Employing RNA sequencing to enhance treatment options for cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3628-3628
Author(s):  
Gargi D. Basu ◽  
Janine LoBello ◽  
Audrey Ozols
Keyword(s):  
Rna Sequencing ◽  
Myogenic Differentiation ◽  
Treatment Options ◽  
Targeted Treatment ◽  
Low Grade ◽  
Genomic Profiling ◽  
Molecular Abnormalities ◽  
Transcript Variants ◽  
Comprehensive Genomic Profiling ◽  
Variant Detection

3628 Background: Fusions and translocations account for 20% of cancer mortality globally. Maximizing their detection enhances the utility of precision medicine for various solid and hematologic cancers. Practice guidelines stress the importance of RNA sequencing. Novel assay techniques employing a comprehensive genomic profiling approach, including RNA sequencing, yield information beyond conventional DNA next generation sequencing (NGS) alone. Methods: Tumor samples (N = 1517) were assayed combining whole transcriptome (RNA) sequencing, whole exome (DNA) sequencing, and comparison of tumor sequence vs. paired normal DNA. Results were analyzed to determine the frequency of rare and common RNA fusion and variant detection. Findings were mapped to a knowledge-base of targeted treatment options. Results: Analysis detected 79 (5.2%) actionable fusions and 15 (1%) transcript variants across major solid and heme-based malignancies. Notably, we observed actionable transcript variants that are not detectable at the DNA level including: EGFRvIII, EGFRvIVa and EGFRvIVb in GBM; ARv7 in prostate, and METe14 in TNBC. Many fusion cases (42%, n = 33) had no other actionable molecular abnormalities. Novel fusions included: SLC12A/ROS1 in low-grade spindle cell neoplasm with myogenic differentiation, KANK1/NTRK2 in ganglioneuroblastoma, ETV6/NTRK3 in metastatic mammary analogue secretory carcinoma, FGFR1/SCT in germ cell tumor, ZNF33B/RET fusion in GBM, SH3BP4/ERBB4 and EML4/ALK in RCC, VTCN1/NRG1 in pancreatic cancer, and AGRN/NRG1 in cholangiocarcinoma. More common actionable fusion events included: EML4/ALK in NSCLC, KIAA1549/BRAF in pilocytic astrocytoma, FGFR2 and FGFR3 in cholangiocarcinoma and urothelial cancers and ESR1 in endocrine therapy-resistant breast cancers. The fusion events detected in heme-based malignancies included MLLT10 and MLLT4 in AML, BCR/ABL in leukemias, TCF3/PBX1 in B cell ALL, NPM1/ALK in ALCL, and novel fusion CIITA/CD274 in DLBCL. All RNA fusions and transcript variants found were matched to FDA-approved or investigational treatment options. Conclusions: Maximizing the rate of variant detection for targeted therapy relies on precise identification of common and rare fusion events. Without the addition of RNA sequencing, 15 transcript variants in our cohort would have been missed and 33 of the fusions may have gone undetected by conventional DNA NGS testing, resulting in zero targeted treatment options for this vulnerable population. Further use of comprehensive genomic profiling is vital to optimizing cancer care.

scholarly journals Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Maurício Fernando Silva Almeida Ribeiro ◽  
Micelange Carvalho de Sousa ◽  
Samir Abdallah Hanna ◽  
Marcos Vinicius Calfat Maldaun ◽  
Ceci Obara Kurimori ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Systemic Treatment ◽  
Treatment Options ◽  
Axial Skeleton ◽  
Low Grade ◽  
Complete Excision ◽  
Systemic Treatments ◽  
Tumor Reduction ◽  
Comprehensive Genomic Profiling ◽  
Multifocal Recurrence

Introduction. Chordomas are rare malignancies of bone origin that occur in the axial skeleton, typically the skull base and lumbar/sacral regions. Although often classified as low-grade neoplasms, its locally infiltrative behavior may result in significant morbidity and mortality. Optimal surgical resection may be curative, but up to 50% of the cases relapse within 5 years, and currently there are no systemic treatments approved in this setting. A large proportion of these tumors express stem-cell factor receptor (c-KIT) and platelet-derived growth factor receptors (PDGFRs), providing a rationale for the use of tyrosine-kinase inhibitors (TKIs). Case report. A 27-year-old male presented with recurrent chordoma of the lumbar spine 4 years after initial diagnosis. Salvage therapies in the interval included repeat resections and radiation therapy. He ultimately developed multifocal recurrence not amenable to complete excision or reirradiation. A comprehensive genomic profiling assay was performed and revealed nondrugable alterations. Decision was made to proceed with systemic treatment with pazopanib 800 mg/day, resulting in tumor reduction (−23.1% reduction in size) and prolonged disease control. Conclusion. For this patient with a multiple recurrent chordoma and limited treatment options, pazopanib resulted in sustained clinical benefit following initial tumor reduction.

