NIMG-04. PREDICTING THE BRAF MUTATIONAL STATUS IN PATIENTS WITH MELANOMA BRAIN METASTASES USING RADIOMICS - A BICENTRIC STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi127-vi128
Author(s):  
Anna-Katharina Meissner ◽  
Robin Gutsche ◽  
Norbert Galldiks ◽  
Martin Kocher ◽  
Stephanie T Juenger ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Test Data ◽  
Targeted Therapies ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Support Vector ◽  
Mutational Status ◽  
Melanoma Brain Metastases ◽  
Group 2 ◽  
Group 1

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

P14.06 Radiomics for the non-invasive determination of the BRAF mutational status in patients with melanoma brain metastases

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii39-ii39
Author(s):  
A Meissner ◽  
R Gutsche ◽  
N Galldiks ◽  
M Kocher ◽  
S T Juenger ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Structural Mri ◽  
Braf V600e ◽  
Non Invasive ◽  
Mutational Status ◽  
Melanoma Brain Metastases ◽  
Group 2 ◽  
Data Group ◽  
Group 1

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of structural MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. MATERIAL AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) underwent surgery with subsequent genetic analysis of the brain metastases tissue to determine the BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing, 1,316 radiomics features were extracted using the open-source PyRadiomics package. A test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data (group 2). Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using a six parameter radiomics signature, a linear support vector machine classifier yielded an average area under the ROC curve (AUC) of 0.87 (accuracy, 85%; sensitivity, 78%; specificity, 91%) for prediction of the BRAF mutational status in the training data (group 1). Finally, the classifier achieved an AUC of 0.85 (accuracy, 86%; sensitivity, 83%; specificity, 88%) in the test data (group 2). CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

Relationship with programmed cell death ligand 1 (PD-L1) and DTI features in brain metastases of non-small cell lung cancer; Preliminary study

2021 ◽  
Vol 17 ◽  
Author(s):  
Temel Fatih Yilmaz ◽  
İsmail Yurtsever ◽  
Hacı Mehmet Turk ◽  
Mehmet Ali Gultekin ◽  
Mehmet Besiroglu ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Metastases ◽  
Small Cell ◽  
Peritumoral Edema ◽  
Small Cell Lung ◽  
Protein Status ◽  
Adc Values ◽  
Group 2 ◽  
L1 Protein ◽  
Group 1

Objectives: The purpose of the study was to determine DTI properties of brain metastases in subjects with non-small cell lung carcinoma (NSCLC), to evaluate whether there was a correlation between DTI findings and programmed cell death ligand-1 (PD-L1). Methods: The study population (n:22) was assigned to PD-L1 negative (Group 1: PD-L1 expression<%50) (n=11) or positive (Group 2: PD-L1 expression ≥%50) (n=11). We compared ADC and FA values measured from the enhanced solid metastases and peritumoral edema area with PD-L1 protein status. Results: The mean ADC values were lower in group 2 compared to group 1. The peritumoral ADC values were higher in group 2 compared to group 1. Mean peritumoral edema FA values are lower in group 2 compared to group 1. The peritumoral edema nADC values were higher in group 2 compared to group 1. As PD-L1 expression frequency increased, ADC values in the peritumoral edema area increased and FA values decreased. Conclusions: We thought that the existence of PD-L1 protein doesn’t affect ADC and FA values of brain metastasis (BM) originating from NSCLC. DTI characteristics of the peritumoral edema area could be a guide in determining PD-L1 protein status of brain metastases of NSCLC. The relationship between PD-L1 expression status and DTI features in BM from NSCLC could help us to have an idea in response to immunotherapy.

