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Abraham J.E.,University of Cambridge | Abraham J.E.,Cambridge Experimental Cancer Medicine Center | Guo Q.,University of Cambridge | Dorling L.,University of Cambridge | And 16 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer. Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated. Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P=0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28-0.79; P=0.004] and rs9501929(TUBB2A) (OR=1.80; 95% CI, 1.20-2.72; P=0.005). A further 9 SNPs were significant at P-value ≤ 0.05. Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility. © 2014 AACR.

Dawson S.-J.,University of Cambridge | Rueda O.M.,University of Cambridge | Aparicio S.,University of British Columbia | Aparicio S.,British Columbia Cancer Research Center | And 2 more authors.
EMBO Journal | Year: 2013

Breast cancer is a group of heterogeneous diseases that show substantial variation in their molecular and clinical characteristics. This heterogeneity poses significant challenges not only in breast cancer management, but also in studying the biology of the disease. Recently, rapid progress has been made in understanding the genomic diversity of breast cancer. These advances led to the characterisation of a new genome-driven integrated classification of breast cancer, which substantially refines the existing classification systems currently used. The novel classification integrates molecular information on the genomic and transcriptomic landscapes of breast cancer to define 10 integrative clusters, each associated with distinct clinical outcomes and providing new insights into the underlying biology and potential molecular drivers. These findings have profound implications both for the individualisation of treatment approaches, bringing us a step closer to the realisation of personalised cancer management in breast cancer, but also provide a new framework for studying the underlying biology of each novel subtype. © 2013 European Molecular Biology Organization.

Dawson S.-J.,University of Cambridge | Dawson S.-J.,Peter MacCallum Cancer Center | Tsui D.W.Y.,University of Cambridge | Murtaza M.,University of Cambridge | And 16 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer. METHODS: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. RESULTS: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). CONCLUSIONS: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.). Copyright © 2013 Massachusetts Medical Society.

Vire E.,University of Cambridge | Curtis C.,Cancer Research UK Research Institute | Curtis C.,University of Southern California | Davalos V.,Bellvitge Biomedical Research Institute IDIBELL | And 10 more authors.
Molecular Cell | Year: 2014

Amplification of the EMSY gene in sporadic breast and ovarian cancers is a poor prognostic indicator. Although EMSY has been linked to transcriptional silencing, its mechanism of action is unknown. Here, we report that EMSY acts as an oncogene, causing the transformation of cells invitro and potentiating tumor formation and metastatic features invivo. Weidentify an inverse correlation between EMSY amplification and miR-31 expression, an antimetastatic microRNA, in the METABRIC cohort of human breastsamples. Re-expression of miR-31 profoundly reduced cell migration, invasion, and colony-formation abilities of cells overexpressing EMSY or haboring EMSY amplification. We show that EMSY is recruited to the miR-31 promoter by the DNA binding factor ETS-1, and it represses miR-31 transcription bydelivering the H3K4me3 demethylase JARID1b/PLU-1/KDM5B. Altogether, these results suggest a pathway underlying the role of EMSY in breast cancer and uncover potential diagnostic and therapeutic targets in sporadic breast cancer. © 2014 The Authors.

De Mattos-Arruda L.,University of Cambridge | De Mattos-Arruda L.,University of Barcelona | De Mattos-Arruda L.,Autonomous University of Barcelona | Caldas C.,University of Cambridge | Caldas C.,Cambridge Experimental Cancer Medicine Center
Molecular Oncology | Year: 2016

Recent developments in massively parallel sequencing and digital genomic techniques support the clinical validity of cell-free circulating tumour DNA (ctDNA) as a 'liquid biopsy' in human cancer. In breast cancer, ctDNA detected in plasma can be used to non-invasively scan tumour genomes and quantify tumour burden. The applications for ctDNA in plasma include identifying actionable genomic alterations, monitoring treatment responses, unravelling therapeutic resistance, and potentially detecting disease progression before clinical and radiological confirmation. ctDNA may be used to characterise tumour heterogeneity and metastasis-specific mutations providing information to adapt the therapeutic management of patients. In this article, we review the current status of ctDNA as a 'liquid biopsy' in breast cancer. © 2015 Federation of European Biochemical Societies.

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