scholarly journals Precision Medicine in Osteosarcoma: MATCH Trial and Beyond

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 281
Author(s):  
Elisa Tirtei ◽  
Anna Campello ◽  
Sebastian D. Asaftei ◽  
Katia Mareschi ◽  
Matteo Cereda ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Age Distribution ◽  
Malignant Tumour ◽  
Genetic Alterations ◽  
Match Trial ◽  
Genomic Landscape ◽  
Technical Issues ◽  
Real Challenge ◽  
Tissue Origin ◽  
Generation Sequencing

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient’s tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients.

scholarly journals Molecular and Genomic Profiling of Lung Cancer in the Era of Precision Medicine: A Position Paper from the Italian Association of Thoracic Oncology (AIOT)

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1627
Author(s):  
Nicola Normanno ◽  
Massimo Barberis ◽  
Filippo De Marinis ◽  
Cesare Gridelli ◽  
Keyword(s):  
Lung Cancer ◽  
Clinical Practice ◽  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Genetic Alterations ◽  
Position Paper ◽  
Genomic Profiling ◽  
Next Generation ◽  
Italian Association ◽  
Generation Sequencing

The identification of the optimal cancer treatment has become progressively more intricate for non-small-cell lung cancer (NSCLC) patients due to the multitude of options available. The testing of biomarkers to predict clinical responses to therapies is pivotal to stratify the patients based on the molecular features of their tumors. The number of actionable genetic alterations to be tested is increasing together with the comprehension of the molecular mechanisms underlying tumor growth and development. The possibility of using next generation sequencing-based approaches enhanced the acquisition of genetic data with potential clinical usefulness, and favored the integration of precision medicine in clinical practice. The availability of targeted sequencing panels that cover genetic alterations in hundreds of genes allows the performance of a comprehensive genomic profiling (CGP) of lung tumors. However, different issues still need to be solved, from the tissue needed for next generation sequencing analysis, to the choice of the test and its interpretation in the clinical context. This position paper from the Italian Association of Thoracic Oncology (AIOT) summarizes the results of a discussion from a Precision Medicine Panel meeting on the challenges to bringing CGP and, therefore, precision medicine into the daily clinical practice.

scholarly journals Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3296
Author(s):  
Ioannis Chanias ◽  
Kristina Stojkov ◽  
Gregor Stehle ◽  
Michael Daskalakis ◽  
Helena Simeunovic ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Myelodysplastic Syndromes ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Future Perspectives ◽  
Hematopoietic Stem ◽  
Secondary Acute Myeloid Leukemia ◽  
Stem And Progenitor Cells ◽  
Unfit Patients ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

scholarly journals LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii372-iii372
Author(s):  
Margot A Lazow ◽  
Austin Schafer ◽  
Mariko D DeWire-Schottmiller ◽  
Adam Lane ◽  
Daniel R Boué ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Rapid Progression ◽  
Low Grade ◽  
Valuable Insight ◽  
Histologic Diagnosis ◽  
Low Grade Gliomas ◽  
Genomic Landscape ◽  
Cdkn2a Deletion ◽  
Diagnostic Biopsy ◽  
Over Time

Abstract INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3087-3087
Author(s):  
David Michael Jackman ◽  
Opeyemi Jegede ◽  
Marjorie Glass Zauderer ◽  
Edith P. Mitchell ◽  
James Zwiebel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Stable Disease ◽  
Objective Response ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Outcome Analysis ◽  
Clinical Activity ◽  
Match Trial ◽  
Best Response

3087 Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (< 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]

scholarly journals The integration of emerging omics approaches to advance precision medicine: How can regulatory science help?

2018 ◽  
Vol 2 (5) ◽  
pp. 295-300
Author(s):  
Joan E. Adamo ◽  
Robert V. Bienvenu ◽  
F. Owen Fields ◽  
Soma Ghosh ◽  
Christina M. Jones ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Working Group ◽  
Regulatory Science ◽  
Translational Science ◽  
Next Generation ◽  
Clinical Validity ◽  
Knowledge Gaps ◽  
Recent Advances ◽  
Generation Sequencing

Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.

scholarly journals Co-occurrence of immature T-lymphoblastic lymphoma and acute myeloid leukemia—microenvironment-dependent lineage differentiation derived from a common progenitor?

2021 ◽  
Author(s):  
Edit Porpaczy ◽  
Wolfgang R. Sperr ◽  
Renate Thalhammer ◽  
Gerlinde Mitterbauer-Hohendanner ◽  
Leonhard Müllauer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Lymphoblastic Lymphoma ◽  
Simultaneous Occurrence ◽  
Next Generation ◽  
T Lymphoblastic Lymphoma ◽  
Generation Sequencing ◽  
Acute Myeloid

AbstractMixed phenotype acute leukemia (MPAL) is an uncommon disease characterized by currently only limited knowledge concerning biology, clinical presentation, and treatment outcome. We here describe a most unusual case of simultaneous occurrence of T-lymphoblastic lymphoma in cervical and mediastinal lymph nodes and acute myeloid leukemia in the bone marrow (BM) successfully treated with allogeneic stem cell transplantation (SCT). Although the blasts in both locations showed additional aberrant expression of other lineage markers (even B-cell markers), diagnostic criteria of MPAL were not fulfilled either in the LN or in the BM. We performed next generation sequencing (NGS) with the objective to look for common genetic aberrations in both tissues. Histology, immunohistochemistry, flow cytometry, AML-associated genetic alterations (FLT3, NPM1, KIT D816V, CEPBA), and clonal T-cell receptor β and γ gene rearrangements were performed according to routine diagnostic workflows. Next generation sequencing and Sanger sequencing were additionally performed in BM and LN. Somatic mutation in the EZH2 gene (p.(Arg684Cys)) was detected in the BM by NGS, and the same mutation was found in the LN. Since an identical genetic aberration (EZH2 mutation) was detected in both locations, a common progenitor with regional dependent differentiation may be involved.

scholarly journals Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy

2021 ◽  
Vol 11 ◽  
Author(s):  
Liang Huang ◽  
Shuanglin Luo ◽  
Xingwei Zhang ◽  
Yonghua Cai ◽  
Fangqin Xue ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Mucinous Carcinoma ◽  
Molecular Signature ◽  
Response To Treatment ◽  
Mutation Rates ◽  
Genomic Features ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
New Treatment ◽  
Generation Sequencing

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF-β pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

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