The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS)

Introduction Ductal carcinoma in situ (DCIS) is a noninvasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials). Methods and analysis COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients. Ethics and dissemination The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for noninferiority trials

Diagnostic Odyssey: Investigating the Role of a Mutation in the CUL4B Gene and its Effect on the CUL4B Protein Complex in a Patient with Seizures and Developmental Delay

For many patients with complex diseases the time from onset of symptoms to diagnosis may involve many years. If a diagnosis can be reached, it often comes at great financial and emotional cost. With the advent of sequencing technologies, the ability to identify gene variants has increased exponentially. Interpreting these findings, however, remains challenging. The purpose of this study was to analyze a mutation in the CUL4B gene revealed by whole exome sequencing (WES) in a patient with seizures and developmental delay. Recognizing that complex disease may involve the interaction of many genes and their protein products, an analysis of variants in selected CUL4B associated proteins and CUL4A was also undertaken with the ultimate goal of determining their potential clinical relevancy. WES was performed by Ambry Genetics and mRNA studies were performed by University of California CLIA laboratory MitoMed. WES identified a variant in CUL4B located on the X chromosome. Analysis revealed a splice site mutation resulting in skipping of exon 14 or inclusion of intron 14. Examination of the biological structure indicated that in either case no functional protein would be found. Fifteen intronic variants and one synonymous exonic variant were identified in CUL4B related genes. Fourteen intronic variants in CUL4A were also identified. Current understanding of these types of variants suggests they would not be contributory, however further study is required. Taken together, these results contribute to the growing body of evidence that mutations in the CUL4B gene may be causal in cases of X linked intellectual disability

Diagnostic Odyssey: Investigating the Role of a Mutation in the CUL4B Gene and its Effect on the CUL4B Protein Complex in a Patient with Seizures and Developmental Delay

For many patients with complex diseases the time from onset of symptoms to diagnosis may involve many years. If a diagnosis can be reached, it often comes at great financial and emotional cost. With the advent of sequencing technologies, the ability to identify gene variants has increased exponentially. Interpreting these findings, however, remains challenging. The purpose of this study was to analyze a mutation in the CUL4B gene revealed by whole exome sequencing (WES) in a patient with seizures and developmental delay. Recognizing that complex disease may involve the interaction of many genes and their protein products, an analysis of variants in selected CUL4B associated proteins and CUL4A was also undertaken with the ultimate goal of determining their potential clinical relevancy. WES was performed by Ambry Genetics and mRNA studies were performed by University of California CLIA laboratory MitoMed. WES identified a variant in CUL4B located on the X chromosome. Analysis revealed a splice site mutation resulting in skipping of exon 14 or inclusion of intron 14. Examination of the biological structure indicated that in either case no functional protein would be found. Fifteen intronic variants and one synonymous exonic variant were identified in CUL4B related genes. Fourteen intronic variants in CUL4A were also identified. Current understanding of these types of variants suggests they would not be contributory, however further study is required. Taken together, these results contribute to the growing body of evidence that mutations in the CUL4B gene may be causal in cases of X linked intellectual disability