Clinicopathologic features of non-small cell lung cancer (NSCLC) harboring an NTRK gene fusion.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11580-11580 ◽  
Author(s):  
Anna F. Farago ◽  
Martin S Taylor ◽  
Robert Charles Doebele ◽  
Alexander I. Spira ◽  
Theresa A Boyle ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Smoking History ◽  
Study Cohort ◽  
Gene Fusions ◽  
Clinicopathologic Features ◽  
Oncogenic Driver ◽  
Specific Position ◽  
Trk Inhibitors ◽  
Tumor Types ◽  
Next Generation Sequencing Ngs

11580 Background: Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C, respectively. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. An estimated 0.1 – 1% of NSCLCs harbor NTRK fusions. To date, clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs (Farago et al., 2015; Hong et al., 2016). Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion NSCLCs are not well characterized. Methods: Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database. A central pathologist (M.M.) reviewed tumor histology in cases with available tissue. Results: 10 NSCLC cases with NTRK gene fusions were identified. Of these, TRK kinase domain-containing potentially activating fusions were verified by next-generation sequencing (NGS) in 7, forming the study cohort. Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners. Four (57%) patients were male. Median age at diagnosis was 47.6 years (range 27.9 – 86.0). The average smoking pack year history was 8.9 (range 0 to 30). Five (71%) presented with metastatic disease. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases. On pathologic review of 4 cases, all were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features. Of the 3 remaining non-study cohort cases, 1 was a non-kinase domain-containing NTRK1 fusion with a concurrent KRAS G12C mutation, 1 was an NTRK2 intragenic deletion disrupting the exon 18 3’ splice site, and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation. Conclusions: NTRK fusions occur in both men and women across wide ranges in age and smoking history. We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions. Notably, not all NTRK alterations are activating, requiring validation of the specific position of the fusion.

scholarly journals Constitutively active TrkB kinase signalling reduces actin filopodia dynamics and cell migration

2020 ◽  
Author(s):  
Rohini Gupta ◽  
Melanie Bauer ◽  
Gisela Wohlleben ◽  
Vanessa Luzak ◽  
Vanessa Wegat ◽  
...  
Keyword(s):  
Cell Migration ◽  
Biological Function ◽  
Kinase Domain ◽  
Signalling Pathways ◽  
Precision Oncology ◽  
Gene Fusions ◽  
Trk Receptors ◽  
Constitutive Activation ◽  
Trk Inhibitors ◽  
Constitutively Active

AbstractTrk receptors and gene fusions of NTRK are targets in precision oncology. Classical Trk signalling concepts fail to explain ligand-independent signalling of intracellular TrkB or NTRK fusion proteins. Here, we show that abundance of the intracellular domain of TrkB is sufficient for ligand-independent autophosphorylation. This constitutive TrkB signalling reduced actin filopodia dynamics, could phosphorylate FAK, and changed cell morphology. Mutating Y705 in the kinase domain of TrkB alone specifically blocked these pathways. Engineered intracellular kinase domain proteins and a cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive activation. In migrating glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. Moreover, we found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. Structural modelling of the kinase domain let us postulate that ‘release from cis-autoinhibition by abundance’ is sufficient for TrkB/FAK/Actin signalling via Y705. These constitutive signalling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. In conclusion, our data provide an explanation and biological function for TrkB kinase domain signalling in the absence of a ligand.

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.

NTRK1 gene fusions as a novel oncogene target in lung cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8023-8023 ◽  
Author(s):  
Robert Charles Doebele ◽  
Aria Vaishnavi ◽  
Marzia Capelletti ◽  
Anh T. Le ◽  
Severine Kako ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Kinase Domain ◽  
Cloning And Expression ◽  
Egfr Mutations ◽  
Fish Analysis ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Investigation Methods ◽  
Trk Inhibitors

8023 Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.

scholarly journals Therapeutic strategies in RET gene rearranged non-small cell lung cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Leylah M. Drusbosky ◽  
Estelamari Rodriguez ◽  
Richa Dawar ◽  
Chukwuemeka V. Ikpeazu
Keyword(s):  
Acquired Resistance ◽  
Kinase Domain ◽  
Significant Activity ◽  
Gene Fusions ◽  
Multiple Tumor ◽  
Ret Gene ◽  
Clinical Benefits ◽  
Nsclc Patients ◽  
Tumor Types

AbstractThe recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.

