Showing papers by "Nichola Johnson published in 2022"

Rare germline copy number variants (CNVs) and breast cancer risk

Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

“What Do You Think She’s Going to Do Next?” Irresolution and Ambiguity as Resources for Collective Engagement

Abstract: Abstract Understanding how learning environments productively mobilize children’s ideas as resources for participation in joint activity is an ongoing focus of research on classroom instruction. We investigated whole-class mathematics conversations in which multiple students participated in ways previous research suggests are consequential for learning. We found that in such conversations, students rarely presented the entirety of their solutions before other students engaged. Rather, incomplete explanations and written representations that emerged over time created entry points for other students to contribute in mathematically substantive ways. These aspects of student participation operated in combination with teachers’ in-the-moment responses to create opportunities for, and publicly recognize, different kinds of contributions as resources for collective work. Our findings suggest that, rather than challenges to communication that must be overcome, students’ vague, unfinished, and ambiguous ideas present productive contributions that can be leveraged to support collective mathematical work.

Making Competence Explicit: Helping Students Take Up Opportunities to Engage in Math Together

Abstract: Background: Current efforts to promote reasoning, problem solving, and discussion are often framed as advancing equity, but scholarship suggests individual students’ opportunities to learn can vary considerably in classrooms that attempt to take up these approaches to teaching mathematics. Noticing students’ mathematical strengths and positioning their contributions as competent is among aspects of instruction associated with more equitable learning outcomes for students from marginalized groups, but research has yet to comprehensively examine the range and nuance of this aspect of teachers’ practice in classrooms that feature broad distributions of participation. Purpose: The purpose of this study was to examine teachers’ instructional practice with respect to assigning competence in two mathematics classrooms that demonstrated high levels of student participation. We investigated the kinds of situations in which teachers positioned students as competent, and the ways assigning competence opened opportunities to participate. Setting: Data were collected at a public elementary school in a culturally, linguistically, and economically diverse neighborhood in southern California. Participants: Participants included two teachers and 45 students from two third-grade classrooms. Teachers had participated in ongoing professional development focused on leveraging children’s mathematical thinking in instruction. Research Design: We drew from qualitative methods for analyzing video to investigate classroom interactions from 12 mathematics lessons. Data sources included video recordings, transcripts, and student work. We used Studiocode software to parse each lesson into phases and episodes. Drawing from previous studies, we identified a subset of episodes in which teachers explicitly positioned a student’s contribution as competent. An iterative process of coding and discussion was used to analyze patterns with respect to student participation, teacher support, and the unfolding of rights and obligations related to participating in mathematical activity. Findings: Analyses revealed different kinds of situations in which students participated in mathematically substantive ways (in terms of providing detailed explanations of their ideas or engaging with the details of a peer’s idea) and teachers positioned their contributions as competent. These situations included highlighting, clarifying, and amplifying contributions; supporting the specificity of student contributions; recognizing emergent ideas; and validating unprompted attention to mathematical details. Assignments of competence emerged in ways that were integrated into teachers’ ongoing efforts to surface and make explicit the details of their mathematical ideas, while also broadening the kinds of contributions students could make to joint mathematical work. Conclusions: Helping students to know what it could look and sound like to participate in the moment while recognizing a wide range of contributions as competent created openings for students who in many classrooms might be excluded or relegated to the periphery of conversations. Making competence explicit was a contingent, relational practice that required teachers to find specific ways of leveraging student strengths to support their participation. Recommendations for advancing mathematics teaching must attend to the nuances with which particular practices unfold to open or constrain individual students’ opportunities to learn.

Abstract OT2-24-01: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract: Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. Germline BRCA (gBRCA) breast cancer and TNBC share some phenotypic and molecular similarities, with 10%-20% of TNBC patients having gBRCA mutations. Homologous recombination deficient tumours are particularly sensitive to PARP inhibitors such as olaparib (Lynparza). It has been shown that adjuvant olaparib for patients with high-risk, HER2-negative early breast cancer and gBRCA pathogenic or likely pathogenic variants after adjuvant or neoadjuvant chemotherapy significantly improves 3-year invasive and distant disease-free survival compared to placebo (OlympiA). Aim: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR) rate). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) aiming to establish if the addition of new agents (ATR inhibitor and PDL1 inhibitor) can improve response in those patients with evidence of residual disease before surgery. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; clinical stage T1-4 N0-2; performance status 0-1; treatment commenced within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and the TNBC non-gBRCA cohort) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. It is planned to recruit a minimum of 188 gBRCA patients. A maximum of 15 patients will be allocated into each PARTNERING cohort. Present accrual: Recruitment commenced 27 May 2016 and 678 patients from 30 sites have been accrued to date. The IDSMC reviewed the trial after Stages 1 and 2 and recommended to continue the trial without change. Data analysis for Stage 2 revealed no safety concerns and research arm 2 (olaparib on day 3 to day 14) was selected. Stage 3 Phase I recruitment is in progress (recruiting TNBC non-gBRCA and gBRCA patients) and we anticipate moving to Phase II (recruiting gBRCA patients only) by early 2022. Four patients have been accrued to the PARTNERING optional pathway to date. The trial is open and enrolling patients to UK and international sites. Contact information: partner@addenbrookes.nhs.uk Citation Format: Lynsey M Drewett, Karen A Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Jessica Martin, Camila Maida de Pontes, Nicola Johnson, Caron Harvey, Erdem Demir, Kimberley St John Green, James Jones, Gemma Young, Anne-Laure Vallier, Wendi Qian, Andrea Machin, Karen McAdam, Rebecca Roylance, Ellen R Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-01.