Characteristic mutations in gastrointestinal stromal tumors (GISTs) and their role in the selection of appropriate treatment:
Gastrointestinal stromal tumors (GISTs) are the most common STS, which accounts for about 5% to 10% of all sarcomas and almost always express of CD117 antigen (found in 95% of cases) on their surface. Other commonly expressed markers in GISTs include CD34 antigen (70%), smooth muscle actin (25%), desmin (less than 5%), and DOG1.
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Majority of GISTs are resulted from activating mutations in genes responsible for the production of KIT (c-KIT) receptor tyrosine kinase (80%) or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase (5% to 10%). Approximately 10% to 15% of GISTs do not have KIT or PDGFRA mutations but have the mutations in the SDH gene leading to the loss of SDHB protein expression on their surface. Such GISTs are known as wild-type GISTs or SDH-deficient GIST.
Immunohistochemical (IHC) staining technique is generally used for the detection of CD117, DOG1, SDHB, and/or CD34 protein expression. Molecular genetic testing technique is used for the detection of KIT and/or PDGFRA mutations. GISTs lacking KIT and PDGFRA mutations should be evaluated for SDHB immunostaining for confirming SDH-deficient tumor types.
GISTs are typically resistant to conventional chemotherapy but due to the presence of KIT mutations in the majority of cases, they respond well to tyrosine kinase inhibitor (TKI) therapy that has transformed the treatment landscape of GISTs. The detection of KIT or PDGFRA mutation is important because these mutations are predictive of response to TKI therapy. SDH-deficient GISTs are relatively refractory to conventional TKI therapy.
Role of Next-Generation Sequencing (NGS) in suggesting most appropriate treatment for patients not responding to standard treatment for STSs:
NGS of multiple genes can be done to identify molecular abnormalities in the tumor cells of patients with refractory disease. The identified molecular abnormalities may potentially match with several targeted therapies that are being tested in clinical trials or are available/approved for treatment of other cancer types.
Thus, NGS can help in the identification of potential clinical trial candidates. This approach can also be helpful in providing an alternative treatment to patients who are not responding to standard treatment or in the discovery of new treatment options for other such patients.
A most recent example of this application is the approval of larotrectinib for the treatment of pediatric and adult patients with STS or other tumors who have gene fusions involving one of the neurotrophic tropomyosin receptor kinase (NTRK) genes.
Following is the list of Tyrosine Kinase Inhibitors (TKIs) currently approved for the treatment of GISTs and other STSs:
Imatinib is an inhibitor of the KIT protein tyrosine kinase and has been reported to be associated with a durable clinical benefit in most patients with advanced-stage GIST. It has been approved by the US FDA for the treatment of patients with KIT-positive unresectable and/or metastatic GISTs.
Several research studies have revealed that the efficacy of imatinib is generally seen in patients with KIT exon 11 deletions but not in patients with KIT exon 11 insertion/point mutation, KIT exon 9 mutation, PDGFRA exon 18 D842V mutation, or wild-type GISTs. Such resistance observed during the first 6 months of treatment is referred to as primary resistance. Higher dose (800 mg/d) of imatinib has been reported to benefit patients who progressed on lower imatinib dose (400 mg/d) or patients who have KIT exon 9 mutations.
Although imatinib has shown clinical benefit in most patients with advanced-stage GISTs, about half of the patients deriving benefit from imatinib therapy eventually progress due to the development of secondary resistance to the treatment. The most common reason for secondary resistance development is the outgrowth of tumor clones with secondary mutations in KIT. Such patients require treatment with novel targeted agents.
Imatinib has also shown clinical benefit for patients with dermatofibrosarcoma protuberans (DFSP) and pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor (TGCT).
Imatinib may cause side effects including fluid retention (edema), nausea, fatigue, muscle cramps, abdominal pain, diarrhea, and rash.
Sunitinib is a small molecule multitargeted TKI that confers clinical benefit to patients with imatinib-resistant GIST, that is, SDH-deficient GIST and treatment of patients with GIST who have progressed on or have developed resistance to imatinib treatment.
Several clinical research studies have revealed that sunitinib has higher response rates in patients with KIT exon 9 mutations compared to those with KIT exon 11 mutations as opposed to imatinib. Also, it has been reported that patients with SDH-deficient, unresectable, recurrent, or metastatic GIST have a higher probability of deriving benefit from sunitinib compared to imatinib. Apart from its proven efficacy in GISTs, sunitinib is also a preferred treatment option for first-line treatment of patients with advanced alveolar soft part sarcoma, solitary fibrous tumor (SFT or hemangiopericytoma), and clear cell sarcoma.
