KIT-Associated Familial GIST Syndrome: Response to Tyrosine Kinase Inhibitors and Implications for Risk Management

Abstract

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.

Familial Gastrointestinal Stromal Tumor Associated with Zebra-like Pigmentation

“…The occurrence of GISTs associated with familial syndromes is extremely rare, and most cases present wild-type KIT and platelet-derived growth factor alpha (PDGFRA) [ 13 ]. To date, GISTs with germline KIT pathogenic variants have been described in only 30 families worldwide [ 14 ]. Here, we report the case of a 32-year-old male patient diagnosed in the cancer genomic medicine unit with advanced GISTs throughout the upper stomach and hyperpigmented skin.…”

“…Cancer gene panel examination simultaneously investigates multiple genes in cells from resected cancer tissue. If pathogenic variants (i.e., druggable variants) are detected, drugs or substances tested in clinical trials/clinical studies potentially effective against the pathogenic variants are selected, including from the cancer genomic database, based on clinical guidelines on chemotherapy [ 14 , 15 ]. In other words, when a cancer genome test detects pathogenic variants of genes in tumor-constituting cells, it is preferable to select antitumor agents that specifically act on the pathogenic variants.…”

Development and validation of a prognostic model to predict the prognosis of patients with colorectal gastrointestinal stromal tumor: A large international population-based cohort study

“…In recent decades, there has been a great interest in determining the genetic characteristics of these neoplasms, and it was identified and determined that GISTs are characteristically driven by activating mutations of KIT in approximately 85–90% of cases ( 12 – 14 ). Recent studies have shown that introducing effective tyrosine kinase inhibitors (TKIs), particularly imatinib, have been investigated as potential treatments for GISTs with inoperable or metastatic disease ( 15 , 16 ). In 2002, TKIs was first approved by the FDA for the treatment of patients with metastatic GISTs, which improved median overall survival (OS) from less than 1 year to 5 years ( 17 , 18 ).…”