scholarly journals P13.14 Use of Foundation one CDx for molecular screening in patients with primary brain tumors: Gustave Roussy Experience

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii65
Author(s):  
C Baldini ◽  
W Boulfoul ◽  
L Lacroix ◽  
E Rouleau ◽  
J Scoazec ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Tumors ◽  
Tumor Tissue ◽  
Therapeutic Strategies ◽  
Braf V600e ◽  
Tumor Type ◽  
Molecular Screening ◽  
Primary Brain Tumors ◽  
Molecular Alterations ◽  
Multidisciplinary Meeting

Abstract BACKGROUND Patients with primary brain tumors usually have poor prognosis and few therapeutic options. However recent report showed that they may benefit from molecular screening to improve treatment benefit and enrollment in clinical trials. We aimed to evaluate if molecular screening using Foundation One Dx may help therapeutic strategies in primary brain tumor patients. MATERIAL AND METHODS Between October 2018 and December 2018, we enrolled prospectively patients in the MOSCATO (Molecular Screening for cancer Treatment Optimization) 02 trial using the Foundation One Dx test. Patients were eligible if they had good Performans status (PS) (0 or 1) and tumor tissue material available. Results were reviewed during a molecular multidisciplinary meeting weekly at the Drug Development Department at Gustave Roussy to decide on orientation and matched therapy according to molecular alterations. RESULTS Finally thirty-three patients were enrolled in the study. Twenty six tumor tissues were analysed and 7 patients were screen failures due to tumor tissue unavailability. Median age was 49 years old (19 - 72). Patients had a good PS with a median of 1 (0–2) and were mostly males (76%). The most common tumor type was glioblastoma (79%). Five patients had a high grade tumor including 2 medulloblastomas. Median time between consent and multidisciplinary meeting was 70 days (49 - 156). Median percentage of tumor cells was 78% (30–80%). The tumor mutational burden (TMB) was available in 26 patients. The median TMB was 4 mutations per megabase (0 - 277). The most frequent alterations were TERT promoter mutation 22/26 (85%), CDKN2A loss 14/26 (54%), MTAP loss 11/26 (42%), EGFR amplification (38%) including 4 EGFRvIII amplification, TP53 mutation and PTEN deletion 9/26 (35%) respectively, PIK3CA mutation 5/26 (19%), CDK4 or 6 amplification 4/26 (15%), NF1 mutation 3/26 (12%), 2 IDH1 mutations, 2 MET amplifications, 2 HGF amplifications, 1 FGFR2 mutation, 1 BRAF V600E mutation, 1 PDGFRA amplification, 1 EZH2 mutation and 1 SMARCA4 mutation. Finally 11 patients (42%) were oriented according to molecular alterations (EGFR amplifications, BRAF mutation), 1 patient was treated and is ongoing with a BRAF inhibitor and 1 patient is in screening in atrial with an EGFR inhibitor. CONCLUSION Molecular screening with Foundation One Dx test is feasible in patients with primary brain tumors and can help therapeutic strategies. However the time between consent and multidisciplinary meeting was the main limitation to our study and affected enrollment in clinical trials.

EPID-17. COMPARATIVE EPIDEMIOLOGY OF PRIMARY BRAIN TUMORS AMONG ADOLESCENTS AND YOUNG ADULTS (AYA)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi89-vi89
Author(s):  
Nayan Lamba ◽  
Bryan Iorgulescu
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Cox Regression ◽  
Adolescent And Young Adult ◽  
Lower Grade ◽  
Diffuse Glioma ◽  
Tumor Type ◽  
Primary Brain Tumors ◽  
Diffuse Gliomas ◽  
Hiv Aids

