Using Liquid Biopsy to Detect FGFR2 and Other Actionable Rearrangements in GI Malignancies

An analysis of circulating tumor DNA–based comprehensive genomic profiling to detect actionable rearrangements in patients with gastrointestinal malignancies was presented by Pashtoon Kasi, MD, MS.

Growing interest in actionable rearrangements (REs) as therapeutic targets for gastrointestinal (GI) cancers stems from their potential to impact treatment response.^1,2 Tissue biopsies (TBx) have typically been used for the detection of REs, but there is uncertainty whether liquid biopsy (LBx) assays using circulating tumor DNA (ctDNA) can detect REs with the same precision.² Concordance between cell-free DNA and FGFR2 fusions was previously reported to be noticeably low, highlighting the difficulties in properly identifying these REs using LBx techniques.³

This study’s findings showed that REs can be detected across the GI cancer samples tested with LBx, including several that result in known oncogenic drivers that may be targeted by current treatments.

Pashtoon Kasi, MD, MS, presented findings from the study “Liquid-Biopsy Detection of FGFR2 and Other Actionable Rearrangements in GI Malignancies” at the 2023 ASCO meeting. The study’s goal was to show the value of ctDNA-based comprehensive genomic profiling (CGP) for identifying REs in patients, particularly those with GI malignancies.²

Researchers reviewed an institutional research database of CGP results for TBx (FoundationOne CDx) and LBx (FoundationOne Liquid CDx) from patients with GI cancers.² In patients with cholangiocarcinoma (CCA) or carcinoma of unknown primary (CUP), the sensitivity to detect FGFR2 REs was also investigated using CGP data. A total of 7870 LBx samples were available: 2891 were from patients with colorectal cancer (CRC), 2785 from those with pancreatic cancer, 833 from those with CCA, 543 from those with esophageal cancer, 368 from those with stomach cancer, 167 from those with liver cancer, 162 from those with gallbladder cancer, and 121 from those with small intestinal cancer.² A total of 1094 predicted pathogenic REs were identified from 826 cases, which included 283 oncogenic REs in genes encoding kinases (kinase gain of function [GOF]), 686 inactivating REs (loss of function [LOF]), and 125 GOF REs in nonkinase genes (other). Some samples included multiple pathogenic REs.² Across the different cancer types, FGFR2 was the most frequently rearranged gene and was more commonly detected in patients with CCA (4.4%, 37/833) and stomach cancer (3%, 11/368). Additional REs detected were EGFR (n=38), BRAF (n=31), ROS1 (n=21), and RET (n=21); other GOF REs detected were CTNNB1 (n=44) and MYC (n=36), and LOF REs observed were BRCA1 (n=28), ARID1A (n=24), STK11 (n=22), and PTEN (n=17).²

The most common FGFR2 REs detected in patients with CCA were FGFR2 fusions, and the most common FGFR2 fusion partner observed with both TBx and LBx was BICC1, which was consistent with an external data set (AACR Genie). In addition, FGFR2 REs in patients with CCA were more common in instances where the estimated ctDNA tumor fraction (26/342 or 7.6%) was elevated (defined as ≥1%), which was similar to what was observed in TBx samples (505/6492 or 7.8%).² When assessing samples from the 14 patients with CCA or CUP who had both TBx and LBx samples available, FGFR2 REs were detected in ≥1 of the samples in each patient; positive detection of FGFR2 RE was observed in 12 tissue/ liquid pairs.² In 1 paired sample, FGFR2 RE detection was positive in tissue but not in liquid, which may be attributable to a low estimated ctDNA fraction (0.52%) in the liquid sample. In another paired tissue/liquid sample, FGFR2 RE detection was negative in the tissue sample but positive in the liquid sample. The authors postulated that these findings may have been due to an identified concurrent FGFR2 driver mutation (H314_ V324del); the rearrangement was detected at 4 reads in the liquid sample and may represent a subclonal variant.² This study also explored the ability of LBx to detect FGFR2 resistance mutations. In all, 11 LBx samples from patients with CCA had FGFR2 resistance mutations. Of those 11 samples, LBx was able to detect a driver FGFR2 RE in 10 samples and a driver C382R mutation in 1 sample.²

Finally, in all samples of patients with GI malignancies, the study observed a diverse range of EGFR and BRAF REs using LBx. There were 38 EGFR-activating REs in patients with CRC, liver, esophageal, pancreatic, or stomach cancer, which included fusions, c-terminal truncations, deletions/inversions, kinase domain duplications, and other complex REs.² A total of 31 BRAF REs were detected in patients with CRC or pancreatic cancer, including fusions, deletions/truncations, and kinase domain duplications.²

In summary, this study’s findings showed that REs can be detected across the GI cancer samples tested with LBx, including several that result in known oncogenic drivers that may be targeted by current treatments. Furthermore, Dr Kasi and researchers observed reliable detection of FGFR2 fusions using LBx in patients with CCA or CUP. This study’s findings show that LBx can use ctDNA to detect REs and other actionable targets, which may be useful when TBx is unavailable or there is not enough tissue.²

References

1. Lee SH, Lee B, Shim JH, et al. Landscape of actionable genetic alterations profiled from 1,071 tumor samples in Korean cancer patients. Cancer Res Treat. 2019;51(1):211-222.
2. Kasi PM, Lee JK, Tukachinsky H, et al. Liquid-biopsy detection of FGFR2 and other actionable rearrangements in GI malignancies. Poster presented at: ASCO 2023 Annual Meeting, June 2-6, 2023; Chicago, IL.
3. Berchuck JE, Facchinetti F, DiToro DF, et al. The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer. Ann Oncol. 2022;33(12):1269-1283.