Niamh Coleman, MD, PhD, MD Anderson Cancer Center, discusses results following whole exome sequencing (WES) of tumor tissue and circulating tumor DNA (ctDNA) in gastrointestinal tumors (GIST), presented at the 2021 AACR Annual Meeting.

Transcript

Hello, my name is Niamh Coleman. I am a fellow in the Phase I Unit in MD Anderson. I am excited to be here today to discuss the results of our study that I presented at the annual AACR meeting this year on whole exome sequencing of tumor tissue and circulating tumor DNA in gastrointestinal tumors.

We know that the discovery of oncogenic mutations as potential targets for cancerous therapies revolutionized the way that we treat GIST and other cancers, but adaptive resistance ultimately develops in nearly all patients.

This highlights the need for more detailed understanding of the underlying molecular genetic profile. Tumor-derived cell-free DNA in plasma can be used for molecular testing and provides an attractive alternative to tumor tissue due to its ease of sampling for genomic analysis.

GISTs, or gastrointestinal tumors, shed relatively low amounts of cfDNA. To date, there are limited data on whole exome sequencing in GISTs. We aim to characterize the molecular profile of 15 unresectable stage IV GIST patients using tumor and ctDNA.

We aim to assess the concordance between tumor tissue and ctDNA and to monitor the clonal evolution of these patients while on systemic therapy. How do we do this? We used the Personalis ImmunoID NeXT Platform and performed whole exome sequencing on paired baseline tumor and normal tissue.

How did we do this? We used the Personalis ImmunoID NeXT Platform and performed whole exome sequencing on paired tumor baseline tumor and normal tissue.

We used the Personalis NeXT Liquid Biopsy for whole exome sequencing of plasma-derived ctDNA from serially collected samples at baseline after one month of therapy and on progression to systemic therapies in 15 of our patients with advanced metastatic GIST. A dynamic changes then in ctDNA profile to systemic therapy and concordance between the tumor tissue were then assessed.

Our results showed that whole exome sequencing of tumor samples from all 15 patients confirmed underlying KIT or PDGFRA mutations in all patients, and there was a large heterogeneity of other molecular alterations.

Importantly, we showed strong that tumor plasma concordance as KIT, or PDGFRA mutations, were detected in serially collected ctDNA samples in 87% of our patients in therapy.

We also dynamically tracked clonal evolution while on anticancer therapies and noted dynamic shifts in exon-specific KIT and PDGFRA variants during treatment progression.

Whole exome sequencing then of plasma identify a broad range of concordant variants in addition to plasma-only de novo variants. We are currently investigating the significance of these.

What is the clinical significance of these data? We showed that comprehensive genomic profiling using whole exome sequencing of tumor tissue and of serially collected ctDNA in GIST is feasible. It allows for longitudinal tracking of dynamic VAF changes and clonal evolution.