Abstract INTRODUCTION We utilized national registry data to evaluate the unique epidemiology of primary adolescent and young adult (AYA) brain tumors according to the WHO2016 classification. METHODS AYA patients (15≤age≤39) presenting between 2004-2017 with a brain tumor were identified by ICD-O-3 coding from the National Cancer Database (comprising >70% of newly-diagnosed cancers in the U.S.), and compared to pediatric and adult populations. Epidemiology and overall survival (estimated by Kaplan-Meier techniques and multivariable Cox regression) were assessed by WHO2016 tumor type. RESULTS 108,705 AYA brain tumor patients were identified (56.9% female), compared to 23,928 pediatric (46.8% female) and 748,272 adult (55.6% female) patients. Among the 69.4% of AYA brain tumors with pathological diagnosis, diffuse gliomas (31.4%), sellar tumors (19.2%), and meningiomas (15.3%) predominated in both sexes. Diffuse glioma (31.4%), sellar (19.2%), cranial nerve (7.3%), and mesenchymal non-meningothelial (4.1%) tumors represented a greater proportion of AYA brain tumors than in either pediatric or adult populations. A majority of all intracranial GCTs (59.2%) and neuronal & mixed neuronal-glial tumors (51.6%) presented during AYA. Although the prevalence of diffuse gliomas was similar between AYAs and adults, AYA gliomas were more likely to be grade 2-3 astrocytomas (38.9% vs 14.3%) and oligodendrogliomas (19.3% vs 4.3%) than in adults. GBMs represented 76.0% of adult diffuse gliomas vs. only 25.7% of AYA diffuse gliomas, but with a similar prevalence of MGMT promoter methylation (40.8% vs 38.4%). Notably, 50.7% of AYA PCNSLs were associated with HIV/AIDS, vs only 7.1% in adults (p< 0.001). CONCLUSIONS The distribution, epidemiology, and survival outcomes of primary brain tumors in the AYA population are distinct from their pediatric and adult counterparts. Notably, AYA infiltrative gliomas were more often of lower grade than adults and AYA PCNSL were far more likely to be associated with HIV/AIDS. Primary brain tumors in AYA patients require specialized management.

scholarly journals Apolipoprotein D Expression in Primary Brain Tumors: Analysis by Quantitative RT-PCR in Formalin-fixed, Paraffin-embedded Tissue

2005 ◽  
Vol 53 (8) ◽  
pp. 963-969 ◽  
Author(s):  
Stephen B. Hunter ◽  
Vijay Varma ◽  
Bahig Shehata ◽  
J.D.L. Nolen ◽  
Cynthia Cohen ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Type ◽  
Rt Pcr ◽  
Who Grade ◽  
Primary Brain Tumors ◽  
Formalin Fixed Paraffin ◽  
Pilocytic Astrocytomas ◽  
Formalin Fixed Paraffin Embedded ◽  
Apolipoprotein D ◽  
Formalin Fixed

Apolipoprotein D (apoD) expression has been shown to correlate both with cell cycle arrest and with prognosis in several types of malignancy, including central nervous system astrocytomas and medulloblastomas. ApoD expression was investigated by real-time quantitative RT-PCR using RNA extracted from 68 formalin-fixed, paraffin-embedded brain specimens. Glyceraldehyde phosphate dehydrogenase was used as an internal control. Quantitation was achieved on all specimens. Sixteen poorly infiltrating WHO grade I glial neoplasms (i.e., pilocytic astrocytomas and gangliogliomas) showed an average 20-fold higher apoD expression level compared with the 20 diffusely infiltrating glial neoplasms (i.e., glioblastoma, anaplastic astrocytoma, oligodendrogliomas; p=0.00004). A small number of exceptions (i.e., two high-expressing glioblastomas and three low-expressing gangliogliomas) were identified. Analyzed as individual tumor groups, poorly infiltrating grade I pilocytic astrocytomas and gangliogliomas differed significantly from each tumor type within the diffusely infiltrating higher-grade category ( p<0.05 for each comparison) but not from each other ( p>0.05). Conversely, each individual tumor type within the diffusely infiltrating category differed significantly from both pilocytic astrocytomas and gangliogliomas ( p<0.05) but did not vary from other infiltrating tumors ( p>0.05). Ependymomas, non-infiltrating grade II neoplasms, expressed levels of apoD similar to or lower than levels expressed by the diffusely infiltrating gliomas. Ten medulloblastomas with survival longer than 3 years averaged slightly higher apoD expression than four fatal medulloblastomas; however, this result was not statistically significant and individual exceptions were notable. In 17 of the medulloblastomas, MIB-1 proliferation rates quantitated by image cytometry did not correlate with apoD expression. In addition, apoD expression was 5-fold higher in the slowly proliferating grade I glial neoplasms compared with non-proliferating normal brain tissue ( p=0.01), suggesting that apoD expression is not simply an inverse measure of proliferation. ApoD expression measured by quantitative RT-PCR may be useful in the differential diagnosis of primary brain tumors, particularly pilocytic astrocytomas and gangliogliomas.

