1,721,059 research outputs found
An investigation of DNA sequence variants of unknown significance in hereditary breast cancer
No full textInheritance of a protein truncating mutation of the tumour suppressor gene BRCA1 causes approximately 5% of breast tumours. Over 450 distinct BRCA1 missense mutations have also been found in patients with a family history of breast cancer and the functional significance of most of these is unclear. Increasing evidence suggests that DNA missense mutations can affect RNA stability or sequence by disrupting splicing regulators. I have used a variety of techniques to investigate the effect of genomic BRCA1 missense mutations on transcript expression. BRCA1 monoallelic expression has previously been reported in association with missense mutations. I therefore initially used the technique of Pyrosequencing™ to identify imbalances in BRCA1 cDNA allele expression. Analysis of patients with known BRCA1 truncating mutations, missense mutations and controls identified no examples of monoallelic expression and indicated that a previous report of monoallelic BRCA1 expression was erroneous. I subsequently developed a series of multiplex RT-PCR reactions using overlapping primer pairs to identify alternative BRCA1 transcripts in the same groups of subjects. This technique effectively demonstrated the common BRCA1 isoforms and confirmed that the c4185A>G silent mutation is associated with deletion of exon 12. To provide a systematic analysis of the effect of BRCA1 mutations on splicing regulation I designed minigenes centred on 4 different BRCA1 exons; 5,6,10 and 18. All mutations within these exons reported to the Breast Cancer Information Core database were introduced into the appropriate minigenes, and wildtype and mu'tant miriigel1es were transfected into HEK 293 cells. The resulting transcripts were examined to identify aberrant splicing. Only one of twenty-one missense mutations investigated resulted in alternative transcripts, suggesting that only a small proportion of BRCA1 missense mutations do affect splicing. Additional work was also performed to investigate whether the MDM2 SNP 309 acts as a disease modifying gene in BRCA1 associated hereditary cancer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Pembrolizumab for early triple-negative breast cancer
No full textPembrolizumab is an immune checkpoint inhibitor (ICPI), a type of immunotherapy that blocks the programmed death 1 (PD1) receptor expressed on T cells. In cancer, PD1 binds to its ligand, programmed death ligand 1 (PDL1), which is expressed by both innate immune cells and tumour cells and prevents T cells from killing cancer cells. Triple-negative breast cancer (TNBC) is characterised by a higher density of immune cell infiltrates, a higher expression of PDL1 and a higher tumour mutational burden than other breast cancer subtypes, making ICPI a promising treatment option in TNBC. 1 Furthermore, the use of anthracyclines, taxanes and platinum-based neoadjuvant chemotherapy is associated not only with improved pathological complete responses (pCRs) but also with increased PDL1 expression in tumour cells in TNBC. 2 The KEYNOTE-522 study investigated whether the combination of chemotherapy and ICPI improves clinical outcomes in this group of patients.</p
Dose-dense adjuvant chemotherapy for high-risk early breast cancer: its role in the era of personalised oncology
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Exploring the ‘teachable moment’: logic model for an alcohol brief intervention in breast screening and symptomatic breast clinics
No full textExisting research on alcohol brief interventions (ABI) has yet to examine the potential for symptomatic breast cancer clinics and breast screening mammography as a ‘teachable moment’ for alcohol prevention. We are preparing an early phase study set in symptomatic breast clinics at University Hospital Southampton to assess:- women’s information needs regarding effects of alcohol on cancer risk,- the nature of tailored feedback required, and- the potential of a digital ABI to develop alcohol awareness into a long-term intrinsic motivation to reduce alcohol consumption.This knowledge is required to develop an intervention that meets patient need. The early development work for this research has shaped the following intervention logic model:- Context: annually, symptomatic breast clinics in England see approximately 275,000 women. Mammography screening appointments are attended by a further 4.4 million. These stressful health events have for the wide majority no further medical implications. But they are a missed opportunity to address women’s concerns and promote healthy lifestyles.- Input: a digital interface accessed by patients in the waiting room.- Outputs: information on the alcohol dose-response of alcohol on breast cancer risk and advice on healthy lifestyles.- Short-terms outcomes of this intervention are increased motivation and readiness to change in the short-term. The expected medium-term outcome is a reduction in frequency and intensity of drinking.The poster aims to present the different components of this logic model, prompt discussions with the addiction research community an invite feedback and suggestions for the design of our intervention development study
