Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research

Can routine data be used to support cancer clinical trials? A historical baseline on which to build: retrospective linkage of data from the TACT (CRUK 01/001) breast cancer trial and the National Cancer Data Repository

Abstract Background Randomised clinical trials (RCTs) are the gold standard for evaluating new cancer treatments. They are, however, expensive to conduct, particularly where long-term follow-up of participants is required. Tracking participants via routine datasets could provide a cost-effective alternative for ascertaining follow-up information required to evaluate disease outcomes. This project explores the potential for routine data to inform cancer trials, using, the historical National Cancer Data Repository (NCDR) for English NHS sites and, for validation, mature data available from the TACT trial. Methods Datasets were matched using patients’ NHS number, date of birth (dob) and name/initials. Demographics, clinical characteristics and outcomes were assessed for agreement and completeness. Overall survival was compared between NCDR and TACT. Results A total of 3151 patients underwent linkage; 3047 (96.7%) of which had matched records. Extensive cleaning was required for some registry data fields, e.g. cause of death, whilst others had large amounts of missing data, e.g. tumour size (22.1%). Other data had high levels of matching such as dob (99.6%) and date of death (89.6%). There was no evidence of differential survival rates (8-year survival: TACT = 75% (95% CI 73, 76); NCDR = 76% (95% CI 74, 77)). Conclusions Data quality and completeness requires improvement before routine data could be used for RCTs. Introduction of new routine datasets, including COSD, is welcomed although reporting of disease-recurrence events remains a concern. Prospective validation of such datasets is required before RCTs can confidently switch patient follow-up to utilise routinely collected NHS-based data. TACT Trial registration Clinicaltrials.gov NCT00033683 , registered on 9 April 2002; ISRCTN79718493 , registered on 1 July 2001