FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape
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Published on: August 25, 2015
Samuel J Klempner1,2, Russell Madison3, Vivek Pujara4
1The Angeles Clinic and Research Institute, Los Angeles California, USA sklempner@theangelesclinic.org.
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.
Insights
Fibroblast growth factor receptor 2 (FGFR2) alterations occur in 4% of advanced gastroesophageal adenocarcinomas (GEA). Comprehensive genomic profiling reveals FGFR2-altered GEA is a heterogeneous subgroup with frequent co-occurring alterations, guiding targeted therapy selection.
Area of Science:
- Oncology
- Genomics
- Gastroenterology
Background:
- Receptor tyrosine kinase (RTK) targeted therapies have limited success in gastroesophageal adenocarcinomas (GEA), except for trastuzumab.
- Fibroblast growth factor receptor 2 (FGFR2) alterations are present in GEA, but the genomic landscape of FGFR2-altered GEA is not well understood.
Purpose of the Study:
- To examine the frequency of FGFR2 alterations in GEA.
- To investigate co-occurring alterations in FGFR2-altered GEA.
Main Methods:
- Genomic profiling of 6,667 advanced GEA tissue specimens using hybrid capture.
- Analysis of tumor mutational burden (TMB) and microsatellite instability.
Main Results:
- FGFR2 alterations were identified in 4.0% of GEA cases (amplification, mutation, rearrangement).
- Frequent co-occurring alterations included ERBB2, EGFR, MET, MYC, KRAS, and PIK3CA.
- FGFR2-amplified and rearranged GEA were microsatellite stable; TMB was not significantly different from FGFR2 wild-type GEA.
Conclusions:
- FGFR2-altered GEA is a heterogeneous subgroup, with approximately 20% harboring concurrent RTK alterations.
- Frequent oncogenic alterations (MYC, KRAS, PIK3CA) suggest the need for pretreatment molecular analysis for combination therapies.
- Genomic profiling of FGFR2-altered GEA supports its utility in advanced GEA, similar to HER2-amplified GEA.
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