Incidence of ERBB gene fusions (EGFR, ERBB2, ERBB4) across tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3091-3091
Author(s):  
Laura Schubert ◽  
Andrew Elliott ◽  
Robert Charles Doebele ◽  
Emil Lou ◽  
Hossein Borghaei ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Gastroesophageal Junction ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Data Sets ◽  
Gene Fusions ◽  
Cancer Subtypes ◽  
Multiple Tumor ◽  
Public Data ◽  
Tumor Types

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing > 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( > 60% average across public data sets), with higher co-mutation rates ( > 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.

scholarly journals IMG-22. A DEEP LEARNING MODEL FOR AUTOMATIC POSTERIOR FOSSA PEDIATRIC BRAIN TUMOR SEGMENTATION: A MULTI-INSTITUTIONAL STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii359-iii359
Author(s):  
Lydia Tam ◽  
Edward Lee ◽  
Michelle Han ◽  
Jason Wright ◽  
Leo Chen ◽  
...  
Keyword(s):  
Deep Learning ◽  
Posterior Fossa ◽  
Ground Truth ◽  
Learning Model ◽  
Tumor Segmentation ◽  
Dice Similarity Coefficient ◽  
Study Cohort ◽  
Navigation Systems ◽  
Tumor Types ◽  
Deep Learning Model

Abstract BACKGROUND Brain tumors are the most common solid malignancies in childhood, many of which develop in the posterior fossa (PF). Manual tumor measurements are frequently required to optimize registration into surgical navigation systems or for surveillance of nonresectable tumors after therapy. With recent advances in artificial intelligence (AI), automated MRI-based tumor segmentation is now feasible without requiring manual measurements. Our goal was to create a deep learning model for automated PF tumor segmentation that can register into navigation systems and provide volume output. METHODS 720 pre-surgical MRI scans from five pediatric centers were divided into training, validation, and testing datasets. The study cohort comprised of four PF tumor types: medulloblastoma, diffuse midline glioma, ependymoma, and brainstem or cerebellar pilocytic astrocytoma. Manual segmentation of the tumors by an attending neuroradiologist served as “ground truth” labels for model training and evaluation. We used 2D Unet, an encoder-decoder convolutional neural network architecture, with a pre-trained ResNet50 encoder. We assessed ventricle segmentation accuracy on a held-out test set using Dice similarity coefficient (0–1) and compared ventricular volume calculation between manual and model-derived segmentations using linear regression. RESULTS Compared to the ground truth expert human segmentation, overall Dice score for model performance accuracy was 0.83 for automatic delineation of the 4 tumor types. CONCLUSIONS In this multi-institutional study, we present a deep learning algorithm that automatically delineates PF tumors and outputs volumetric information. Our results demonstrate applied AI that is clinically applicable, potentially augmenting radiologists, neuro-oncologists, and neurosurgeons for tumor evaluation, surveillance, and surgical planning.

scholarly journals Molecular Characterization and Prognostication of Large Cell Neuroendocrine Carcinoma and Large Cell Carcinoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Ying Chen ◽  
Xiaoying Cui ◽  
Di Wang ◽  
Guojie Xia ◽  
Minyan Xing ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Cell Carcinoma ◽  
Neuroendocrine Carcinoma ◽  
Large Cell Carcinoma ◽  
Large Cell ◽  
Large Cell Neuroendocrine Carcinoma ◽  
Gene Panel ◽  
Smoking History ◽  
Study Cohort ◽  
Poor Outcome

PurposeLarge cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored.Patients and MethodsPathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted.ResultsBoth LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort.ConclusionLCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.

scholarly journals Új célzott terápiás lehetőség az onkológiában: tropomiozin receptor-tirozin-kináz gátlók

