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Δευτέρα 8 Οκτωβρίου 2018

Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1‐Deficient Carcinoma

AbstractIntegrase interactor 1 (INI‐1)‐deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non‐Fermentable‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30‐year‐old woman with INI‐1‐deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next‐generation‐sequencing‐based targeted cancer‐related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single‐patient expanded‐use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI‐1‐deficient tumors, warranting further evaluation in clinical studies.Key Points. Loss of the SWItch/Sucrose Non‐Fermentable‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 gene (SMARCB1), which encodes integrase interactor 1 (INI‐1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity.INI‐1‐deficient carcinoma can be very aggressive, and there is no known treatment option available.There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI‐1‐deficient malignancies, including INI‐1‐deficient carcinomas.Loss of INI‐1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer.Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options.

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