crizotinib and Sarcoma

Sarcomatoid carcinoma of the upper aerodigestive tract, a variant of squamous cell carcinoma, is a rare biphasic tumor consisting of epithelial and mesenchymal components.. We report a case of 34-year-old woman with a relapsed refractory sarcomatoid carcinoma in the maxillary sinus. Because anaplastic lymphoma kinase (ALK) translocation is common in sarcoma, ALK fluorescence in situ hybridization (FISH) was performed and the result was positive. After crizotinib was administered, clinical improvement and stable disease lasted for 4 months. To identify the incidence of ALK rearrangement in this disease entity, ALK FISH was performed on tumor samples of 10 patients. Among them, 2 patients were positive.. To the best of our knowledge, this is the first case report demonstrating the clinical benefit of crizotinib in sarcomatoid carcinoma of the head and neck with ALK translocation. Our results suggest that the ALK FISH test may be suitable and encouraged for patients with sarcomatoid carcinoma of the head and neck.

Topics: Adult; Anaplastic Lymphoma Kinase; Carcinoma, Squamous Cell; Cohort Studies; Crizotinib; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; In Situ Hybridization, Fluorescence; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Sarcoma; Translocation, Genetic; Treatment Outcome

Soft tissue sarcomas (STS) are a set of very heterogeneous tumors with numerous histological categories. The development of the molecular biology allowed identifying recurring molecular anomalies in certain subgroups of sarcomas, being able to represent diagnostic, prognosis and therapeutic tools. The molecular classification of STS includes until today 5 main groups of abnormalities: sarcomas with "simple genomic profile" showing reciprocal (1) chromosomal translocations, (2) activating mutation, (3) inhibitive mutation or (4) simple amplification; (5) sarcomas with "complex genomic profile" can include several tens of molecular abnormalities. The development of new-targeted therapies is based on the identification of a target, specific of a tumors subgroup and involved in carcinogenesis mechanisms and/or tumoral growth. Then, the aim of clinical research is to establish the proof of the concept through clinical trials, demonstrating the benefit brought to the patient and ending in the marketing of the drug. This proof of the concept was clearly established for imatinib, sunitinib and regorafenib in gastrointestinal stromal tumors, for imatinib in dermatofibrosarcoma protuberans and pigmented vilo-nodular synovitis, for denosumab in giant cell tumors of the bone, ending in the authorization to use these new therapies in these indications. It is in progress and promising for anti-IGF-1R in Ewing sarcomas, for crizotinib in myofibroblastic inflammatory tumors, for mTOR inhibitor in PEComas... The role of molecular abnormalities identified in the mechanisms of tumoral progress for sarcomas and their potential therapeutic impact will be detailed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Benzamides; Bone Neoplasms; Crizotinib; Denosumab; Dermatofibrosarcoma; Gastrointestinal Stromal Tumors; Gene Amplification; Gene Deletion; Giant Cell Tumor of Bone; Humans; Imatinib Mesylate; Indoles; Molecular Targeted Therapy; Phenylurea Compounds; Piperazines; Point Mutation; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sarcoma; Sarcoma, Ewing; Sunitinib; Synovitis, Pigmented Villonodular; Translocation, Genetic

Epithelioid inflammatory myofibroblastic sarcoma is extremely rare and belongs to a variant of inflammatory myofibrobalstic tumor with aggressive clinical course. We describe a case of a 22 years old man presented with an abdominal huge tumor. Microscopically, the neoplasm cells were rounded and epithelioid in shape. Abundant interstitial edema and less myxoid stroma were also present together with an inflammatory infiltrate. Fluorescence in situ hybridization revealed that ALK gene presented mutation. After surgery the patient received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor, crizotinib. The patient continues to be alive with disease for 16 months and has no recurrence. Although EIMS has a poor prognosis, this is the few successful case with sustained response of targeted therapy.

Topics: Abdominal Neoplasms; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Chemotherapy, Adjuvant; Crizotinib; DNA Mutational Analysis; Epithelioid Cells; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Molecular Targeted Therapy; Mutation; Myofibroblasts; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Sarcoma; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden; Young Adult

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal malignancy that occurs primarily in children and adolescents. The clinical and pathological features of IMT in adult patients are not well understood.. We retrospectively searched for records of adult patients with IMT at Fudan University Shanghai Cancer Center from 2006 to 2021. Clinicopathological data, treatments, and outcomes were collected and analyzed.. Thirty adult patients with IMT, mostly women (60.0%), were included. The median age of the patients was 38 (21-77). The most common primary site was abdominopelvic region (53.3%), followed by lungs (20.0%). Seven patients had an abdominal epithelioid inflammatory myofibroblast sarcoma (EIMS). The positivity rate of anaplastic lymphoma kinase (ALK) was 81.5% (22/27). Sixteen patients with advanced ALK-positive disease received crizotinib, with an objective response rate (ORR) of 81.3% and a disease control rate of 87.5%. The median progression-free survival was 20.8 months. EIMS was associated with more aggressive behavior; however, the prognosis was similar to that of non-EIMS patients after treatment with an ALK inhibitor. At a median follow-up time of 30 months (95% confidence interval [CI], 13.6 to 46.4), the 5-year overall survival was 77% (95% CI, 66 to 88) in all patients.. Adult IMTs appeared more aggressive, with a higher incidence of recurrence and metastases, and patients with EIMS had more aggressive cases. Treatment with ALK inhibitors resulted in a high ORR and a durable response, which suggested that ALK inhibitors could be used as a first-line treatment option in adult patients with ALK-positive advanced IMT.

