Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

The value of secondary pathology review

6 Background: Improving the value of cancer care is a major focus for the Alliance of Dedicated Cancer Centers (ADCC). Looking to align with the Institute of Medicine’s (IOM) initiative to “Develop and deploy approaches to identify, learn from, and reduce diagnostic errors and near misses in clinical practice,” the ADCC implemented a study to examine the clinical impact of expert secondary pathology review. The goal of this project was to: 1) demonstrate the value of secondary review of outside pathological specimens by ADCC subspecialty pathologists in identifying significant errors that can potentially impact treatment; and 2) create an opportunity to improve patient cancer care. Methods: All consult slides from patients referred to each ADCC center were reviewed by designated pathologists. Patient-level data for original and revised diagnoses were collected for two months in 2014. Discrepancies were classified as: 1) major - diagnosis changes treatment or surveillance; or, 2) minor - diagnosis does not change affect treatment or surveillance. To verify these assessments, disease-specific, multi-center teams of clinical experts reviewed each discrepant case and provided treatment recommendations for the original and revised diagnoses. Results: A total of 13,109 cases were collected across all ADCC centers and the discrepancy rate was 11% (1,488/1309); 3% (359/13,109) were major and 9% (1,129/13,109) were minor. The most common discrepancy was reclassification of the neoplasm cell type. The highest discrepancy rate was shown in the neuro-oncology and head and neck cases, with a 7% and 4% major discrepancy rate respectively. Conclusions: We identified an overall discrepancy rate of 11%, with 3% of cases leading to a change in treatment or surveillance. This demonstrates the importance of expert pathology review and that secondary pathology review can significantly improve clinical outcomes through precise and accurate pathological diagnoses. As indicated in the recent IOM report, this project further demonstrates that “diagnostic errors may cause harm to patients by preventing or delaying appropriate treatment, providing unnecessary or harmful treatment, or resulting in psychological or financial repercussions.