The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta‐analysis

Cancer ◽  
2019 ◽  
Vol 125 (21) ◽  
pp. 3776-3789 ◽  
Author(s):  
Eliana Rulli ◽  
Lorenzo Legramandi ◽  
Lorenzo Salvati ◽  
Mario Mandala
Keyword(s):  
Systematic Review ◽  
Brain Metastases ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Melanoma Brain Metastases ◽  
The Impact

13q14 Chromosome Deletion Size and Number of Deleted Cells Influence Prognosis In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3578-3578
Author(s):  
Francesca Maria Rossi ◽  
Davide Rossi ◽  
Clara Deambrogi ◽  
Francesco Bertoni ◽  
Michele Dal Bo ◽  
...  
Keyword(s):  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Single Institution ◽  
Group 4 ◽  
Median Size ◽  
Mutational Status ◽  
Genome Wide ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3578 Introduction: Chronic lymphocytic leukemia (CLL) patients bearing 13q14 deletion are known to experience a more favorable clinical course. Recent studies, focusing on patients with loss of 13q as the sole cytogenetic aberration at diagnosis (del13q-only cases), showed that the number of malignant cells carrying this genetic lesion correlates with a more aggressive clinical behavior. However, whether the size of the 13q deletion may also influence the clinical outcome remains to be elucidated. Patients and Methods: Probes for chromosome 13q (LSI-RB1, LSI-D13S319), 11q (LSI-ATM), 17p (LSI-p53) and chromosome 12 (CEP12) were utilized on nuclei collected at diagnosis from: i) a multi-institutional CLL cohort (342 del13q-only cases) and ii) a consecutive unselected single-institution cohort of 265 cases. RB1 deleted cases (delRB1) were defined as having at least 5% of deleted nuclei. Time to treatment (TTT) intervals, as well as Rai staging, IGHV mutational status, CD38 and ZAP70 expression, B2-microglobulin levels, all evaluated at diagnosis, were also available for all cases that entered the study. Genome wide DNA profile was performed in a pilot series of 90 CLL samples using Affymetrix GeneChip Human SNP6 arrays. Results: According to genome wide DNA analysis, delRB1 occurred in a proportion of del13q-only cases (36/90; 40%), always comprising the deleted region detected with the LSI-D13S319 probe (that covers the miR-15a/16-1 cluster and the DLEU2 gene) and characterized by a larger chromosome loss (median size 2.07 Mb vs. a median size of 0.86 Mb for the canonical del13S319). Maximally selected log-rank statistics identified the 70% of nuclei bearing del13S319 as the most appropriate cut-off value capable of separating del13q-only cases into two subgroups with different TTT distributions. Consistently, del13q-only cases with at least 70% of nuclei bearing del13S319 showed a significantly shorter TTT than del13q-only cases with less than 70% deleted nuclei (p=0.0001). Del13q-only cases were then divided in four subsets according to the percentage of nuclei bearing del13S319 with or without a concomitant delRB1: del13S319 <70% (group 1), 144 cases; del13S319 <70% + delRB1 (group 2), 95 cases; del13S319 >70% (group 3), 64 cases; del13S319 >70% + delRB1 (group 4), 39 cases. The median TTT of group 1 (not reached) was significantly longer than the median TTT of group 2 (92 months, p=0.012), group 3 (68 months, p<0.0001), and group 4 (82 months, p=0.0025; see Fig. 1A). Multivariate Cox proportional hazard analyses selected the presence of delRB1 (p=0.029), along with the IGHV mutational status (p<0.0001), as an independent negative prognosticator in the context of del13q-only cases with low/intermediate Rai risk (Rai stage of 0/I at diagnosis) and <70% of del13S319. Cases belonging to the consecutive unselected single-institution CLL cohort were divided into subsets according to the classification proposed by Döhner et al (NEJM, 2000). Notably, the presence of del13S319 in <70% of cells in the absence of delRB1 identified a patient subset with particularly stable and benign clinical course (group A in Fig. 1B, 48 cases; median TTT not reached). Conversely, patients characterized by del13S319 in <70% of cells but with a larger deletion, as determined by concomitant delRB1 (group B, 24 cases), or del13S319 in >70% of cells (with or without delRB1, group C, 25 cases) or a normal karyotype (group D, 75 cases) had shorter median TTT intervals (ranging from 105 to 129 months, p<0.01 in all the comparisons). Finally, patients affected by CLL bearing trisomy 12 (group E, 48 cases) and del11q or del17p (group F, 45 cases) experienced the worst clinical courses (p<0.0001). Conclusion: In the context of del13q-only cases, different clinical outcomes were associated to the percentage of 13q14 deleted cells, as well as to the size of the 13q14 deletion, as detected by the LSI-RB1 probe. Moreover, the presence of delRB1 emerged as a feature capable of refining the prognostic assessment in the context of CLL cases with <70% del13S319. The underlying genetic mechanisms correlated with the different clinical outcomes and associated with the size of the 13q deletion are presently under investigation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals What's New in Molecular Targeted Therapies for Thyroid Cancer?