TP8.1.7 The utility of a timeline and episode structured breast cancer data system to study outcomes following neoadjuvant chemotherapy for cases stratified by HER2 status
No full textBackground: breast neoplasia displays complex patterns of whole-of-life disease progression, which are difficult to study using legacy data systems. Our timeline- and episode-structured breast cancer data set of 20,000 records allows direct visualisation of the entire documentary record of every patient. The embedded data mining module permits research into a wide range of patient cohorts by pathology, treatment and outcome.Methods: we selected the cohort of patients aged between 15 and 75 with HER-2 –ve and HER-2 +ve breast cancer who were treated with neoadjuvant chemotherapy (NAC), with or without anti-HER2 therapy between 2002 and 2019. We also studied the patterns and time intervals (in months) of disease progression and response to treatment from primary diagnosis, through loco-regional recurrence and distant metastasis to final outcome.Results: of 301 women with confirmed early stage breast cancer were treated with NAC over that time, 186 had HER2- and 115 had HER2+ tumours. The patterns and intervals of disease progression, as displayed on the Master Lifetrack, were mapped and measured for every patient. The proportions of patients with Her2+ve tumours receiving trastuzumab and analogues, and the tumour responses to treatment, were audited. The underlying data set was validated by review of the original records.Conclusions: the whole-of-life timeline structured cancer data system introduces a new direction for clinical data visualisation, record management and user utility in surgical practice. This study validates the model as a tool for the better understanding of treatment effects and longitudinal behaviours in any selected range of cancer phenotypes
Modifiable risk factors
No full textBreast cancer is the most common form of cancer among women in industrialised countries. In the UK, breast cancer accounts for 15% of all new cancer cases and is the most common cancer. A range of associations have been linked with the development of primary breast cancer. Many of these are inherent and cannot be modified by individual behaviour. The Collaborative Group on Hormonal Factors in Breast Cancer brought together and re-analysed the worldwide epidemiological evidence on the association between breast cancer risk and the use of hormonal contraceptives, and produced a number of conclusions. Breast cancer risk is lower the younger childbearing begins, the relative risk declining by 3% for each year earlier that the first child is born. Obesity is a universal health concern in both developed and developing countries. An increasing proportion of all populations are obese or overweight and approximately 65 million additional adults who are obese are projected for the United States by 2030
Early breast cancer: why does obesity affect prognosis?
No full textHigh body mass index (BMI) is associated with an increased risk of breast cancer in post-menopausal women but poorer outcomes in all age groups. The underlying mechanism is likely to be multi-factorial. Patients with a high BMI may present later due to body habitus. Some studies have also indicated an increased incidence of biologically adverse features, including a higher frequency of oestrogen receptor (ER negative) tumours, in obese patients. Obese patients have a higher frequency of surgical complications, potentially delaying systemic therapies, and reports suggest that chemotherapy and endocrine therapy are less effective in patients with BMIs of ≥30 kg/m2 High BMI is generally interpreted as excess adiposity and a World Cancer Research Fund report judged that the associations between BMI and incidence of breast cancer were due to body fatness. However, BMI cannot distinguish lean mass from fat mass, or characterise body fat distribution. Most chemotherapy drugs are dosed according to calculated body surface area (BSA). Patients with a similar BSA or BMI may have wide variations in their distribution of adipose tissue and skeletal muscle (body composition); however few studies have looked at the effect of this on chemotherapy tolerance or effectiveness. Finally, adjuvant treatments for breast cancer can themselves result in body composition changes. Research is required to fully understand the biological mechanisms by which obesity influences cancer behaviour, and the impact of obesity on treatment effectiveness and tolerance so that specific management strategies can be developed to improve the prognosis of this patient group
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