Use of real world data to generate evidence on the effectiveness of oncological treatment provision in older/underrepresented populations of women diagnosed with breast cancer

Background: Evidence on oncological treatment efficacy from randomised controlled trials (RCTs) forms the backbone to national guidance on clinical practice but their findings may have limited generalisability. This is a particular concern when applying guidance about treatments to older patient populations who can be poorly represented within RCTs. This thesis examined the value of routinely-collected data sources in evaluating oncological treatments for patients with invasive breast cancer (IBC). Methods: Cancer Registration records for women aged 50+ years newly-diagnosed with IBC in England from 2014-2019 were used, linked at patient/tumour-level to routine national datasets providing information on patient and tumour characteristics, treatment and survival outcomes. Initial work examined methodological challenges in understanding oncological treatments using routine data sources. Work then investigated clinical aspects of oncological treatments received in practice, focusing on their uptake, and the safety and benefit of trastuzumab-based treatment for HER2-positive early invasive breast cancer (EIBC) among older, less fit patients. Results: There were systematic differences in oncological treatment recording within available national data sources, with records less complete for older patients. For endocrine therapy, completeness was excellent in primary care data but linkage to secondary care data identified initial hospital-based prescriptions, providing more comprehensive information about treatment timings. Use of oncological treatments was consistently lowest among older women, independent of other relevant factors. Trastuzumab-based treatment for HER2-positive EIBC had comparable overall safety among both younger and older women, although increasing age was associated with increased odds of cardiovascular problems. There was no evidence of differences in the effect of trastuzumab on survival by age. Conclusions: This research has demonstrated the value of routine national data in understanding treatment use and associated outcomes among patients with IBC treated in routine care. Similar studies may address evidence gaps in other treatment areas where patient representation in RCTs is an issue

Adding new experimental arms to randomised clinical trials: Impact on error rates

Background: Experimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started. / Methods: We show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations. / Results: Our results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Šidák’s correction if the correlation between the test statistics of pairwise comparisons is less than 0.30. / Conclusions: The findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required

Surgical decisions in older women with early breast cancer: patient and disease factors.

BACKGROUND: Studies reporting lower rates of surgery for older women with early invasive breast cancer have focused on women with oestrogen receptor (ER)-positive tumours. This study examined the factors that influence receipt of breast surgery in older women with ER-positive and ER-negative early invasive breast cancer . METHODS: Women aged 50 years or above with unilateral stage 1-3A early invasive breast cancer diagnosed in 2014-2017 were identified from linked English and Welsh cancer registration and routine hospital data sets. Logistic regression analysis was used to evaluate the influence of tumour and patient factors on receipt of surgery. RESULTS: Among 83 188 women, 86.8 per cent had ER-positive and 13.2 per cent had ER-negative early invasive breast cancer. These proportions were unaffected by age at diagnosis. Compared with women with ER-negative breast cancer, a higher proportion of women with ER-positive breast cancer presented with low risk tumour characteristics: G1 (20.0 versus 1.5 per cent), T1 (60.8 versus 44.2 per cent) and N0 (73.9 versus 68.8 per cent). The proportions of women with any recorded co-morbidity (13.7 versus 14.3 per cent) or degree of frailty (25 versus 25.8 per cent) were similar among women with ER-positive and ER-negative disease respectively. In women with ER-positive early invasive breast cancer aged 70-74, 75-79 and 80 years or above, the rate of no surgery was 5.6, 11.0 and 41.9 per cent respectively. Among women with ER-negative early invasive breast cancer, the corresponding rates were 3.8, 3.7 and 12.3 per cent. The relatively lower rate of surgery for ER-positive breast cancer persisted in women with good fitness. CONCLUSION: The reasons for the observer differences should be further explored to ensure consistency in treatment decisions

Change in the Use of Fractionation in Radiotherapy Used for Early Breast Cancer at the Start of the COVID-19 Pandemic: A Population-Based Cohort Study of Older Women in England and Wales.

AIMS: Adjuvant radiotherapy is recommended for most patients with early breast cancer (EBC) receiving breast-conserving surgery and those at moderate/high risk of recurrence treated by mastectomy. During the first wave of COVID-19 in England and Wales, there was rapid dissemination of randomised controlled trial-based evidence showing non-inferiority for five-fraction ultra-hypofractionated radiotherapy (HFRT) regimens compared with standard moderate-HFRT, with guidance recommending the use of five-fraction HFRT for eligible patients. We evaluated the uptake of this recommendation in clinical practice as part of the National Audit of Breast Cancer in Older Patients (NABCOP). MATERIALS AND METHODS: Women aged ≥50 years who underwent surgery for EBC from January 2019 to July 2020 were identified from the Rapid Cancer Registration Dataset for England and from Wales Cancer Network data. Radiotherapy details were from linked national Radiotherapy Datasets. Multivariate mixed-effects logistic regression models were used to assess characteristics influential in the use of ultra-HFRT. RESULTS: Among 35 561 women having surgery for EBC, 71% received postoperative radiotherapy. Receipt of 26 Gy in five fractions (26Gy5F) increased from <1% in February 2020 to 70% in April 2020. Regional variation in the use of 26Gy5F during April to July 2020 was similar by age, ranging from 49 to 87% among women aged ≥70 years. Use of 26Gy5F was characterised by no known nodal involvement, no comorbidities and initial breast-conserving surgery. Of those patients receiving radiotherapy to the breast/chest wall, 85% had 26Gy5F; 23% had 26Gy5F if radiotherapy included regional nodes. Among 5139 women receiving postoperative radiotherapy from April to July 2020, nodal involvement, overall stage, type of surgery, time from diagnosis to start of radiotherapy were independently associated with fractionation choice. CONCLUSIONS: There was a striking increase in the use of 26Gy5F dose fractionation regimens for EBC, among women aged ≥50 years, within a month of guidance published at the start of the COVID-19 pandemic in England and Wales

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.

Background There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.Methods We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.Discussion We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.Conclusions Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks

The Calcitonin and Glucocorticoids Combination: Mechanistic Insights into Their Class-Effect Synergy in Experimental Arthritis

PMCID: PMC3564948This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

PP2A/B55 and Fcp1 regulate Greatwall and Ensa desphorylation during mitotic exit

Entry into mitosis is triggered by activation of Cdk1 and inactivation of its counteracting phosphatase PP2A/B55. Greatwall kinase inactivates PP2A/B55 via its substrates Ensa and ARPP19. Both Greatwall and Ensa/ARPP19 are regulated by phosphorylation, but the dynamic regulation of Greatwall activity and the phosphatases that control Greatwall kinase and its substrates are poorly understood. To address these questions we applied a combination of mathematical modelling and experiments using phospho-specific antibodies to monitor Greatwall, Ensa/ARPP19 and Cdk substrate phosphorylation during mitotic entry and exit. We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194. Ensa/ARPP19 dephosphorylation is mediated by the RNA Polymerase II carboxy terminal domain phosphatase Fcp1. Surprisingly, neither Fcp1 nor PP2A appear to essential to dephosphorylate the bulk of mitotic Cdk1 substrates following Cdk1 inhibition. Taken together our results suggest a hierarchy of phosphatases coordinating Greatwall, Ensa/ARPP19 and Cdk substrate dephosphorylation during mitotic exit

Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichiacoli and Acinetobacterbaumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy