Polymorphisms of FGFR Pathway-related Factors and Capecitabine-induced Hand-foot Syndrome in Japanese Patients With...

Hand-foot syndrome (HFS) is a common adverse event associated with capecitabine. While the fibroblast growth factor receptor (FGFR) signaling pathway is involved in skin wound healing, its essential role in capecitabine-induced HFS remains unclear. We examined the association between polymorphisms in FGFR signaling pathway-related genes and capecitabine-induced HFS in patients with colorectal cancer (CRC).

This retrospective study included patients with CRC who received capecitabine and oxaliplatin. HFS was evaluated using CTCAE v5.0, up to 2 cycles. Polymorphisms were identified using whole-exome sequencing and confirmed using direct sequencing. The association between HFS and polymorphisms was analyzed using Fisher's exact test. The Bonferroni correction for multiple testing was performed to calculate the corrected p-value (Pc).

Overall, 937 polymorphisms were identified in 71 genes. Intronic FGFR2 rs2981460 C/C, and rs2981461 T/T genotypes, and haplotype II/II comprising the C and T alleles were associated with a lower HFS incidence (p=0.0161, Pc=0.113; p=0.0163, Pc=0.114; and p=0.0161, Pc=0.113, respectively). Synonymous FGFBP2 rs2286459 A/A was associated with a lower HFS frequency (p=0.0469, Pc=0.328). 3'-Untranslated region and nonsynonymous variants SPRY2 rs11911 T/G or G/G and rs504122 G/A or A/A, and homozygotes or heterozygotes of haplotype 2 comprising respective G and A alleles, were significantly associated with higher HFS incidence (p=0.0000803, Pc=0.000562; p=0.0000803, Pc=0.000562; and p=0.0000803, Pc=0.000562, respectively). A significantly higher HFS incidence was observed in patients with a combined risk genotype and diplotypes of FGFR2 any/II or any/any, FGFBP2 rs2286459 G/G or G/A, and SPRY2 2/2 or any/2 (p=0.0000314).

Variants in FGFR signaling pathway-related factors were significantly associated with capecitabine-induced HFS.