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

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.

Keywords: Colorectal cancer; FGFR4; NGS; TAS-102.

Fig. 1

Representative computed tomography (CT) restaging images depict FA, CC, and NA patients with long-lasting disease control (FA, CC, and NA represent patients' initials). Baseline CT scans at TAS-102 treatment initiation are outlined in green frames, while CT scans at the last available restaging (third for FA and CC patients, second for NA patients) are framed in blue. Measurable lesions in the peritoneum (FA: 58 mm vs 59 mm), abdominal lymph nodes (CC: 22 mm vs 0 mm; 25 mm vs 23 mm), and lungs (NA: 10 mm vs 8 mm, 6 mm and 8 mm vs 0 mm and 0 mm) are delineated by their longest diameters, with measurements in millimeters reported within the images

Fig. 2

Venn diagram illustrating the coding genetic variant shared among patients exhibiting long-lasting disease control with TAS-102 (FA, CC, and NA represent patients' initials). The sole shared genetic variation (highlighted in red) is FGFR4 p.G388R. DNA extraction was performed from formalin-fixed and paraffin-embedded (FFPE) primary colorectal cancer tissue specimens. Libraries were prepared using the TruSigtTMOncology 500 kit, which assesses 523 cancer-relevant genes, and sequenced on an Illumina NovaSeq 6000 platform. Sequences were aligned to the human reference genome GRCh37 using the Burrows–Wheeler Aligner tool (for further details, refer to the Methods section)

Fig. 3

Kaplan–Meier survival curves depict patient outcomes from the initiation of TAS-102 therapy until death, stratified by the presence or absence of the rs351855 FGFR4 polymorphism. Time is represented on the x-axis, while survival probability is depicted on the y-axis. The number of patients at risk is reported below the figure, with data categorized based on FGFR4 polymorphism status