scholarly journals P14.127 From next generation sequencing and comparative genomic hybridization to personalised medicine for adult primary brain tumors: the profiler trial

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii99-iii99
Author(s):  
A Bonneville-levard ◽  
D Frappaz ◽  
D Pissaloux ◽  
Q Wang ◽  
D Perol ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Next Generation Sequencing ◽  
Brain Tumors ◽  
Comparative Genomic Hybridization ◽  
Comparative Genomic ◽  
Next Generation ◽  
Genomic Hybridization ◽  
Primary Brain Tumors ◽  
Generation Sequencing

Abstract BACKGROUND Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors. MATERIAL AND METHODS Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy. RESULTS between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression. CONCLUSION routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.

Pretreatment Neuropsychological Status and Associated Factors in Children with Primary Brain Tumors

Neurosurgery ◽  
1990 ◽  
Vol 27 (6) ◽  
pp. 887-891 ◽  
Author(s):  
Bonnie Brookshire ◽  
Donna R. Copeland ◽  
Bartlett D. Moore ◽  
Joann Ater
Keyword(s):  
Brain Tumors ◽  
Motor Skills ◽  
Neuropsychological Test ◽  
Fine Motor ◽  
Tumor Type ◽  
Primary Brain Tumors ◽  
Normal Limits ◽  
Neuropsychological Status ◽  
Motor Tests ◽  
Visual Motor

Abstract We report on the neuropsychological status of 31 children with primary brain tumors who underwent assessment before receiving therapy. Overall, the children performed within normal limits in all test areas. The exception was the group with anterior hemispheric tumors who demonstrated deficits in executive cognitive functions. Also, when compared according to tumor type, children with midline tumors and hydrocephalus performed more poorly than others on measures of intelligence, executive abilities, visual-motor skills, and fine-motor functions. Although one-half to two-thirds of the children with supratentorial midline and infratentorial tumors had cranial nerve, oculomotor, or cerebellar deficits, only the latter were associated with specific neuropsychological deficits (poorer performance on fine-motor and visual-motor tests). Age did not appear to be a factor in these children's neuropsychological test performances.

scholarly journals Small Molecule and Monoclonal Antibody Therapies in Neurooncology

2005 ◽  
Vol 12 (2) ◽  
pp. 116-124 ◽  
Author(s):  
Nicholas Butowski ◽  
Susan M. Chang
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Small Molecule ◽  
Cell Biology ◽  
Genetic Defect ◽  
Cytotoxic Agents ◽  
Molecular Alterations ◽  
Molecular Abnormalities

Background: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors. Methods: We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years. Results: Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing. Conclusions: The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed.

