NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types.

BACKGROUND: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. METHODS: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. RESULTS: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. CONCLUSION: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Practical and cost-effective model to build and sustain a cardio-oncology program.

BACKGROUND: Cardio-Oncology (CO) is a new subspecialty that thrives mostly in large academic quaternary centers. This study describes how to establish a successful cardio-oncology program, with limited resources, in order to effectively manage the unique care required by this patient population. METHODS: Clinical data was collected from 25 consecutive months. There were four foundational elements to establish a CO program: 1. Clinical program: integrating staff and resources from the Heart and Vascular, and Cancer Centers; 2. Education Program: establishing a platform to educate/advocate with respect to CO; 3. Engagement with professional societies: active engagement allowed for the successful establishment of the proposed CO program; and 4. Research program: establishing data collection modalities/cooperation with other institutions. RESULTS: 474 consecutive patients were treated by our CO program during the first 25 months of operation. Clinical data, information about cancer treatment, cardiovascular co morbidities, cardiac testing and impact of CO management are reported. CONCLUSIONS: A successful CO program can be established utilizing existing resources without the need for significant additional assets. Integration with professional societies, advocacy, education and research, provide a platform for learning and growth. This model improves access to care and can be reproduced in a variety of settings.

Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel.

PURPOSE: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing. EXPERIMENTAL DESIGN: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated. RESULTS: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit. CONCLUSIONS: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887.

Warfarin-induced skin necrosis mimicking calciphylaxis: a case report and review of the literature.

Warfarin-induced skin necrosis (WISN) and calciphylaxis share similar early clinical findings and can both lead to significant morbidity and mortality. The authors reviewed the literature on both conditions and describe a case of extensive skin necrosis in a patient with end-stage renal disease who was initially suspected to have calciphylaxis. Further investigation supported a diagnosis of WISN. The pathogenesis, clinical manifestations and treatment of WISN and calciphylaxis are discussed, with emphasis on a diagnostic approach for early recognition.