FGFR2-fusions define a clinically actionable molecular subset of pancreatic cancer

Abstract

Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.

Fig. 1. Patients with metastatic pancreatic cancer and FGFR2 fusions demonstrate response and clinical benefit when treated with FGFR kinase inhibitors.

A Overview of treatment time course in four patients with metastatic pancreatic cancer who received FGFR kinase inhibitors. Patient 1 had stable disease as best response, while patient 2-4 experienced partial responses. B Partial response to FGFR kinase inhibitor infigratinib after 10 months of treatment in patient 3 demonstrated by decreased size of lung metastases. Left is pretreatment CT scans and right is after 10 months on infigratinib. C Serial monitoring of CA19-9 and plasma cell free DNA for FGFR2 fusion during FGFR inhibitor targeted therapy. Patient 4 developed known FGFR2 resistance mutations alongside of his fusion VAF (%). Areas shaded in blue represent FGFR inhibitor treatment, areas shaded in gray represent chemotherapy treatment, and non-shaded areas represent no treatment. VAF, Variant Allele Frequency.

Fig. 2. Genomic landscape of FGFR2 fusion-positive pancreatic cancer.

A The most common FGFR2 fusion partners found in pancreatic cancer (N = 30,229). B Volcano plot of the FGFR2 fusion cohort of co-occurring (red dots) and mutually exclusive (blue dots) with the FGFR alteration, respectively. Only genes with an adjusted p ≤ 0.05 and gene prevalence ≥0.5% were labeled. C Oncoplot of the FGFR2 fusion cohort illustrating co-occurring alterations, tumor-mutational burden (TMB), and MSI status.