2021 ◽  
Vol 37 (2) ◽  
pp. 1-9
Author(s):  
Seonyoung Min ◽  
Hyunseok Kang
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapies ◽  
Radioactive Iodine ◽  
Checkpoint Inhibitors ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Thyroid Cancers ◽  
Ret Mutation ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Thyroid cancer refers to various cancers arising from thyroid gland. Differentiated thyroid cancers (DTCs) include papillary, follicular, and Hurthle cell carcinomas and represent cancers retain normal thyroid functions such as iodine uptake. Radioactive iodine (RAI) is generally used for upfront treatment of metastatic DTCs, but RAI refractory DTCs remain to be clinical challenges. Sorafenib and lenvatinib were approved for the treatment of RAI refractory DTCs and more recently, genomics-based targeted therapies have been developed for NTRK and RET gene fusion-positive DTCs. Poorly differentiated and anaplastic thyroid cancers (ATCs) are extremely challenging diseases with aggressive courses. BRAF/MEK inhibition has been proven to be highly effective in BRAF V600E mutation-positive ATCs and immune checkpoint inhibitors have shown promising activities. Medullary thyroid cancers, which arise from parafollicular cells of thyroid, represent a unique subset of thyroid cancer and mainly driven by RET mutation. In addition to vandetanib and cabozantinib, highly specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated impressive activity and are in clinical use.

scholarly journals Tolerance and Effectiveness of Targeted Therapies in Aged Patients with Metastatic Melanoma

2021 ◽  
Author(s):  
Ondine Becquart ◽  
Bastien Oriano ◽  
Stéphane Dalle ◽  
Laurent Mortier ◽  
Marie Thérèse Leccia ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Elderly People ◽  
Targeted Therapies ◽  
Objective Response ◽  
Real Life ◽  
Standard Regimen ◽  
Aged Patients ◽  
Group 2 ◽  
Group 1

Purpose: Melanoma&rsquo;s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population. Materials and Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 &lt;65-year-old (yo), group 2 &gt;65 yo, analyzed for tolerance and efficacy. Results: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3&ndash;4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5&ndash;27.9) and 16.3 M (CI: 14.5&ndash;26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4&ndash;9.9) and 7.7 M (CI: 5.8&ndash;11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6). Conclusion: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable.

scholarly journals THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i12-i13
Author(s):  
Adam Lauko ◽  
Soumya Sagar ◽  
Addison Barnett ◽  
Wei Wei ◽  
Samuel Chao ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tertiary Care ◽  
Rank Test ◽  
P Value ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutational Status ◽  
Melanoma Brain Metastases ◽  
Melanoma Patients ◽  
Braf Mutant

Abstract BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

2019 ◽  
Vol 22 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Erdener Ozer ◽  
Akin Sevinc ◽  
Dilek Ince ◽  
Resmiye Yuzuguldu ◽  
Nur Olgun
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Disease Relapse ◽  
Multisystem Disease ◽  
Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

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