Successes and limitations of targeted cancer therapy in gastrointestinal stromal tumors

Research output: Contribution to journalArticlepeer-review

Abstract

In gastrointestinal stromal tumors (GIST), molecularly targeted therapies, starting with imatinib, are directed against an activating mutation of KIT or PDGFRA, which drives the disease. Their efficacy has brought the median survival from one to at least 5 years in the metastatic setting. Tumor response patterns may include tumor shrinkage or not, but are marked by pathologic and radiological changes in tumor tissue. Tumor sensitivity to imatinib can be precisely predicted by the mutational status. However, the metastatic disease has not been truly converted into a chronic condition since secondary resistance to imatinib remains a major limiting factor occurring after a median of 2 years at least in most patients. Further-line therapies are available, i.e. with sunitinib and regorafenib, which can prolong progression-free survival for limited time intervals. Resistance is due to secondary mutations. These give rise to a molecular heterogeneity, which represents a formidable therapeutic challenge. However, the scenario has aspects of a 'liquid resistance'. In fact, resistance may spread in a stepwise fashion throughout the tumor: focal progression may be one possible clinical presentation, and tyrosine kinase inhibitors may impact tumor growth even beyond conventional progression. In addition, sensitive and resistant clones may expand and shrink depending on the selective pressure of tyrosine kinase inhibitors, with be possible responses on rechallenge with drugs. In the adjuvant treatment of high-risk molecularly sensitive GIST, imatinib is able to substantially delay relapses, if due to occur, with a limited survival benefit, though, apparently, without impacting the cure rate.

Original languageEnglish
Pages (from-to)51-61
Number of pages11
JournalProgress in tumor research
Volume41
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Medicine(all)

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