Topics: Adolescent; Adult; Child; China; Crizotinib; Female; Humans; Male; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Sarcoma

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and aggressive inflammatory myofibroblastic tumour (IMT) variant. This report identifies the first case of EIMS with leukemoid reaction. This is also the first case in which pancreatic infiltration occurred from the disease onset. A 14-year male patient presented with an 18×18×10 cm mass at the retroperitoneal space and a white blood cell (WBC) count of 85×109/L. The mass and the invaded tissues were surgically removed with tumour-free margins. Histopathology and bone marrow aspiration confirmed the diagnosis of EIMS with leukemoid reaction. The tumour recurred with hepatic and pulmonary metastasis one month after the surgery. WBC count also increased progressively with the tumour recurrence. There is no consensus on the treatment of EIMS. Since ALK rearrangement presents in all the EIMS cases, surgical resection combined with crizotinib or other targeted drugs may improve the prognosis. Key Words: Sarcoma, Soft tissue neoplasms, Leukemoid reaction, Crizotinib.

Topics: Crizotinib; Humans; Leukemoid Reaction; Male; Neoplasm Recurrence, Local; Sarcoma; Soft Tissue Neoplasms

Crizotinib is a first-generation tyrosine kinase inhibitor used for anaplastic lymphoma kinase (ALK) positive cancers. Simple and complex renal cyst formation is a rare complication of crizotinib use that has been reported previously in the adult population.. We report a case of a right renal mass in a 17-year-old with ALK-positive epithelioid inflammatory myofibroblastic sarcoma treated with Crizotinib. After cessation of Crizotinib and initiating Alectenib, a second generation ALK inhibitor, the mass decreased in size and the patient remained asymptomatic without evidence of recurrence at three months of follow-up.

Topics: Adolescent; Antineoplastic Agents; Crizotinib; Humans; Kidney Diseases, Cystic; Male; Neoplasms, Muscle Tissue; Receptor Protein-Tyrosine Kinases; Sarcoma

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.. 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.. 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.

Topics: Adaptor Proteins, Signal Transducing; Crizotinib; DNA-Binding Proteins; Gene Fusion; Humans; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion; Prognosis; Receptor, trkA; RNA-Binding Proteins; Sarcoma

Topics: Biomarkers, Tumor; Colon, Sigmoid; Colonoscopy; Crizotinib; Humans; Leukocyte Count; Sarcoma; Sigmoid Neoplasms; Tomography, X-Ray Computed

Inflammatory myofibroblastic tumor (IMT), a rare sarcoma, is primarily treated via resection of the mass. However, in cases of recurrence or unresectable tumors, no standard care exists. While crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is only approved for non-small-cell lung cancer with ALK mutation, it is reportedly effective for other malignant tumors with ALK mutation. We herein report a case involving a 37-year-old woman with retroperitoneal IMT with ALK mutation, who experienced recurrence after complete resection, in whom crizotinib treatment resulted in complete response. ALK-inhibitor efficacy against malignancies with ALK mutations should be investigated in future.

Topics: Adult; Anaplastic Lymphoma Kinase; Crizotinib; DNA Mutational Analysis; DNA, Neoplasm; Female; Humans; Magnetic Resonance Imaging; Mutation; Protein Kinase Inhibitors; Retroperitoneal Neoplasms; Sarcoma

High-grade spindle cell sarcomas are a subtype of rare, undifferentiated pleomorphic sarcomas (UPSs) for which diagnosis is difficult and no specific treatment strategies have been established. The limited published data on UPSs suggest an aggressive clinical course, high rates of local recurrence and distant metastasis, and poor prognosis.. Here we present the unusual case of a 45-year-old male patient with a lumbosacral UPS extending into the sacrum. An initial diagnosis of a low-grade malignant spindle cell tumor was based on a tumor core biopsy. After complete extensive resection, the diagnosis of an UPS of the lumbosacral region was confirmed by excluding other types of cancers. Despite treatment with neoadjuvant radiotherapy, extensive resection, and adjuvant chemotherapy, the patient presented with multiple pulmonary metastases 3 months after surgery. The patient then began treatment with crizotinib at an oral dose of 450 mg per day, based on the detection of a LMNA-NTRK1 fusion gene in the tumor by next-generation sequencing. Over 18 months of follow-up through July 2018, the patient maintained a near-complete clinical response to crizotinib.. The LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient, and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target. Molecular and cytogenetic evaluations are critical to accurate prognosis and treatment planning in cases of UPS, especially when treatment options are limited or otherwise exhausted. Molecularly targeted therapy of these rare but aggressive lesions represents a novel treatment option that may lead to fewer toxic side effects and better clinical outcomes.

