scholarly journals Investigating the Natural History and Prognostic Nature of NTRK Gene Fusions in Solid Tumors

2021 ◽  
Author(s):  
Limin Zhu ◽  
Brian Hobbs ◽  
Jason Roszik ◽  
Vijaykumar Holla ◽  
David S. Hong
Keyword(s):  
Natural History ◽  
Solid Tumors ◽  
Gene Fusion ◽  
Early Stage ◽  
The Cancer Genome Atlas ◽  
Cancer Center ◽  
Gene Fusions ◽  
Risk Of Progression ◽  
Md Anderson ◽  
Trk Inhibitors

Abstract BackgroundSeveral TRK inhibitors have demonstrated clinical efficacy in patients with solid tumors harboring NTRK gene fusions. However, the natural history and prognostic implications of NTRK fusions in solid tumors remain unknown.MethodsA cohort of 77 MD Anderson Cancer Center patients (MDACC) with NTRK gene fusions was identified and retrospectively compared to a second cohort from the Cancer Genome Atlas (TCGA) database. Due to paucity of events in early stage cancers and lack of TCGA data in rare tumors, 25 randomly selected MDACC patients were matched to 122 TCGA patients without NTRK gene fusion. Next we assessed the associations between NTRK gene fusion and overall (OS) and progression-free survivals (PFS).ResultsAmong the 77 MDACC patients with NTRK gene fusions, 18 NTRK fusion partners were identified. There were insufficient OS events for analysis in the matched cohort. PFS was not significantly different (p=0.49) between the NTRK-fusion positive MDACC patients (median PFS 786 weeks, 95% CI 317-NE) and the NTRK-fusion negative TCGA patients (median PFS NE). The adjusted hazard ratio comparing TCGA patients to MDACC patients was HR=0.72 (95% CI: 0.23-2.33), which trended towards a reduced rate of progression or death experienced by TCGA patients.ConclusionsThis study did not identify statistically significant associations between NTRK fusion and PFS. Nonsignificant trends estimated increases in the risk of progression or death events for patients with NTRK fusions when compared to matched controls. Our findings help illuminate the influence of NTRK fusions on the natural history of a variety of solid tumors.

scholarly journals Early-stage pulmonary adenocarcinoma (T1N0M0): a clinical, radiological, surgical, and pathological correlation of 104 cases. The MD Anderson Cancer Center Experience

2013 ◽  
Vol 26 (8) ◽  
pp. 1065-1075 ◽  
Author(s):  
Annikka Weissferdt ◽  
Neda Kalhor ◽  
Edith M Marom ◽  
Marcelo F Benveniste ◽  
Myrna C Godoy ◽  
...  
Keyword(s):  
Early Stage ◽  
Pulmonary Adenocarcinoma ◽  
Cancer Center ◽  
Pathological Correlation ◽  
Md Anderson

Plasma GH as a diagnostic and prognostic biomarker in HCC without cirrhosis.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 227-227
Author(s):  
Roberto Carmagnani Pestana ◽  
Manal Hassan ◽  
Reham Abdel-Wahab ◽  
Yehia I. Abugabal ◽  
Lauren Girard ◽  
...  
Keyword(s):  
Cox Regression ◽  
Early Stage ◽  
Tnm Staging ◽  
Cancer Center ◽  
Limited Information ◽  
Cox Regression Analysis ◽  
Diagnostic Role ◽  
Md Anderson ◽  
Plasma Gh