Side effects of sunitinib include fatigue, fever, diarrhea, nausea, vomiting, abdominal pain, constipation, high blood pressure, edema, rash, and hepatotoxicity.
Regorafenib is a small molecule multitargeted TKI that can inhibit a variety of kinases including KIT, PDGFR alpha, PDGFR beta, and all three subtypes of vascular endothelial growth factor receptor (VEGFR). It has been approved by the US FDA for the treatment of patients with locally advanced, unresectable, or metastatic GIST who have previously received treatment with imatinib and sunitinib.
It has also shown benefit in the treatment of patients with advanced Liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma, and some other non-GIST STS subtypes.
Side effect observed with the drug include pain, fatigue, diarrhea, decreased appetite, hypertension, increased chances of infection, speech disorders, fever, weight loss, rash, nausea, hepatotoxicity and hand-foot skin reaction.
Sorafenib is a kinase inhibitor that is active against a variety of kinases including KIT, VEGFR-1–3, and PGDFR beta. It has shown clinical benefit for the treatment of patients with unresectable, KIT-positive GISTs who have received prior treatment with imatinib and sunitinib. It is also used in patients with solitary fibrous tumor, advanced epithelioid hemangioendothelioma, desmoid tumors (aggressive fibromatosis), angiosarcoma, and solitary fibrous tumor (Hemangiopericytoma).
Side effects of the drug include diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, abdominal pain, high blood pressure, and bleeding problems.
Pazopanib is a multitargeted TKI that inhibit several kinases including VEGFR-1–3, PDGFR alpha and beta, KIT and others. It has been approved for the treatment of advanced soft tissue sarcomas other than adipocytic tumors and GISTs that have not responded to chemotherapy.
Pazopanib can cause side-effects like fatigue, nausea, diarrhea, decreased appetite, high blood pressure, headaches, changes in hair color, low blood cell counts, and liver problems.
Some clinical studies have reported that nilotinib can confer clinical benefit in patients with unresectable, KIT-positive GIST who have received imatinib and sunitinib and progressed on these drugs, especially with KIT exon 17 mutations and not with KIT exon 9 mutation.
Dasatinib is another kinase inhibitor that has demonstrated activity against PDGFRA D842V mutation that is commonly involved in the development of resistance to imatinib treatment. Thus, it could be a potentially effective treatment option for patients with imatinib-resistant GIST.
Role of mTOR inhibitors in the treatment of STSs:
Perivascular epithelioid cell tumors (PEComas) are mostly benign but can be malignant or aggressive, such as in the case of advanced-sage or recurrent lymphangioleiomyomatosis or angiomyolipomas. In most cases, PEComa tumors show dysregulated mammalian target of rapamycin (mTOR) signaling due to a mutation in the TSC1 or TSC2 genes leading to the tumor development and progression.
The mutation in the indicated genes may be inherited or sporadic. Targeted drugs directed towards mTOR, for example, sirolimus, temsirolimus, and everolimus have shown benefit in the treatment of advanced-stage PEComas. Sirolimus has been approved by US FDA for treatment of patients with pulmonary lymphangioleiomyomatosis.
Role of monoclonal antibodies in the treatment of STSs:
Following are the 2 monoclonal antibodies which are currently recommended for the treatment of STSs:
Olaratumab is a novel monoclonal antibody that binds to and inhibits PDGFR alpha. The activation of PDGFR alpha is thought to drive tumorigenesis and disease progression in STSs. Olaratumab, in combination with doxorubicin (a chemotherapeutic drug), has been approved for the treatment of patients with untreated, unresectable, or metastatic STS. Interestingly, the reported clinical benefit was consistent among all patients including those with the presence or absence of PDGFR alpha expression.
Side effects of combined treatment (olaratumab + doxorubicin) include infusion reactions, fatigue, nausea, musculoskeletal pain, hair loss, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache.
Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits its interaction with VEGFR. The drug has shown clinical benefit as single agent treatment for patients with highly vascular tumors, such as angiosarcoma and solitary fibrous tumor (hemangiopericytoma), or in combination with temozolomide (a chemotherapeutic drug) in patients with malignant SFT.