Proton Magnetic Resonance Spectroscopic Imaging in Children With Recurrent Primary Brain Tumors

2000 ◽  
Vol 18 (5) ◽  
pp. 1020-1020 ◽  
Author(s):  
Katherine E. Warren ◽  
Joseph A. Frank ◽  
Jeanette L. Black ◽  
Rene S. Hill ◽  
Josef H. Duyn ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Brain Tumors ◽  
Biochemical Markers ◽  
Proton Magnetic Resonance ◽  
Spectroscopic Imaging ◽  
Magnetic Resonance Spectroscopic Imaging ◽  
Investigational Drug ◽  
Tumor Type ◽  
Histologic Subtype ◽  
Primary Brain Tumors

PURPOSE: Proton magnetic resonance spectroscopic imaging (1H-MRSI) is a noninvasive technique for spatial characterization of biochemical markers in tissues. We measured the relative tumor concentrations of these biochemical markers in children with recurrent brain tumors and evaluated their potential prognostic significance. PATIENTS AND METHODS: 1H-MRSI was performed on 27 children with recurrent primary brain tumors referred to our institution for investigational drug trials. Diagnoses included high-grade glioma (n = 10), brainstem glioma (n = 7), medulloblastoma/peripheral neuroectodermal tumor (n = 6), ependymoma (n = 3), and pineal germinoma (n = 1). 1H-MRSI was performed on 1.5-T magnetic resonance imagers before treatment. The concentrations of choline (Cho) and N-acetyl-aspartate (NAA) in the tumor and normal brain were quantified using a multislice multivoxel method, and the maximum Cho:NAA ratio was determined for each patient’s tumor. RESULTS: The maximum Cho:NAA ratio ranged from 1.1 to 13.2 (median, 4.5); the Cho:NAA ratio in areas of normal-appearing brain tissue was less than 1.0. The maximum Cho:NAA ratio for each histologic subtype varied considerably; approximately equal numbers of patients within each tumor type had maximum Cho:NAA ratios above and below the median. Patients with a maximum Cho:NAA ratio greater than 4.5 had a median survival of 22 weeks, and all 13 patients died by 63 weeks. Patients with a Cho:NAA ratio less than or equal to 4.5 had a projected survival of more than 50% at 63 weeks. The difference was statistically significant (P = .0067, log-rank test). CONCLUSION: The maximum tumor Cho:NAA ratio seems to be predictive of outcome in children with recurrent primary brain tumors and should be evaluated as a prognostic indicator in newly diagnosed childhood brain tumors.

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity

2020 ◽  
Vol 133 (6) ◽  
pp. 1704-1709 ◽  
Author(s):  
Aaron Bernstein ◽  
Oliver D. Mrowczynski ◽  
Amrit Greene ◽  
Sandra Ryan ◽  
Catherine Chung ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Pilocytic Astrocytoma ◽  
Case Series ◽  
Mek Inhibitor ◽  
Pleomorphic Xanthoastrocytoma ◽  
Inhibitor Therapy ◽  
Braf V600e ◽  
Dual Inhibitor ◽  
Cutaneous Toxicity ◽  
Primary Brain Tumors

OBJECTIVEBRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.METHODSThe authors treated 4 BRAF V600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib.RESULTSThe patients with pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma experienced near-complete radiographic and complete clinical responses after 8 weeks of therapy. A substantial partial response (by RANO [Response Assessment in Neuro-Oncology] criteria) was observed in the patient with ganglioglioma. The patient with craniopharyngioma developed dramatic, diffuse verrucal keratosis within 2 weeks of starting dabrafenib. This completely resolved within 2 weeks of adding trametinib.CONCLUSIONSDual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor–related adverse events.