227 Background: The association between the GH/IGF-1 axis and HCC was reported in patients (pt) with underlying cirrhosis. However, there is limited information among HCC pt without (w/o) cirrhosis. We herein investigated the role of GH as a circulating biomarker for HCC diagnosis and prognosis in pt w/o cirrhosis. Methods: Under IRB approval, we prospectively enrolled 1267 newly-diagnosed HCC pt in a case control study at the MD Anderson Cancer Center (2000-2015). Controls were healthy individuals (n = 1104). Plasma GH and AFP were measured 274 HCC pt w/o cirrhosis 200 healthy controls. IGF-1 was measured in 133 and 82 pt, respectively. We classified HCC pt into higher and lower GH values (cutoff for women, 3.7 µg/L; men, > 0.9 µg/L). Results: Most pt (74%) were male, with advanced BCLC staging (C-D, 74%) and 61% were older than 60y. Baseline GH was higher in HCC w/o cirrhosis (mean 3.3 µg/L) than controls (mean 0.4 µg/) (p < .001). ROC curve was plotted to assess diagnostic role. The AUC for AFP was 82.9 (p < .001); for GH 78.2 (p < .001). When only non-cirrhotic HCC pt with early stage (CLIP 0-2) and AFP < 20 ng/m were compared to controls, the GH/IGF-1 ratio had high prediction of early stage HCC - AUC 83 (95% CI 78-89%) (p < .0001). At a specificity of 90%, sensitivity of GH/IGF ratio was 67%. In addition, among HCC w/o cirrhosis, higher GH levels correlated with presence of vascular invasion (p < .001) and thrombosis (p = .004), tumor involvement of > 50% liver (p = .003), and more advanced BCLC (p < .001) and TNM staging (p < .001). Median overall survival (months) of HCC pt w/o cirrhosis with high GH levels was 13.1 (10.8-15.4) compared to 37.4 (19.8-55.1) of pt with lower plasma GH (p < .001). Multivariate cox-regression analysis identified high GH as an independent risk factor for mortality (HR = 1.8; 95% CI, 1.3-2.4; p < .001). Conclusions: Our study demonstrates the diagnostic and prognostic role of plasma GH in non-cirrhotic HCC and identifies the GH/IGF-1 ratio as a promising diagnostic marker for early stage HCC w/o cirrhosis and low AFP; this analysis excludes the confounding effect hepatocyte impaired function by presence of cirrhosis. Further studies are warranted to assess the causes of the observed differences.

scholarly journals High Levels of Common Cold Coronavirus Antibodies in Convalescent Plasma Are Associated With Improved Survival in COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Uri Greenbaum ◽  
Kimberly Klein ◽  
Fernando Martinez ◽  
Juhee Song ◽  
Peter F. Thall ◽  
...  
Keyword(s):  
Survival Time ◽  
Common Cold ◽  
Early Stage ◽  
Cancer Center ◽  
Specific Antibodies ◽  
Promising Therapeutic Target ◽  
Younger Age ◽  
Common Domain ◽  
Md Anderson ◽  
Antibody Levels

BackgroundCOVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP.Patients and MethodsPatients ≥18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed.ResultsCCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex.ConclusionsCommon cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.

scholarly journals The landscape of gene fusions in hepatocellular carcinoma

2016 ◽  
Author(s):  
Chengpei Zhu ◽  
Yanling Lv ◽  
Liangcai Wu ◽  
Jinxia Guan ◽  
Xue Bai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Gene Fusion ◽  
Early Stage ◽  
Pcr Analysis ◽  
Gene Fusions ◽  
Fusion Genes ◽  
Rna Seq ◽  
Rt Pcr ◽  
Critical Function

AbstractMost hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages and suffer limited treatment options. Challenges in early stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated.Paired-end RNA sequencing was performed on noncancerous and cancerous lesions in two representative HBV-HCC patients. Potential fusion genes were identified by STAR-Fusion in STAR software and validated by four publicly available RNA-seq datasets. Fourteen pairs of frozen HBV-related HCC samples and adjacent non-tumor liver tissues were examined by RT-PCR analysis for gene fusion expression.We identified 2,354 different gene fusions in the two HBV-HCC patients. Validation analysis against the four RNA-seq datasets revealed only 1.8% (43/2,354) as recurrent fusions that were supported by public datasets. Comparison with four fusion databases demonstrated that three (HLA-DPB2-HLA-DRB1, CDH23-HLA-DPB1, and C15orf57-CBX3) out of 43 recurrent gene fusions were annotated as disease-related fusion events. Nineteen were novel recurrent fusions not previously annotated to diseases, including DCUN1D3-GSG1L and SERPINA5-SERPINA9. RT-PCR and Sanger sequencing of 14 pairs of HBV-related HCC samples confirmed expression of six of the new fusions, including RP11-476K15.1-CTD-2015H3.2.Our study provides new insights into gene fusions in HCC and could contribute to the development of anti-HCC therapy. RP11–476K15.1-CTD–2015H3.2 may serve as a new therapeutic biomarker in HCC.

scholarly journals Unclassified mesenchymal sarcoma with NTRK1-KHDRBS1 gene fusion: a case report of long-term tumor-free survival with crizotinib treatment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weijie Chen ◽  
Huimei Wang ◽  
Dongxian Jiang ◽  
Lijuan Luan ◽  
Yuhong Zhou ◽  
...  
Keyword(s):  
Gene Fusion ◽  
Immunohistochemical Analysis ◽  
Genetic Alterations ◽  
Detection Methods ◽  
Gene Fusions ◽  
Term Survival ◽  
Pseudomyogenic Hemangioendothelioma ◽  
Dendritic Cell Sarcoma ◽  
Trk Inhibitors

