Germline predisposition to soft tissue sarcoma

Soft tissue sarcoma (STS) most often occurs sporadically, but can also arise in the setting of a germline cancer predisposition syndrome (CPS). There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies, occur in all age groups, and can occur in any location in the body. This diversity is also reflected in the many known associated germline cancer predisposition associations. Some STS diagnoses, such as anaplastic rhabdomyosarcoma, are associated with high heritability and other STS, such as Ewing sarcoma, are notably absent from known CPS. Recognizing when a STS is more likely to be hereditary can influence clinical management. Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection. Additionally, family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies. Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency. This review summarizes current knowledge of selected STS and their associations with CPS

應用遙測技術建立全國土地利用調查系統之研究

Introduction Patients with germline TP53 pathogenic variants (Li–Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost‐effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically. Methods A Markov decision analytic model was developed from a third‐party payer perspective to estimate cost‐effectiveness of routine cancer surveillance over a patient\u27s lifetime. The model consisted of four possible health states: no cancer, cancer, post‐cancer survivorship, and death. Model outcomes were costs (2015 United States Dollars [USD]), effectiveness (life years [LY] gained), and incremental cost‐effectiveness ratio (ICER; change in cost/LY gained). One‐way sensitivity analyses and probabilistic sensitivity analyses examined parameter uncertainty. Results The model showed a mean cost of $46 496 and$117 102 and yielded 23 and 27 LY for the nonsurveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17 125 per additional LY gained. At the commonly accepted willingness to pay threshold of$100 000/life‐year gained, surveillance had a 98% probability of being the most cost‐effective strategy for early cancer detection in this high‐risk population. Conclusions Presymptomatic cancer surveillance is cost‐effective for patients with germline pathogenic variants in TP53. Lack of insurance coverage or reimbursement in this population may have significant consequences and leads to undetected cancers presenting in later stages of disease with worse clinical outcomes

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

PURPOSE: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of alterations () in pediatric cancers to inform future clinical trial design. METHODS: Tumors with alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children\u27s Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an alteration was identified by OncoPanel sequencing were further assessed. RESULTS: We identified 41 patients with tumors harboring an oncogenic alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions (:: [n = 3], :: [n = 1], :: [n = 1], :: [n = 1], and :: [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION: In summary, activating alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors