Targeted FGFR Blockade for the Treatment of Tumor-Induced Osteomalacia

Hartley, Iris R; Miller, Carole B.; Papadakis, Georgios Z.; Bergwitz, Clemens; Rivero, Jaydira Del; Blau, Jenny; Florenzano, Pablo; Berglund, Jason A; Tassone, Jing; Roszko, Kelly L; Moran, Susan; Gafni, Rachel I; Isaacs, Randi; Collins, Michael T.

doi:10.1056/nejmc2020399

Cited by 29 publications

(24 citation statements)

References 5 publications

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“…Cinacalcet, an agonist of the calcium-sensing receptor, has shown some benefit in increasing renal phosphate reabsorption when used as adjuvant therapy with conventional treatments [ 63 ]. Promising results have also recently been published with the pan-FGFR tyrosine kinase inhibitor, infigratinib, in a case of metastatic TIO [ 64 ].…”

Section: Treatmentmentioning

confidence: 99%

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Dahir

Zanchetta

Stanciu

et al. 2021

Journal of the Endocrine Society

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Purpose Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the non-specific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO. Methods A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment. Results This report provides a summary of our collective experiences in the management of TIO. Main conclusions Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of non-operable patients with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.

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Section: Treatmentmentioning

confidence: 99%

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Dahir

Zanchetta

Stanciu

et al. 2021

Journal of the Endocrine Society

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“…This is of particular importance for those with clinically advanced or refractory disease. [25][26][27][28][29] For those tumors that morphologically resemble a fibrosarcoma or malignant peripheral nerve sheath tumor, NTRK and RET fusions have been reported. 8,10,13 Our reported case showed markedly increased tumor cellularity with intersecting fascicles of spindle cells exhibiting moderate atypia, brisk mitosis, and necrosis.…”

Section: Discussionmentioning

confidence: 99%

The novel finding of an FGFR1::TACC1 fusion in an undifferentiated spindle cell sarcoma of soft tissue with aggressive clinical course

Yau

Lacambra

Chow

et al. 2022

Genes Chromosomes & Cancer

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We report an aggressive soft tissue sarcoma with FGFR1-TACC1 fusion occurring in the thigh of an 83-year-old man. Microscopically, the tumor was composed of monomorphic spindle cells arranged in intersecting fascicles. The tumor cells showed ovoid nuclei, fine chromatin, indistinct nucleoli, and elongated eosinophilic cytoplasm. Focal increase in nuclear atypia was noted. Immunohistochemistry showed only focal rare positivity to S100, but negative to SOX10, CD34, STAT6, TLE-1, SMA, and other myogenic markers. An extensive panel of immunostains did not reveal a definite lineage of cellular differentiation. The fusion junction of the chimeric transcript involved FGFR1 exon 16 and TACC1 exon 7, which was similar to those reported in other types of neoplasms such as glioblastomas and epithelial cancers. The transcript was predicted to be in-frame and confirmed by Sanger sequencing after reverse transcriptase-polymerase chain reaction. The patient was treated by marginal excision of tumor without receiving adjuvant therapy. He experienced rapid tumor recurrence with distant metastases and succumbed at 3.5 months after presentation. The finding of FGFR1-TACC1 fusion in a high-grade, undifferentiated spindle cell sarcoma of soft tissue is novel and may offer a potential therapeutic target in the near future.

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“…The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling ( Lee et al, 2016 ). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO ( Hartley et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia

et al. 2021

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Targeted FGFR Blockade for the Treatment of Tumor-Induced Osteomalacia

Cited by 29 publications

References 5 publications

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

The novel finding of an FGFR1::TACC1 fusion in an undifferentiated spindle cell sarcoma of soft tissue with aggressive clinical course

Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia

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