Abstract Background Mesenchymal sarcomas are tumors that originate from mesenchymal tissue. Most mesenchymal sarcomas can be accurately classified, but some are unclassifiable in clinical practice. Molecular detection methods enable patients to benefit from molecular-targeted therapies for many cancers, including lung, breast, and bowel cancers. Further, even unclassified tumors can have therapeutic targets. NTRK gene fusions are sporadic genetic alterations that occur across tumor entities. If NTRK gene fusions are detected, TRK inhibitors can be used regardless of the tumor entity. Case presentation This report describes a case with an unclassifiable mesenchymal sarcoma carrying a neurotrophic tyrosine receptor kinase NTRK1-KHDRBS1 gene fusion that was diagnosed and treated at multiple hospitals. Diagnostic work-up included pathological and immunohistochemical analysis, which excluded angiosarcoma, dendritic cell sarcoma, and pseudomyogenic hemangioendothelioma. The patient achieved a long-term survival without tumor relapse after treatment with crizotinib. Conclusions This case will be of significant interest to pathologists because, despite the tumor being unclassified, a molecular target was identified. Although the FDA does not currently approve crizotinib for treatment of patients harboring NTRK gene fusions, this case provides new insights for diagnosis and treatment of mesenchymal sarcomas with NTRK1 gene translocations. Similar to ALKomas, which can be successfully treated using NTRK molecular-targeted therapy, tumors with NTRK gene translocations can be classified as NTRKomas, even when they occur at different organ sites, and with varying histological morphologies, and immunophenotypes.

scholarly journals Thoracic Cancer: 2021 ASCO Annual Meeting Highlights for the Advanced Practitioner

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Elizabeth S. Waxman, RN, MSN, AOCN, ANP-BC
Keyword(s):  
Annual Meeting ◽  
Early Stage ◽  
Cancer Center ◽  
Important Research ◽  
Early Stage Lung Cancer ◽  
Advanced Practitioner ◽  
Thoracic Cancer ◽  
Md Anderson ◽  
Doublet Chemotherapy ◽  
Stage Lung Cancer

Elizabeth S. Waxman, RN, MSN, AOCN®, ANP-BC, of MD Anderson Cancer Center, reviews important research in thoracic cancers presented at the 2021 ASCO Annual Meeting, including atezolizumab in early-stage lung cancer, the addition of doublet chemotherapy to doublet immunotherapy in advanced-stage NSCLC, the first-in-class KRAS G12C inhibitor sotorasib, and the combination of amivantamab and lazertinib. Coverage provided by The ASCO Post.

scholarly journals Investigating the natural history and prognostic nature of NTRK gene fusions in solid tumors

2021 ◽  
Author(s):  
Limin Zhu ◽  
Brian Hobbs ◽  
Jason Roszik ◽  
Vijaykumar Holla ◽  
David S. Hong
Keyword(s):  
Natural History ◽  
Solid Tumors ◽  
Gene Fusions

NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC

2021 ◽  
Author(s):  
Yan Kong ◽  
Rong Bu ◽  
Sandeep Kumar Parvathareddy ◽  
Abdul K Siraj ◽  
Nabil Siraj ◽  
...  
Keyword(s):  
Gene Fusion ◽  
Middle Eastern ◽  
Fish Analysis ◽  
Gene Fusions ◽  
Wild Type ◽  
Pediatric Age Group ◽  
Middle Eastern Population ◽  
Fusion Analysis ◽  
Trk Inhibitors ◽  
Tumor Types

Objective: Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as predictor of targeted therapy since selective NTRK inhibitors are now approved in US and Europe for patients with solid tumors harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinico-pathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency and investigate the utility of pan-Trk immunohistochemistry (IHC) as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. Methods: FISH analysis for NTRK gene fusions and pan-Trk IHC was performed on 315 Middle Eastern PTCs. Correlation of NTRK gene fusion and protein expression with clinico-pathological markers and patient outcome were determined. Results: In our cohort, 6.0% (19/315) patients showed NTRK gene fusions and were significantly associated with pediatric PTC (p = 0.0143), lymph node metastasis (p = 0.0428) and BRAF wild-type tumors (p < 0.0001). Pan-Trk IHC was positive in 9.2% (29/315) of cases and significantly associated with NTRK fusions, with a sensitivity of 73.7% and specificity of 94.9% in this cohort. Conclusions: This study confirms the presence of NTRK fusions in Middle Eastern PTC which is significantly enriched in BRAF wild-type as well as pediatric age group and proposes the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.