Palliative endoscopic third ventriculostomy for pediatric primary brain tumors: a single-institution case series

2021 ◽  
pp. 1-8
Author(s):  
Robert C. Rennert ◽  
Michael G. Brandel ◽  
Shanmukha Srinivas ◽  
Divya Prajapati ◽  
Omar M. Al Jammal ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Endoscopic Third Ventriculostomy ◽  
Successful Outcome ◽  
Third Ventriculostomy ◽  
Tumor Type ◽  
Primary Brain Tumors ◽  
Leptomeningeal Spread ◽  
Significant Difference ◽  
The Mean

OBJECTIVE Children with nonoperative brain tumors, such as diffuse intrinsic pontine gliomas (DIPGs), often have life-threatening hydrocephalus. Palliative shunting is common in such cases but can be complicated by hardware infection and mechanical failure. Endoscopic third ventriculostomy (ETV) is a minimally invasive alternative to treat hydrocephalus without implanted hardware. Herein, the authors report their institutional experience with palliative ETV for primary pediatric brain tumors. METHODS The authors conducted a retrospective review of consecutive patients who had undergone palliative ETV for hydrocephalus secondary to nonresectable primary brain tumors over a 10-year period at Rady Children’s Hospital. Collected variables included age, sex, tumor type, tumor location, presence of leptomeningeal spread, use of a robot for ETV, complications, ETV Success Score (ETVSS), functional status, length of survival, and follow-up time. A successful outcome was defined as an ETV performed without clinically significant perioperative complications or secondary requirement for a new shunt. RESULTS Fifteen patients met the study inclusion criteria (11 males, 4 females; average age 7.9 years, range 0.8–21 years). Thirteen patients underwent manual ETV, and 2 patients underwent robotic ETV. Preoperative symptoms included gaze palsy, nausea/vomiting, headache, lethargy, hemiparesis, and seizures. Tumor types included DIPG (3), intraventricular/thalamic glioblastoma (2), and leptomeningeal spread of medulloblastoma (2), anaplastic oligo-/astrocytoma (2), rhabdoid tumor (2), primitive neuroectodermal tumor (1), ganglioglioma (1), pineoblastoma (1), and embryonal carcinoma (1). The mean preoperative ETVSS was 79 ± 8.8. There was 1 perioperative complication, a wound breakdown consistent with refractory hydrocephalus. The mean follow-up was 4.9 ± 5.5 months overall, and mean survival for the patients who died was 3.2 ± 3.6 months. Two patients remained alive at a mean follow-up of 15.7 months. Palliative ETV was successful in 7 patients (47%) and unsuccessful in 8 (53%). While patients with successful ETV were significantly older (11.9 ± 5.6 vs 4.4 ± 4.1 years, p = 0.010), there were no significant differences in preoperative ETVSS (p = 0.796) or postoperative survival (p = 0.476) between the successful and unsuccessful groups. Overall, functional outcomes were similar between the two groups; there was no significant difference in posttreatment Karnofsky Performance Status scores (68.6 ± 19.5 vs 61.3 ± 16.3, p = 0.454), suggesting that including ETV in the treatment algorithm did not worsen outcomes. CONCLUSIONS Palliative ETV is a safe and potentially efficacious treatment option in selected pediatric patients with hydrocephalus from nonoperative brain tumors. Close follow-up, especially in younger children, is required to ensure that patients with refractory symptoms receive appropriate secondary CSF diversion.

DNA Diagnosis in Oncology

1994 ◽  
Vol 10 (4) ◽  
pp. 644-654
Author(s):  
Janet D. Rowley
Keyword(s):  
Tumor Tissue ◽  
Response To Therapy ◽  
Tumor Type ◽  
Dna Diagnosis ◽  
Prognostic Information ◽  
Genetic Changes ◽  
Molecular Alterations ◽  
Cytogenetic Aberrations ◽  
Precise Diagnosis ◽  
Cytogenetic Changes

AbstractOur understanding of the genetic changes that transform normal cells into malignant cells is increasing at a remarkable pace. Some of the changes involve detectable cytogenetic aberrations, whereas others are identifiable only at the molecular level. Many of the structural cytogenetic changes have also been defined molecularly because the genes involved have been cloned. Thus, we are approaching the stage in which the DNA obtained from tumor tissue can be analyzed to detect the presence of a series of chromosomal and molecular alterations. These studies provide important information regarding the precise diagnosis of the tumor type as well as prognostic information about the likely response to therapy and survival.

