A new sequencing technique detecting circulating tumor-DNA (ctDNA) may be useful for monitoring gastrointestinal stromal tumor (GIST) activity and treatment resistance, according to a study published in Molecular Cancer Therapeutics.

Researchers used a sequencing strategy based on the SiMSen-Seq technique to detect tumor-specific and tyrosine kinase inhibitor (TKI) resistance mutations in plasma samples of GIST patients. This strategy was able to detect ctDNA at low mutant allele frequencies (<.1%).

The technique was able to detect ctDNA in 9 out of 32 patients with mutant allele frequencies ranging from 0.04% to 93% with high-risk GIST patients being more likely to test positive than other risk groups (P <.05). Patients with positive ctDNA test results also tended to have tumor cells with higher proliferation rates (P <.01) and larger cell size (median 17 cm vs 9 cm; P <.01), according to the researchers.


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The sequencing technique was also able to detect multiple TKI resistance mutations in 2 patients who progressed while receiving TKI treatment.

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“In summary, we have developed a GIST-specific sequencing approach to assess ctDNA in an optimized experimental workflow and report ctDNA dynamics in relation to surgery. Our analyses reveal potential prognostic ctDNA data that may facilitate the management of high-risk GIST patients,” the authors said. The study found that all patients (n=6) who were positive for ctDNA during resection surgery tested negative following 4 weeks after surgery.

In 4 patients who were ctDNA positive prior to the start of neoadjuvant TKI treatment, their ctDNA levels either decreased or became no longer detectable after treatment initiation. Imaging confirmed tumor regression in these patients, the authors said.

The SiMSen-Seq technique was used to create tumor-specific mutation panels for patients with the KIT or PDGFRA genes or genes related to imatinib or sunitinib resistance. These panels were used to detect ctDNA levels in plasma samples obtained from the patients at 3- or 6-month intervals before and after resection surgery. Blood samples were also obtained at the start of surgery, after tumor mobilization, and at wound closure.

A total of 32 patients were recruited for the study and classified as very low or low (n=7), intermediate (n=6), or high-risk (n=19) using the National Institutes of Health classification system. On tumor biopsy, 21 patients had mutations in KIT exon 11, 18 with PDGFRA exon 18 mutations, and 3 with KIT mutations in exons outside of 11.

Reference

Johansson G, Berndsen M, Lindskog S, et al. Monitoring circulating tumor-DNA during surgical treatment in patients with gastrointestinal stromal tumors. Mol Cancer Ther. Published online September 22, 2021. doi:10.1158/1535-7163