Hasil untuk "cs.PL"

Baji Shaik, Dinesh Kumar Chemuduru

Baji Shaik, Dinesh Kumar Chemuduru

Baji Shaik, Dinesh Kumar Chemuduru

Baji Shaik, Dinesh Kumar Chemuduru

C. Swanton

Abstract Chromosomal instability (CIN) is a poor prognostic feature with high prevalence in breast cancer and is responsible for driving Somatic Copy Number Aberrations and Intratumour Heterogeneity (ITH) within subclones during breast cancer evolution. We have observed that SCNAs are enriched in metastatic samples, including gains in chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. However, there have thus far been no prospective, comprehensive studies of intratumor heterogeneity in breast cancer. We will present data from TRACERx Breast/SCANDARE a prospective, multicentre study of triple-negative breast cancer (TNBC) in which multi-region biopsies have been collected from primary TNBC prior to neoadjuvant treatment, and at longitudinal time points including surgery and relapse. We find prevalent intratumor heterogeneity in somatic mutations and SCNAs in the primary tumor prior to treatment. We have leveraged the rich clinical annotation in this cohort to correlate intratumor heterogeneity scores with key clinical outcomes, including treatment response (pathological complete response to neoadjuvant chemotherapy) and survival. We find that CIN manifests as oncogenic amplification on extrachromosomal DNA (ecDNA), which plays a pivotal role in driving drug resistance and tumor evolution. Through analysis of Whole Genome Sequencing data from 2936 breast tumors from the Genomics England breast cancer cohort, we have identified focal amplifications driven by ecDNA in 46.4% of HER2+ breast cancers. EcDNA were enriched in metastatic tumors and was associated with poor clinical outcomes. In addition to oncogenic amplifications such as HER2 derived from ecDNA during cancer evolution, ecDNAs contained immunomodulatory genes associated with reduced T cell infiltration. Further Immune-modulation by CIN results from loss of heterozygosity of the HLA locus (HLA LOH) and is a prevalent subclonal event in breast cancer. CIN is further drives haploid LOH, resulting in the high prevalence of whole genome doubling and further CIN in TNBC. Tumors are heterogeneous compositions of distinct clones with different compliments of SCNAs and varying levels of fitness, hence measuring the proliferation of individual clones to predict future evolutionary outcomes is likely to be critical. We have developed SPRINTER (Single-cell Proliferation Rate Inference in Non-homogeneous Tumours through Evolutionary Routes), a novel computational method to measure proliferation rates in individual tumour clones using single-cell whole-genome DNA sequencing data. We applied SPRINTER to 42,009 triple negative breast cancer cells, demonstrating significant proliferative heterogeneity between distinct tumor clones. Importantly, we show a correlation between higher proliferation rates and increased rates of somatic variants, suggesting proliferation links to clone evolvability. Taken together, these complimentary analyses provide evidence for the importance of CIN in driving ITH, selection, metastasis and immune evasion and provide a framework to determine recurrent evolutionary patterns in breast cancer evolution. Citation Format: C. Swanton. Breast Cancer Evolution, Immune Evasion and Metastasis Driven by Chromosomal Instability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PL-01.

YT Wang, CB Chee, LY Hsu et al.

Matthew J. Ellis

Abstract As a result of improvements in DNA and RNA sequencing techniques the genomic structure of estrogen receptor positive breast cancer is increasingly well documented, but extracting clinically actionable information from these complex data sets has proved fraught with difficulties. Barriers to progress include the lack of pharmacological hypotheses for novel luminal breast cancer tumor suppressor genes (e.g. MAP3K1, MLL3, SF3B1); 2) a lack of a full understanding of interactions between mutation status, the prognosis of ER+ breast cancer, and the effectiveness of endocrine therapy; 3) an inadequate collection of patient-derived xenograft (PDX) models for luminal breast cancer that fully encompass the heterogeneity of the disease; 4) the logistical barriers of developing adjuvant strategies to exploit rare drivers present in less than 5% of tumor samples; 5) insufficient genomic discovery efforts directed towards samples accrued from patients suffering from endocrine therapy resistant disease progression and 6) an incomplete understanding of how complex somatic genotypes drive the biochemical events responsible for the “hallmarks” of luminal cancer. To better address these issues, five areas of investigation will be discussed: 1) somatic mutation diagnosis in DNA from primary breast cancer samples from patients treated with adjuvant tamoxifen and followed for over 20 years; 2) DNA and RNA sequencing of samples accrued from patients treated with neoadjuvant endocrine therapy to define the molecular origins of intrinsic aromatase inhibitor resistance and to identify pharmacological hypothesis; 3) efforts to expand and catalog patient-derived xenografts from ER+ breast cancers, including the use of mass spectrometry-based analysis of their proteomes and phosphoproteomes to expand our knowledge of the biochemistry of individual tumors; 4) a functional and pharmacological investigation of mutations in ESR1, including resistance-activating chromosomal translocations, and 5) the development of a neoadjuvant endocrine therapy strategy that identifies patients with intrinsic endocrine therapy resistance within a month of starting treatment so that they can be triaged to mutation-matched investigational treatment. Citation Format: Matthew J. Ellis. Genome-Directed Therapeutics for Endocrine Therapy Resistant ER+ Breast Cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PL-1.

R Ion, H Allatt

Background The fertility rate in Uganda is 6.1.1 The significance of repeated CS and the risks of labour after caesarean section are well-documented. Often CS is the most appropriate mode of delivery but the decision to operate should be made judiciously to reduce maternal morbidity and mortality. The CS rate in Kisizii Hospital, previously around 23% (2009–2010), had increased steadily to 41% in July 2012. Retrospective case note examination indicated frequent poor decision-making in labour leading to unnecessary CS. Decisions were often made by very junior staff. Method The following were implemented in early August: Tutorials on diagnosing & managing progress in labour and fetal distress Tutorials on vacuum deliveries Algorithms to aid decision-making processes Updated induction of labour guidelines Results Abstract PL.49 Table 1 Feb Mar Apr May Jun Jul Aug Sep Oct CS rate(% del) 39.4 41.8 33.5 34.0 36.0 41.1 26.2 23.5 31.5 Fresh SB rate* 1.1 1.6 2.1 2.8 0.5 2.1 2.7 2.3 2.7 Birth asphyxia rate* 0.6 5.4 1.0 14.9 6.3 1.1 2.0 5.1 3.4 * percentage of live births The CS rate for August to October was statistically significantly less than for January to July (p < 0.05, Fisher’s exact test). There were no significant differences observed in the fresh stillbirth or birth asphyxia rates. Conclusion Simple algorithms with timely tutorials can help junior staff to improve their decision-making processes where the preferable alternative of continual senior support is not feasible. 1 UNICEF 2010

Sue Harper

Adrian Billington

Eberhard Sturm

Eberhard Sturm

Eberhard Sturm

Eberhard Sturm