The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3132-3132
Author(s):  
Yumeng Zhang ◽  
Bindiya G Patel ◽  
Todd C Knepper ◽  
Dung-Tsa Chen ◽  
Jhanelle Elaine Gray ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Real World ◽  
Targeted Therapies ◽  
Gene Fusion ◽  
Treatment Modalities ◽  
Gene Fusions ◽  
Sequencing Data ◽  
Off Label

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]

The Natural History and Treatment Outcome of De-Novo Chromosome 17p Deletion CLL: A Single Institution Experience with 48 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2041-2041
Author(s):  
Constantine S. Tam ◽  
Michael J. Keating ◽  
Susan O’Brien ◽  
Alessandra Ferrajoli ◽  
Lynne V. Abruzzo ◽  
...  
Keyword(s):  
De Novo ◽  
Prognostic Significance ◽  
Bone Marrow Examination ◽  
Cancer Center ◽  
Dismal Prognosis ◽  
Response Table ◽  
Risk Of Progression ◽  
Progression Risk ◽  
Actuarial Risk ◽  
Md Anderson

Abstract The adverse prognostic significance of chromosome17p deletion (del17p) was established in CLL patients (pts) with pretreated disease, and its significance in patients with previously untreated CLL (“de-novo del17p”) is not well defined. We identified 48 consecutive pts with de-novo del17p within a cohort of 708 previously untreated pts tested by FISH for common CLL aberrations and followed prospectively at the MD Anderson Cancer Center. Characteristics of de-novo 17p pts: median age 61 yrs; Rai 0 31%, I–II 44%, III–IV 25%; B2M≥2N 42%; unmutated IGVH 32/45. The proportion of del17p cells were ≥20% in 35 (73%) pts. Twenty-five (52%) pts had stable disease not requiring immediate therapy, and were observed prospectively; for these pts, the actuarial risk of requiring therapy was 41% at a median follow-up of 19 months. Pts in Rai stage 0 had a low risk of progression to therapy (9%) regardless of IGVH status, whereas the progression risk for Rai I–II pts depended on their IGVH status (figure). Thirty-two pts had commenced therapy, of which 25 were assessable for treatment response (table). Overall (OR) and complete clinical response (CCR) rates were 67% and 33% for rituximab-based therapy, and 84% and 50% for fludarabine & rituximab combinations. Bone marrow examination in 8 CCR pts confirmed that 7 were in flow cytometry negative CR, with normalization of cytogenetics and FISH in 6 of 6 tested. Time to progression for CCR pts was 79% at 18 months, with only 3 relapses to date: notably, 2 relapses were with Richter transformation (one of which was confirmed to be del17p negative), and the only indolent relapse was with a non-del17p clone. Survival for all pts (n=48) from FISH date was 85% at 18 months, and survival from start of therapy (n=32) was 86% at 18 months. Five deaths have occurred to date: two pts died of unrelated causes prior to requirement for CLL therapy, two pts in remission died of complications of therapy, and one pt died of obstructive jaundice related to an undiagnosed pancreatic mass. De-novo del17p does not necessarily imply a dismal prognosis in CLL: the disease course may be indolent especially in Rai 0 disease, and therapy with standard regimens can achieve durable clinical and cytogenetic remissions. All pts who commenced therapy in this study received rituximab, and our favorable survival compared to that reported by the German and United Kingdom trials of F vs FC (median survival 18 months or less) suggest that rituximab may be an important agent in the therapy of del17p CLL. Figure Figure Evaluable Response Comp Clin Resp Flow–CR Remission (months) Rit & GMCSF 4 2 1 1 9, 18+ Rituximab 1 1 1 n/a 42+ Rit & Pred 1 1 0 0 3+ RIT-BASED 6 4 (67%) 2 (33%) 1/5 (20%) 53% @ 18mth Evaluable Response Comp Clin Resp Flow- CR Remission (months) FCR ±GMCSF 11 10 5 3/9 2+,6+,8+,9+,11+,12+,15,22+,22,41+ FCMR 2 1 1 0 3+, 18+ FR 1 0 0 0 n/a PCR 1 1 1 1 19+ CFAR 4 4 2 2 11,11,12,12+ 19 16 (84%) 9 (50%) 6/17 (35%) 62% @ 18mth

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