2021 ◽  
Vol 162 (34) ◽  
pp. 1362-1369
Author(s):  
Edina Kiss ◽  
Zsuzsanna Pápai
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
First Generation ◽  
Kinase Inhibitor ◽  
Disease Free Survival ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Precision Oncology ◽  
Gene Fusions ◽  
Trk Inhibitors

Összefoglaló. A molekuláris diagnosztikai módszerek folyamatos fejlődésének köszönhetően egyre több onkogén genetikai eltérést azonosítanak. A neurotrofikus tropomiozin receptor-tirozin-kináz (NTRK-) génfúziók fontos precíziós onkológiai célpontok, melyek mindhárom NTRK-génben előfordulhatnak, onkogén-hajtóerőként viselkednek. A génfúziók különböző molekuláris diagnosztikai módszerekkel azonosíthatók, melyek közül a legpontosabb, legköltségesebb és legidőigényesebb meghatározást az újgenerációs szekvenálási technika jelenti. A tropomiozin receptor-tirozin-kináz (TRK-) fúziós fehérjék szelektív gátlása személyre szabott onkológiai kezelési lehetőséget jelent a tumor típusától, lokalizációjától és a beteg életkorától függetlenül. Az első generációs TRK-gátlók gyors, hatékony és tartós daganatellenes hatást biztosítanak kimutatott NTRK-fúzió-pozitív daganatok esetén, alacsony mellékhatásprofil mellett. Az első generációs TRK-gátlók mellett jelentkező ’on target’ rezisztenciát a második generációs TRK-gátlók oldják fel. Szekvenciális tirozin-kináz-inhibitor-kezeléssel tartós betegségmentes túlélés érhető el. Orv Hetil. 2021; 162(34): 1362–1369. Summary. Due to the continuous development of molecular diagnostic methods, more and more oncogenic genetic abnormalities are being identified. Neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene fusions are important precision oncology targets that can occur in all three NTRK genes and act as oncogenic drivers. Gene fusions can be identified by a variety of molecular diagnostic technologies, of which next-generation sequencing is the most accurate, costly and time-consuming determination. Selective inhibition of tropomyosin receptor tyrosine kinase (TRK) fusion proteins represents a personalized oncology treatment option regardless of tumour type, localization and patient age. First-generation TRK inhibitors provide rapid, efffective and long-lasting antitumor activity in NTRK fusion-positive tumors with a low side-effect profile. On target resistance to first-generation TRK inhibitors is resolved by second-generation TRK inhibitors. Durable disease-free survival can be achieved with sequential tyrosine kinase inhibitor therapies. Orv Hetil. 2021; 162(34): 1362–1369.

scholarly journals Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study

Blood ◽  
2020 ◽  
Vol 135 (8) ◽  
pp. 534-541 ◽  
Author(s):  
Simona Soverini ◽  
Luana Bavaro ◽  
Caterina De Benedittis ◽  
Margherita Martelli ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Kinase Inhibitors ◽  
Clinical Decision Making ◽  
Mutation Screening ◽  
Clinical Decision ◽  
Kinase Domain ◽  
Low Level ◽  
Prospective Assessment ◽  
Next Generation Sequencing Ngs ◽  
First Time

Abstract In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib

2017 ◽  
pp. 1-7 ◽  
Author(s):  
Kasey L. Couts ◽  
Caroline E. McCoach ◽  
Danielle Murphy ◽  
Jason Christiansen ◽  
Jacqueline Turner ◽  
...  
Keyword(s):  
Clinical Response ◽  
Cutaneous Melanoma ◽  
Gene Fusions ◽  
Small Cell Lung ◽  
Durable Response ◽  
Acral Lentiginous Melanoma ◽  
Multiple Tumor ◽  
Alk Inhibitor ◽  
Basket Trial ◽  
Tumor Types

Purpose ROS1 gene fusions demonstrate oncogenic activity, and patients with non–small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma. Patients and Methods Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry. Results Targeted sequencing identified a GOPC- ROS1 fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of −38% at 3 months and −55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas. Conclusion ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.

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