NDLI: Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment

Content Provider	Springer Nature : BioMed Central
Author	Ottaiano, Alessandro Santorsola, Mariachiara Ianniello, Monica Ceccarelli, Anna Casillo, Marika Sabbatino, Francesco Petrillo, Nadia Cascella, Marco Caraglia, Francesco Picone, Carmine Perri, Francesco Sirica, Roberto Zappavigna, Silvia Nasti, Guglielmo Savarese, Giovanni Caraglia, Michele
Abstract	Background TAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity. Methods Forty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m2, twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit. Results Median age of patients was 65 years (range: 46–77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2–12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test). Conclusions This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings. Graphical Abstract
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-024-05184-w.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-024-05184-w
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	22
Language	English
Publisher	BioMed Central
Publisher Date	2024-04-22
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health TAS-102 FGFR4 Colorectal cancer NGS Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment

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Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment