Simple Summary Among sarcomas, which are rare cancers, inflammatory myofibroblastic tumors are extremely rare. Unlike other subtypes, this is a largely oncogene-driven neoplasia, and early gene rearrangement identification is important for accurate advanced stage treatment. In this manuscript, we review the clinicopathologic characteristics of this ultra-rare entity, as well as the current treatment landscape, with a particular focus on opportunities provided by tyrosine kinase inhibitors (TKIs). Abstract An inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory cells, including lymphocytes and eosinophils. It is an ultra-rare tumor, the optimal management of which remains to be defined. Surgery is the treatment of choice for localized tumors. The treatment of advanced disease is not precisely defined. Chemotherapy regimens result in an overall response rate of approximately 50% based on retrospective data. The latest pathophysiological data highlight the role played by tyrosine kinase fusion genes in IMT proliferation. Anaplast lymphoma kinase (ALK) oncogenic activation mechanisms have been characterized in approximately 80% of IMTs. In this context, data regarding targeted therapies are most important. The aims of this article are to review the latest published data on the use of systematic therapy, particularly the use of molecular targeted therapy, and to publish an additional case of an IMT with Ran-binding protein 2 (RANPB2)-ALK fusion showing a long response to a tyrosine kinase inhibitor.

/pdf/inflammatory-myofibroblastic-tumour-state-of-the-art-1ht2d9lo.pdf

Inflammatory Myofibroblastic Tumour: State of the Art

BACKGROUND
Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy.


CASE PRESENTATION
A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events.


CONCLUSION
This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

Background ROS1 fusions are driver molecular alterations in 1–2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. Results 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

/pdf/adk-vr2-a-cell-line-derived-from-a-treatment-naive-patient-11mvxl24.pdf

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

Introduction Inflammatory myofibroblastic tumours are rare neoplasms which most commonly affect children and young adults. With an intermediate malignant potential, they are typically detected in the abdomen, lung, mediastinum, head and neck, gastrointestinal tract, and genitourinary tract. Case description We describe the case of a 33-year-old postpartum woman incidentally diagnosed with a pulmonary inflammatory myofibroblastic tumour following complaints of poorly controlled hypertension a week after caesarean section. She was ALK-negative and received an ALK inhibitor with complete resolution of the lesion. A ROS1–TFG fusion confirmed the diagnosis of an inflammatory myofibroblastic tumour after CT-guided fine needle aspiration. Discussion This case highlights an uncommon presentation posing a diagnostic and therapeutic challenge and the potential treatment option of crizotinib. LEARNING POINTS Inflammatory myofibroblastic tumour (IMT) is a rarely reported neoplasm arising in the abdominal soft tissues, the lung, mediastinum, head, neck, gastrointestinal tract, and genitourinary tract, with intermediate malignant potential. IMT is definitively diagnosed only after histological examination following surgical biopsy, based on immunohistochemical markers and the molecular characteristics of the tumour, but small biopsies may have a role in a large lesion. IMT did not cause any complications during gestation. Therapeutic approaches include surgical resection and chemotherapy, including with crizotinib, an ALK tyrosine kinase inhibitor.

/pdf/a-rare-case-of-incidentally-diagnosed-pulmonary-inflammatory-2a1eb156.pdf

A Rare Case of Incidentally Diagnosed Pulmonary Inflammatory Myofibroblastic Tumour with Dramatic Response to Crizotinib in a Postpartum Woman

ABSTRACT Introduction Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors. The role of molecular testing to inform diagnosis, disease prognosis, and therapy has become critical to optimal treatment. Areas covered This review reports updated data on precision therapy in patients with STS, particularly those of immediate utility in clinical practice. Expert opinion There is a high unmet need for effective systemic therapy for patients with STS. In the era of precision medicine, doxorubicin-based chemotherapy is still the standard of care in first-line treatment for the majority of histologic subtypes with a median overall survival of only 20 months. Precision therapy for STS has only been partially effective. A new wave of targeted therapeutic agents has been approved with preferential benefit in subgroups of patients. Immunotherapy is now undergoing clinical trials. There is a heterogeneity in the benefit of immune checkpoint inhibitors across subtypes. Strategies targeted to antigen bearing sarcomas including vaccine and adoptive T-cell have yielded promising results in selected histotypes.

Personalised pharmacotherapy options for soft tissue sarcomas

Inflammatory myofibroblastic tumor (IMT) is a very rare subtype of sarcoma, which frequently harbor chromosomal rearrangements, including anaplastic lymphoma kinase (ALK) rearrangements (almost 50% of the IMTs) and other kinase fusions such as ROS1. ROS1 fusions are present in about 10% of IMT, almost half of the ALK-negative IMT patients. Apart from radical surgery for resectable tumors, there is no standard-of-care therapy for advanced IMTs. Nonetheless, the use of tyrosine kinase inhibitors has shown promising efficacy in IMT patients with targetable genomic alterations. We report the case of a 24-year-old patient with chemotherapy-refractory metastatic IMT harboring ROS1 kinase fusion, who experienced a significant clinical and pathological response to crizotinib. This clinical case highlights the need to assess all patients with unresectable IMTs for chromosomal abnormalities and gene mutations and address them to targeted agents as well as clinical trials.

/pdf/outstanding-response-in-a-patient-with-ros1-rearranged-f78z3cx51z.pdf

Outstanding Response in a Patient With ROS1-Rearranged Inflammatory Myofibroblastic Tumor of Soft Tissues Treated With Crizotinib: Case Report.

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Outstanding Response in a Patient With ROS1-Rearranged Inflammatory Myofibroblastic Tumor of Soft Tissues Treated With Crizotinib: Case Report.