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Edinburgh, United Kingdom

Dixon J.M.,Breakthrough Research Unit
British journal of hospital medicine (London, England : 2005) | Year: 2010

One in four women attends a breast clinic at some time in their life. Breast cancer is increasing in frequency and the incidence has increased approximately 25% over the last decade. This is in part a result of breast screening which is available to all women between the ages of 50 and 70 years in the UK. The lifetime risk of breast cancer in the UK is now approaching one in eight. Although there have been significant advances in the systemic therapy of breast cancer, surgery remains the mainstay of treatment. Source

Wang L.,Molecular Therapeutics | Ellsworth K.A.,Molecular Therapeutics | Moon I.,Molecular Therapeutics | Pelleymounter L.L.,Molecular Therapeutics | And 14 more authors.
Cancer Research | Year: 2010

Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5′-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors. ©2010 AACR. Source

Bundred N.,University of Manchester | Gardovskis J.,Riga Stradins University | Jaskiewicz J.,Medical University of Gdansk | Eglitis J.,University of Latvia | And 8 more authors.
Investigational New Drugs | Year: 2013

Summary: Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies. © 2013 Springer Science+Business Media New York. Source

Natrajan R.,Institute of Cancer Research | Mackay A.,Institute of Cancer Research | Lambros M.B.,Institute of Cancer Research | Weigelt B.,Cancer Research UK Research Institute | And 33 more authors.
Journal of Pathology | Year: 2012

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4). Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source

Macaskill E.J.,Edinburgh Breast Unit | Dixon J.M.,Breakthrough Research Unit
Current Breast Cancer Reports | Year: 2012

Neoadjuvant endocrine therapy is safe and can be effective in many postmenopausal women with estrogen receptor positive breast cancer. There are limited data available for premenopausal women taking aromatase inhibitors in combination with estrogen suppression. Letrozole, anastrozole, and exemestane have all been shown to be equivalent or superior to tamoxifen in relatively small neoadjuvant trials in postmenopausal women. Tumor factors that appear to have good response are estrogen receptor positivity, characteristics consistent with the so-called Luminal A subtype and lobular carcinomas. Response to neoadjuvant treatment may inform decision making regarding adjuvant treatment, which should include radiotherapy following breast-conserving surgery, or mastectomy, made feasible by neoadjuvant treatment to maintain low local recurrence rates. Chemotherapy may also be required in some cases based on the biological characteristics of the residual tumor and the extent of residual disease. © 2011 Springer Science+Business Media, LLC. Source

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