease and 141 had clinical progression. There were no strong differences in the hazard ratios for any of the metabolites in relation to PCa death and clinical progression. We observed that small particle lipoproteins (HR 0.66, CI: 0.50- 0.85 per standard deviation (SD)) and the mean size of low-density lipoproteins (HR: 1.56, CI: 1.17-2.07 per SD) were related to developing metastases. The predictive model developed using PCa metastasis data, showed potential in predicting PCa metastases (area under the receiver operating characteristic curve (AUC): 0.73, CI:0.65-0.82) and PCa specific mortality (AUC: 0.76, CI:0.66-0.85).

Conclusion

We found metabolic traits that are associated with PCa outcomes and that may have a predictive role in distinguishing between high and low-risk localised PCa.