Topics: Carcinogenesis; Crizotinib; High-Throughput Nucleotide Sequencing; Humans; Lamin Type A; Liposarcoma; Lumbosacral Region; Male; Middle Aged; Oncogene Proteins, Fusion; Prognosis; Pyrazoles; Pyridines; Receptor, trkA; Sacrum; Sarcoma

CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours. Notably, xenografts were histologically similar to the original patient tumour, and the expression of typical biomarkers was confirmed in the xenografts and cell lines. Moreover, the xenograft tumours and cell lines displayed high Src kinase activities, as assessed by peptide-based tyrosine kinase array. Upon screening 119 FDA-approved anti-cancer drugs, we found that only actinomycine D and doxorubicin were effectively suppress the proliferation among the drugs for standard therapy for Ewing sarcoma. However, we identified molecular targeting reagents, such as bortezomib and crizotinib that markedly suppressed the growth of CDS cells. Our models will be useful modalities to develop novel therapeutic strategies against CDS.

Topics: Adult; Animals; Biomarkers, Tumor; Bortezomib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crizotinib; Drug Screening Assays, Antitumor; Female; Humans; In Situ Hybridization, Fluorescence; Molecular Targeted Therapy; Neoplasm Transplantation; Oncogene Proteins, Fusion; Sarcoma

BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Myofibroblasts; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sarcoma; Sulfones

To further understand the molecular pathogenesis of pulmonary sarcomatoid carcinoma (PSC) and develop new therapeutic strategies in this treatment-refractory disease.. Whole-exome sequencing in a discovery set (n = 10) as well as targeted MET mutation screening in an independent validation set (n = 26) of PSC were performed. Reverse transcriptase polymerase chain reaction and Western blotting were performed to validate MET exon 14 skipping. Functional studies for validation of the oncogenic roles of MET exon 14 skipping were conducted in lung adenosquamous cell line H596 (MET exon 14 skipped and PIK3CA mutated) and gastric adenocarcinoma cell line Hs746T (MET exon 14 skipped). Response to MET inhibitor therapy with crizotinib in a patient with advanced PSC and MET exon 14 skipping was evaluated to assess clinical translatability.. In addition to confirming mutations in known cancer-associated genes (TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1), several novel mutations in additional genes, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2, were identified and validated. MET mutations leading to exon 14 skipping were identified in eight (22%) of 36 patient cases; one of these tumors also harbored a concurrent PIK3CA mutation. Short interfering RNA silencing of MET and MET inhibition with crizotinib showed marked effects on cell viability and decrease in downstream AKT and mitogen-activated protein kinase activation in Hs746T and H596 cells. Concurrent PIK3CA mutation required addition of a second agent for successful pathway suppression and cell viability effect. Dramatic response to crizotinib was noted in a patient with advanced chemotherapy-refractory PSC carrying a MET exon 14 skipping mutation.. Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in PSC.

Topics: Adult; Aged; Aged, 80 and over; Cell Growth Processes; Class I Phosphatidylinositol 3-Kinases; Cohort Studies; Crizotinib; DNA Mutational Analysis; DNA, Neoplasm; Exons; Female; Gene Knockdown Techniques; Humans; Isoenzymes; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Phosphatidylinositol 3-Kinases; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Sarcoma

Anaplastic lymphoma kinase is a tyrosine kinase receptor that can become oncogenic. Crizotinib is a tyrosine kinase inhibitor that shows activity in patients with anaplastic lymphoma kinase rearrangements that have failed conventional therapies.. A 34-year-old woman presented with a painful 3-cm left vulvar-vaginal mass, which was excised and determined to be a sarcoma with positive surgical margins. Fluorescence in situ hybridization testing of her tumor was conducted and demonstrated anaplastic lymphoma kinase gene rearrangements. A 3-cm mass recurred 1 month later. Treatment with 250 mg crizotinib orally twice daily resulted in complete regression of all visible or palpable tumor within 3 weeks.. Molecular evaluation techniques can be used to direct targeted therapy for select malignancies. Future technologic advances will expand the number of malignancies for which these treatment approaches can be used.

Topics: Adult; Anaplastic Lymphoma Kinase; Crizotinib; Female; Humans; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Sarcoma; Vaginal Neoplasms

Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy.. We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib.. The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR.. In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Topics: Adult; Anaplastic Lymphoma Kinase; Crizotinib; Drug Resistance, Neoplasm; Humans; Male; Myofibroblasts; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Receptor, Platelet-Derived Growth Factor beta; Sarcoma; Standard of Care; Sulfones; Tropomyosin

Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor.

Topics: Adult; Antineoplastic Agents; Crizotinib; Humans; Inflammation; Male; Neoplasm Recurrence, Local; Neoplasms, Muscle Tissue; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma; Treatment Outcome

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Cell Transformation, Neoplastic; Crizotinib; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Rearrangement; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Sarcoma