KEY TAKEAWAYS
- The study aimed to investigate the predictive significance of the FGFR4 p.G388R polymorphism in patients with mCRC receiving TAS-102 treatment.
- Researchers noticed that the FGFR4 p.G388R variant could be a novel marker for predicting TAS-102 responsiveness in patients with mCRC.
TAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of trifluridine, a thymidine analog, and tipiracil (a thymidine phosphorylation inhibitor). It demonstrates efficacy in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan, and oxaliplatin.
Alessandro Ottaiano and the team aimed to investigate the genotype/phenotype interplay concerning TAS-102 sensitivity.
They performed an inclusive analysis on 47 consecutive patients with mCRC treated with TAS-102 from March 2019 to March 2021. TAS-102 was administered 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, and activity was evaluated using RECIST criteria (v1.1), while toxicity was assessed with NCI-CTC (v5.0).
Survival analysis was conducted through Kaplan-Meier curves. Genetic features were evaluated using Next Generation Sequencing (NGS) via the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit.
The median age of patients was 65 years (range: 46-77). Forty-one patients had 2 or more metastatic sites, and 38 patients underwent more than 2 previous lines of therapies. Eastern Cooperative Oncology Group (ECOG) 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 observed was neutropenia (G3/G4 in 16 patients). No severe (> 3) non-hematological toxicities or treatment-related deaths were reported.
About 26 patients experienced progressive disease (PD), while 21 had stable disease (SD), and 3 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 tumor 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).
The study concluded that the FGFR4 p.G388R variant could be a new marker for identifying patients responsive to TAS-102 treatment. Furthermore, a mechanistic hypothesis was proposed to interpret these findings, indicating promising avenues for personalized treatment strategies in mCRC.
The study received a collaboration and financial support by the Lega Italiana per la Lotta contro I Tumori (LILT)‐sezione di Napoli and was supported by the Ministero delle Imprese e del Made in Italy, “Epi-MET – Funzionalizzazione delle aberrazioni (epi)genomiche nei tumori metastatici”.
Source: https://pubmed.ncbi.nlm.nih.gov/38650006/
Ottaiano A, Santorsola M, Ianniello M, et al. (2024). “Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment.” J Transl Med. 2024 Apr 22;22(1):379. doi: 10.1186/s12967-024-05184-w. PMID: 38650006; PMCID: PMC11036552.