scholarly journals Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Fiona Turkes ◽  
Juliet Carmichael ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Genomic Aberrations ◽  
Oncology Treatment

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

scholarly journals TNS1- ALK Fusion in a Recurrent, Metastatic Uterine Mesenchymal Tumor Originally Diagnosed as Leiomyosarcoma

2019 ◽  
Vol 48 (1) ◽  
pp. 116
Author(s):  
Jessica Lee ◽  
Arun Singh ◽  
Siraj M. Ali ◽  
Douglas I. Lin ◽  
Samuel J. Klempner
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Standard Of Care ◽  
Genomic Profiling ◽  
Curative Intent ◽  
Case Identification ◽  
Complementary Role ◽  
Comprehensive Genomic Profiling ◽  
Standard Of Care Treatment

<p><strong>Objective.</strong> We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care.</p><p><strong>Case Report.</strong> The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP) identifying an TNS1-ALK fusion.</p><p><strong>Conclusion. </strong>In this case, identification of the ALK kinase fusion permitted enrollment in a matched mechanism driven clinical trial after exhausting standard of care treatment options. CGP raises the possibility of uterine inflammatory myofibroblastic tumor as an alternative diagnosisto leiomyosarcoma, highlighting the complementary role of CGP beyond immunohistochemical analyses.</p>

Penile and uterine cervical squamous cell carcinomas: A comparative genomic profiling study.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 514-514 ◽  
Author(s):  
Joseph Jacob ◽  
Rubin Pinkhasov ◽  
Oleg Shapiro ◽  
Nick Liu ◽  
Laurie M. Gay ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Treatment Options ◽  
Cervical Squamous Cell Carcinoma ◽  
Mtor Pathway ◽  
Comparative Genomic ◽  
High Status ◽  
Genomic Profiling ◽  
Hpv Status ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

514 Background: Metastatic penile (mPSCC) and uterine cervical squamous cell carcinoma (mCSCC) are aggressive forms of malignancy with limited treatment options. We used comprehensive genomic profiling (CGP) to compare the genomic alterations (GA) and their potential impact on targeted and immunotherapy options of mPSCC and mCSCC. Methods: 78 metastatic mPSCC and 604 mCSCC underwent CGP using a hybrid-capture-based next-generation sequencing assay with a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median age of mPSCC men was higher than mCSCC women. The HPV+/CDKN2A- status was more frequent in the mCSCC than mPSCC. The GA/tumor were similar for both tumor types (table). TP53 mutations were more common in mPSCC likely linked to loss of original HPV+ status. TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC. MSI-High status was extremely rare in all cases, but the relatively high frequencies of TMB ≥ 10/20 mut/Mb in both mPSCC and mCSCC were noteworthy. Examples of patients with mCSCC and mPSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC and mPSCC share a variety of genomic features, the 2 tumor types can nonetheless be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with viral identification much higher in the mCSCC group. There are opportunities for targeted therapies in both groups predominantly identified in the MTOR pathway. Numerous cases with significantly elevated TMB in both mPSCC and mCSCC suggest that immunotherapies might be of benefit in a subset of patients. [Table: see text]

scholarly journals Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options

2017 ◽  
Vol 22 (7) ◽  
pp. 834-842 ◽  
Author(s):  
Laurie M. Gay ◽  
Sungeun Kim ◽  
Kyle Fedorchak ◽  
Madappa Kundranda ◽  
Yazmin Odia ◽  
...  
Keyword(s):  
Treatment Options ◽  
Additional Treatment ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling

scholarly journals Cell-Free DNA Analysis Demonstrates Comprehensive Genomic Profiling and a Facile Method to Sensitively in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5603-5603
Author(s):  
Juan Du ◽  
Jing Lu ◽  
Wanting Qiang ◽  
Lu Li ◽  
Jin Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Copy Number ◽  
Genomic Profiling ◽  
Cell Free Dna ◽  
Bone Marrow Biopsies ◽  
Molecular Abnormalities ◽  
Free Dna ◽  
Comprehensive Genomic Profiling

Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by complex cytogenetic and molecular abnormalities including translocations involving the immunoglobin heavy chain locus and mutations involving numerous oncogenic signaling pathways. Fluorescence in situ hybridization (FISH) has emerged as the most useful current cytogenetic assessment and provide a new level of insight into the correlation of myeloma prognosis risk model. However, the identification or sorting of malignant cells is required before FISH probes and only involved expansion of the types of probe and number of detectable targets is reached. Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with cancer precision medicine and patient prognosis. Methods: In this retrospective cohort study, we identified 37 patients from 9 relapsed/refractory (RR) and 33 newly diagnosed (ND) patients were analyzed for chromosomal copy number imbalance using the ultrasensitive chromosomal aneuploidy detector (UCAD) platform. Results: Chromosome copy number aberration (CNA) were frequently (82.6%, N=46) detected in MM plasma cell free DNA. Applying UCAD to cfDNA, FISH in CD138 purified bone marrow aspirates, and some matched bone marrow biopsies, we find concordance in copy number alterations (~81%) between liquid and tumor biopsies. Significant copy number changes, including 1q gains, 13q deletion and 17p deletion could be found in 57.89%, 54.05%, and 16.67% in plasma of MM, which is higher percentage than FISH assay (46.81%, 28.26%, and 8.89%), respectively. Besides, chromosome 6p and 6q were determined the higher frequency aberration from UCAD. Moreover, a higher frequency of copy number aberrations and variations was detected in RR patients than ND (100% vs 78.4%, respectively), obviously CNAs heterogeneity displayed in advanced disease. In the inconsistent some samples, UCAD from the plasma and bone marrow showed the similar results, which indicated the FISH is underdetermined and insensitivity in some patients' routine inspection. Conclusion: We conclude that cfDNA analysis as an adjunct to BM biopsy represents a noninvasive and broaden the applicability strategy for comprehensive genomic profiling and therapeutic monitoring of MM. Disclosures No relevant conflicts of interest to declare.

Implementation of reflexive genomic profiling in non-squamous NSCLC: Results of single center experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
Jacqueline T Brown ◽  
Andrew R Moore ◽  
Joshua E Reuss ◽  
Nicholas I Simon ◽  
Ryan D. Gentzler ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Single Gene ◽  
Treatment Options ◽  
Driver Mutations ◽  
Genomic Profiling ◽  
Chi Square ◽  
Single Center Experience ◽  
Before And After ◽  
Comprehensive Genomic Profiling ◽  
Number Of Treatment

e13010 Background: Identification of oncogenic driver mutations (ODM) and targeted therapies have increased the number of treatment options for patients (pts) with non-squamous non-small cell lung cancer (ns-NSCLC). Different methods exist to detect ODM and there is no standard approach. This study examines the changes in detection of ODM over a 2-year period before and after implementing reflexive genomic testing using next generation sequencing (NGS) in January 2015. Methods: We retrospectively reviewed ns-NSCLC cases (stages I-IV) in 2014 and 2015 using the UVA Cancer Registry. We identified pts with pathologically-confirmed ns-NSCLC and reviewed any genotyping - single gene pyrosequencing, NGS, or FISH for gene rearrangements - within 90 days of pathologic confirmation. Comprehensive genomic profiling (CGP) was defined as both NGS and ALK/ROS1 FISH. Chi-square analyses were generated using SAS 9.4. Results: A total of 360 pts were included. 60% had genotyping while 19% underwent CGP. Mutations are summarized in the table below. From 2014 to 2015, genotyping increased from 50% to 69% (p<0.001), with CGP increasing from 2% to 48% of testing performed (p<0.001). Detection of oncogene driver mutations increased from 28% to 46% (p=0.009). Doubletons (pts with 2 driver mutations) increased from 0% to 5% (p=0.036). Conclusions: Reflexive CGP significantly increased the rate of detection of ODM at our center with results similar to previous studies. Previous studies detected low rates of doubleton mutations, perhaps due to lack of uniform NGS testing. Utilization of NGS may increase detection of doubleton mutations, for which further study is necessary to evaluate efficacy of targeted therapies. For centers without reflexive CGP, implementing this approach is likely to increase rates of ODM detection and expand treatment options. [Table: see text]

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