Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors

Abstract

Introduction: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane domain may increase the proliferation of xenografted neuroendocrine cell lines and decrease their sensitivity to everolimus by modulating STAT3 signaling and the mTOR pathway. Aim: To evaluate the prognostic and predictive values of this polymorphism on everolimus efficacy in patients treated for digestive neuroendocrine tumor (NET). Patients and Methods: This monocentric retrospective cohort included patients with small bowel NET (SBNET) and pancreatic NET (PNET) treated with everolimus (2006-2013). The patients were genotyped by classical sequencing, and mTOR pathway activity was assessed by immunochemistry on formalin-fixed paraffin-embedded samples (PTEN/pPTEN/pAKT/pmTOR/pS6/p4EBP1). Results: Forty-one patients (21 males, median age 57 years) with PNET (n = 28), SBNET (n = 12) or NET of unknown origin (n = 1), grade 1 (n = 8), 2 (n = 27), 3 (n = 3) or unknown grade (n = 3), were studied. At least one 388Arg allele was found in 14/23 PNET and 10/11 SBNET. Progression-free survival in the whole population and the PNET subgroup was not influenced by the presence of one or two 388Arg alleles [HR = 1.31 (0.58-2.99), p = 0.52 and HR = 1.11 (0.45-2.73), p = 0.82, respectively]. Similarly, overall survival was not influenced. Finally, mTOR pathway molecule expression was not modified by the presence of at least one 388Arg allele. Conclusion: The Gly388Arg FGFR4 polymorphism does not seem to have a prognostic value in digestive NET. In addition, it neither predicts the response to everolimus nor modifies the activation of the mTOR pathway.

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…Another study genotyped the fibroblast growth factor receptor 4 (FGFR4) using DNA isolated from tissue or blood in panNETs, and found that patients homozygous for FGFR-G388 demonstrated greater tumor shrinkage with everolimus treatment than those harboring only one FGFR4-R388 allele[142]. Although longer PFS and OS were also observed in those homozygous for FGFR4-G388, these were not statistically significant due to small number of patients, which is consistent with the result from another group showing that FGFR4 polymorphism did not have predictive value on everolimus treatment[143]. …”

Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors

“…These patients showed a reduction in everolimus treatment response. On the contrary, in 2016, Cros et al evaluated the prognostic and predictive value of the FGFR4 Gly388>Arg388 mutation in everolimus efficacy in a NET cohort (Cros et al 2016). This study did not confirm the mutations' prognostic nor its predictive value.…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…TSC-2, PTEN), a frequent finding in pNET tumor samples, might be more indicative of tumor response although correlative data to everolimus efficacy are lacking (Missiaglia et al 2010). Different variables have been tested for their predictive value (the occurrence of stomatitis, an early decrease of circulating chromogranin A and the FGFR4 genotype polymorphism), but none of them represents a definite predictor of response to everolimus (Yao et al 2011a, Serra et al 2012, Cros et al 2016, Rugo et al 2016.…”