FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Abstract

Background With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2‐altered GEA. We examined FGFR2 alteration frequency and frequency of co‐occurring alterations in GEA. Subjects, Materials, and Methods A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture‐based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. Results We identified a total of 269 (4.0%) FGFR2‐altered cases consisting of FGFR2‐amplified (amp; 193, 72% of FGFR2‐altered), FGFR2‐mutated (36, 13%), FGFR2‐rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co‐occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2‐altered GEA. Co‐occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2‐altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild‐type samples. Conclusion FGFR2‐altered GEA is a heterogenous subgroup with approximately 20% of FGFR2‐altered samples harboring concurrent RTK alterations. Putative co‐occurring modifiers of FGFR2‐directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. Implications for Practice Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2‐altered GEA parallels the heterogeneity findings in HER2‐amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort

“…Second, we did not study the entire cohort for Fgfr2 amplifications and could not comment on the combined association of FGFR2 protein expression and Fgfr2 -amplification with clinicopathological patient characteristics. However, genomic changes of Fgfr2 known to be oncogenic include amplifications, short variants, and rearrangements, constituting 72%, 13%, and 8.6% of the Fgfr2 -alterations in GC [ 54 ]. Thus, correlating genetic alterations of Fgfr2 with clinicopathological patient characteristics necessitates a more comprehensive analysis and is beyond the scope of the current study.…”

Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments

“…In a hybrid capture-based genomic profiling study using 6667 tissue specimens from advanced GC patients, FGFR2 gene aberrations were found in 269 (4%) with the most frequent alteration being amplification (72%) followed by mutations (13%), translocations (8.6%) and co-occurring alterations (6.3%). 24 Rare (<1%) fusions (FGFR2-TACC2), and single point mutations (N549K) have been discovered however their clinicopathological characteristics and targeting potential remain unclear. 24 Amongst GC, gene amplification is the most common aberration of the FGFR2 gene which leads to FGFR2 protein overexpression and constitutive signalling of the FGFR pathway.…”

“…24 Rare (<1%) fusions (FGFR2-TACC2), and single point mutations (N549K) have been discovered however their clinicopathological characteristics and targeting potential remain unclear. 24 Amongst GC, gene amplification is the most common aberration of the FGFR2 gene which leads to FGFR2 protein overexpression and constitutive signalling of the FGFR pathway. The prevalence of FGFR2 gene amplification ranges from 2% to 9% [13][14][15][16][17] depending on the clinical characteristics of the cohort, and the method used to detect amplification.…”

“… 24 Rare (<1%) fusions ( FGFR2-TACC2) , and single point mutations (N549K) have been discovered however their clinicopathological characteristics and targeting potential remain unclear. 24 …”

“… 18 , 27 , 28 FGFR2 and HER2 amplifications are mutually exclusive, 25 , 28 however rare cases have been reported. 24 Nevertheless, approximately 40% of FGFR2 altered gastroesophageal cancers harbour other mutations ( KRAS, MYC ) which may render it resistant to FGFR pathway targeted therapy. 25 FGFR2 amplification occurs in microsatellite stable (MSS) tumours and does not enrich for PD-L1 expression.…”