scholarly journals MEK Inhibition with Trametinib in Patients with Non-Langerhans Cell Histiocytosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2319-2319
Author(s):  
Filip Janku ◽  
Harsh Patel ◽  
Vaijayanthi Kandadai Raghavan ◽  
Aaron Goodman ◽  
Tamara G. Barnes ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Tumor Tissue ◽  
Mapk Pathway ◽  
Braf V600e ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Advisory Committees ◽  
Molecular Alterations ◽  
Rosai Dorfman Disease

Background: Activation of the MAPK pathway through BRAF mutations or other molecular alterations is a hallmark of the non-Lagerhans cell histiocytosis (non-LCH) such Erdheim-Chester disease (ECD) or Rosai-Dorfman disease (RDD). Conventional clinical molecular testing of tumor tissue fails to identify targetable molecular alteration in about one third of patients with non-LCH. Targeting the MAPK kinase pathway in non-LCH with small molecule inhibitors can be effective in patients with BRAF or other MAPK molecular alterations. Methods: Patients with non-LCH with any, unknown or pending molecular profile (tumor tissue targeted next generation sequencing [NGS], plasma cell-free [cf] DNA targeted NGS) were treated with trametinib, an oral inhibitor of MEK1/2 kinase. Treatment outcomes such as response per RECIST 1.1 or RANO in case of central nervous system involvement, time on therapy and adverse event (AE) were analyzed. Results: Total of 16 patients with ECD (n=12) or RDD (n=3) or ECD/LCH (n=1) were started on oral trametinib dose of 1 mg to 2 mg daily. Of these 16 patients, 3 patients were found to have BRAF V600E mutation in tumor and/or plasma cfDNA, 7 patients had other alteration(s) putatively activating the MAPK pathway (CAPZA2-BRAF fusion [n=1], RAF1 amplification [n=1], GNAS mutation [n=3], HMGA2 rearrangement [n=1], NF1 mutation [n=1], KRAS mutation [n=1] and MAP2K1 mutation [n=1]) and 2 patients had no results from molecular testing. Patients were treatment-naïve (n=9) or received 1 (n=3) or 2 (n=4) prior systemic therapies. To date, 5 (31%) patients had either partial (n=4) or complete response (n=1); 8 (50%) patients had stable disease (n=4) or non-CR/non-PD (n=4) in the absence of measurable disease and 3 (19%) did not have response assessed. At the median follow up of 10.1 months the median progression-free survival has not been reached as only two patients progressed on therapy while 14 remain progression-free for 1.1+ to 36+ months. The therapy was overall well tolerated with grade 1 rash being the most frequent AE. AE > grade 2 included mucositis (n=2), rash (n=2), dizziness (n=1), uveitis (n=1) and decrease in ejection fraction (n=1) and two patients discontinued therapy because of AEs. Conclusions: MEK inhibitor trametinib demonstrated encouraging activity in patients with non-LCH irrespective of underlying molecular profile. Further studies of trametinib in patients with non-LCH are warranted. Disclosures Janku: Ideaya: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees; Primmune Therapeutics: Consultancy; PureTech Health: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Deciphera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Piqur: Research Funding; Bristol-Myers Squibb: Research Funding; IFM Therapeutics: Membership on an entity's Board of Directors or advisory committees; Synlogic: Membership on an entity's Board of Directors or advisory committees; Sotio: Consultancy; Astex: Research Funding; FujiFilm Corporation and Upsher-Smith Laboratories: Research Funding; Astellas: Research Funding; BioMed Valley Discoveries: Research Funding; Plexxikon: Research Funding; Symphogen: Research Funding; Bayer: Research Funding; Agios: Research Funding; Proximagen: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tovagene: Consultancy, Other: Ownership interests; Immunomet: Consultancy. OffLabel Disclosure: We will discuss trametinib (FDA approved for melanoma) to be used in non-LCH

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