Genomic profile of advanced breast cancer in circulating tumour DNA.

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities

Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology

ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer

Fulvestrant is used to treat patients with hormone receptor positive advanced breast cancer but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S associated with poor, and Y537C with good outcome. Sequencing of baseline and EOT ctDNA samples (n=69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, F404V), in cis with activating mutations. In silico modelling revealed that ESR1 F404 contributes to fulvestrant binding to ERa through a pi-stacking bond, with mutations disrupting this bond. In vitro analysis demonstrated that single F404L, E380Q, and D538G models were less sensitive to fulvestrant, while compound mutations D538G+F404L and E380Q+F404L were resistant. Several oral ERa degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant, that can be targeted by treatments in clinical development

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Becoming Accountability: Theorising a different engagement of beneficiaries in nonprofit organisations

The purpose of this paper is to theoretically extend current conceptions of accountability and more specifically accountability toward beneficiaries within nonprofit organisations, through insights garnered from Deleuze and Guattari. The aim is to reconsider relations within nonprofit organisations that contribute to the marginalisation of the beneficiary stakeholder group, including relations presented within extant literature, through considering accountability as becoming within assemblages. Doing so may encourage a pluralised organisational environment where more voices are listened to. Current accounting and accountability tools and processes produce a marginalised voice for some. For that to be different, different productive possibilities are needed. Thinking about nonprofit accountability through assemblages may enable positive change

Promoting Pluralism: Critical dialogic accountability in Nonprofit Organisations through Immanent Evaluation

The research presented in this paper explores the pluralisation of accountability in nonprofit organisations (NPO) through participative evaluation, in order to enhance the inclusion of beneficiary stakeholders in accountability processes. In seeking to move beyond symbolic versions of beneficiary participative evaluation, understandings of immanent evaluation (Deleuze, 1998) are drawn upon to explore beneficiaries’ involvement in evaluation within an Australian NPO. Data was sourced from 19 interviews across three stakeholder groups (beneficiaries, employees, and board members) and organisational documents. Findings suggest beneficiaries were involved in evaluation processes designed by the organisation. However, beneficiaries viewed these as largely unsatisfactory in meeting their needs in relation to meaningful evaluation, accountability, and participation. At the same time, and largely unknown to the NPO, beneficiaries were engaging in evaluation processes of their own accord, including the development of evaluation criteria, and were subsequently expressing evaluation. Here, meaningful evaluation processes and criteria unfolded immanently from the beneficiary, rather than being imposed transcendently by the NPO. Findings emphasise the importance of NPOs developing strategies to understand beneficiaries’ immanent evaluation expressions and to learn their evaluation criteria. The research supports and furthers a critical dialogic vision of accountability by detailing how pluralised evaluative environments, capable of not only hearing beneficiary voice but also listening to it, can be promoted through awareness of beneficiaries’ immanent evaluation processes. In doing so, participative evaluation is conceived beyond the mere involvement of beneficiaries in evaluation, and toward learning, understanding, and valuing beneficiaries’ expressions of evaluation

COVID-19 and change: Enhancing beneficiary inclusion and non-profit accountability though digital innovation

This research explores how organisational responses to the Covid-19 pandemic changed the accountability assemblage within an Australian membership-based nonprofit organisation (NPO), specifically in relation to how the NPO interacts with its beneficiaries via digital platforms. This research draws on Deleuze and Guattari’s (2013) understandings of assemblages to explore change that resulted in enhanced accountability and inclusion within an Australian membership-based NPO. Data included interviews conducted during the 2020 Covid-19 crisis with 10 beneficiaries, two staff members, and three board/committee members, and organisational documents. Data was analysed using rhizoanalysis, an analytical approach seeking to “give readings of experiences in assemblages” (Cumming, 2015, p. 14), drawn from understandings of the rhizome (Deleuze & Guattari, 2013). Findings suggest the addition of Covid-19 into the accountability assemblage ruptured the established territory and cast a ‘line of flight’ where change was affected in a way that fostered inclusivity and beneficiary satisfaction through enhanced digital engagement. This paper presents the mapping of this change and resultant impacts upon accountability relationships and organisational processes toward member-beneficiaries. Contributions to knowledge include highlighting systemic organisational issues where beneficiaries with an increased agency can still struggle to be heard in accountability relationships; understanding how organisational responses to unanticipated change can bring benefits in terms of accountability processes, and employing digital tools in response to unexpected challenges can enhance accountability. The paper also makes a theoretical contribution by demonstrating how theories of assemblages can explain organisational change.References:Cumming, T. (2015). Challenges of ‘thinking differently’with rhizoanalytic approaches: A reflexive account. International journal of research & method in education, 38, 137-148.Deleuze, G., & Guattari, F. (2013). A Thousand Plateaus: Capitalism and Schizophrenia. Bloomsbury Academic

Examining the re-territorialisation of beneficiary accountability: Digitising nonprofit services in response to COVID-19

This research explores change in accountability toward beneficiaries within nonprofit organisations (NPO) during the first wave of COVID-19; specifically, through the digitalisation of NPOs' services. COVID-19 was a time of great change, where chaos replaced a level of order and routine in organisations' established structures and systems. Accordingly, this research uses understandings from Deleuze and Guattari to explore territorial changes within two NPOs' regimes of beneficiary accountability as a result of COVID-19 and their actions in attempting to restore order. Findings suggest that although disruption was produced by COVID-19, responses by the NPOs resulted in digitised changes to service provision that predominantly saw positive experiences for beneficiaries in each NPO. Findings demonstrate how organisational responses to unanticipated change, through the digitalisation of service provision, impacted upon the beneficiary accountability regimes in ways that both expanded and restricted their territories. Here consideration is given to shifts in territory and emphasis on accounting for-the-self versus accounting for-the-other. A theoretical contribution is made toward understanding how NPOs might work to produce order in times of chaos through considering their territories of accountability

Authentic Beneficiary Engagement in the Aged Care Sector: Advancing Nonprofit Governance through Care

The International Standard on Governance of Organizations (ISO 37000) has core outcomes of Responsible Stewardship, Effective Performance, and Ethical Behaviour. Embedded within these, Stakeholder engagement is identified as one of six enabling governance principles, and a fundamental component of effective accountability. ISO 37000 stipulates the “governing body should ensure that the organization’s stakeholders are appropriately engaged, and their expectations considered” (p. 24). Additionally, ISO 37000 emphasises the importance of identifying and prioritising stakeholders and their rights, whilst acknowledging stakeholder groupings and relevance will vary across organisations. This chapter focuses on the ISO 37000 governance principle of Stakeholder engagement and seeks to promote enhanced organisational accountability. Here the conceptual analysis is focussed on beneficiary stakeholders in the nonprofit aged care sector. Narrowing attention to a specific stakeholder group within one industry enables a deeper, more detailed exploration. Drawing upon the theoretical perspective of an ethics of care, the study culminates in the development of an analytical framework for enhanced engagement with and accountability toward beneficiaries within the aged care and human services sector more broadly. This chapter advances the value of organisations prioritising care-based governance practices through meaningful engagement with beneficiary stakeholders, over rights-based approaches that may perpetuate power asymmetries