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Less than 20 years ago, GIST was a disease frequently misdiagnosed – usually as leiomyosarcoma. Today, we know there are a number of types of GIST.  Immunohistochemistry is now used to confirm a diagnosis of GIST, and mutational testing is necessary to identify rare subtypes. With mutational testing, (which is different than your pathology report) these subtypes can also further be broken down by gene mutation and exon. Identifying your mutation means that your GIST experts can individualize treatment giving you the most effective options available for your type of GIST.

Consulting with a GIST expert after your diagnosis is the most effective way to gain the most up-to-date knowledge and best treatment plan for your GIST. Consult our GIST Specialists Database or call The Life Raft Group at 973-837-9092.

A GIST diagnosis can be a confusing thing to receive and even more confusing to decipher. In addition to a jumble of letters and numbers, you may have heard the phrases exon 9, exon 11, BRAF, CD-117, D842V, SDH, or NF1. There may have been terms presented such as KIT-positive, sporadic, familial, heritable, inheritable, or wildtype. What does it all mean?

KIT/PDGFRa Mutant GIST -the most common GIST

KIT/PDGRFa Mutant GIST is a mutation in the KIT/PDGFRa gene and is the most common type of GIST diagnosed (also none known as adult GIST, KIT/PDGFRa positive GIST or ‘normal’ GIST). It can occur anywhere in the gastrointestinal tract and is most commonly diagnosed in older adults. KIT/PDGFRa and other tyrosine kinase driven GIST tumors become cancerous because of a gene mutation that occurs randomly in a cell that does not die and continues to multiply because of a ‘gain-of-function’ which is a constant ‘on’ growth signal caused by the faulty KIT/PDGFRa protein programmed by that gene. In this case, a mutation in one of the two copies of the KIT/PDGFRa gene can cause the problem.

Though many patients are responsive on imatinib therapy (Gleevec), response to medications can vary by mutation type and mutation location (exon 9, 11, etc.) Exon 11 mutations are found in about 60-65% of cases and are the most commonly mutated exon in GIST. Mutations in exon 11 generally respond to treatment with inmatinib better than mutations in other exons. Exon 9 is the next most common mutation.

Mutations in exon 13, and 17 are less common; with exon 13 (typically K642E) generally responding well to imatinib therapy and primary exon 17 mutations being more often non-responsive to imatinib. Mutations that do respond to standard treatments may require vastly different dosages and may be predisposed to eventually becoming resistant to the initial drug therapy.

For more information on treatments and side effects, please see our treatments section and our LRG Webcast Series.

Mutation in PDGFRa D842V

Less common than KIT/PDGFRA Mutant GIST, the most common mutation in PDGFRa is exon 18 mutation1, known as the D842V mutation, is resistant to Gleevec, Sutent, and Stivarga (the first three treatment lines used for the most common GIST diagnoses). PDGFRa D842V mutation is a subset of GIST, related to tyrosine kinase inhibitor resistance, usually presenting in the stomach. A new treatment was approved for PDGFRA exon 18/PDGFRA D842V mutation January 9th, 2020. Read about the release of Ayvakit here.

These details are not presented to confuse, but to emphasize the importance of knowing your mutation in order to treat your GIST effectively. Also, some patients who are initially responsive on Gleevec (imatinib) can develop resistance after a period of time, therefore biomarker/mutational testing and regular scans are recommended. We strongly advocate advanced testing for biomarkers as early as possible after a GIST diagnosis.

Read this caregiver story about a patient journey with avapritinib  – One Perspective on the BLU-285 Trial (avapritinib/Ayvakit)

Dr. Sameer Rastogi
LRG Medical Advisory Board Member
All India Institute of Medical Sciences
New Delhi, India