Association of FGFR2 structural alterations in intrahepatic cholangiocarcinomas with female gender and younger age.

Abstract

537 Background: FGFR2 fusions and other rearrangements are targetable alterations due to the advent of FGFR2 kinase domain inhibitors, and are considerably more common in intrahepatic cholangiocarcinomas (iCCA) than other cancer types. Understanding clinical factors associated with FGFR2 fusions and other rearrangements may guide precision oncology efforts. Prior studies indicate that FGFR2 alterations are more common in younger patients, but it remains unknown whether other demographics are specifically associated with FGFR2 structural alterations. Here, we reviewed the frequency of FGFR2 structural alterations in 8,898 iCCA patients from the AACR Genie and the Foundation Medicine databases. Methods: We reviewed the Foundation Medicine (n= 7,934) and AACR GENIE database (n=964) for intrahepatic cholangiocarcinomas. We identified iCCAs with FGFR2 structural alterations and mutations in other common driver genes and analyzed their distribution by age and sex. Results: FGFR2 structural alterations were more frequent in female (10.4%) compared to male (6.4%) patients across both cohorts. FGFR2 structural alterations had an association with an odds ratio of 2.5 (95% CI 1.6-3.7) and 1.7 (95% CI-2.0) with the female gender in the AACR GENIE and Foundation Medicine databases, respectively. The frequency of FGFR2 fusions/rearrangement was highest during reproductive years (up to age 40) and subsequently declined with age. This decline was greater in females than males. Mutations in other genes associated with iCCA including non-fusion FGFR2 alterations, and mutations in ARID1A, KRAS, and TP53 were not associated with gender or age. Conclusions: Our results show that FGFR2 structural alterations are significantly enriched in younger female patients with iCCA. Clinical assessment of FGFR2 alterations should be prioritized in this patient population, and future clinical studies in this molecular subtype should ensure inclusive enrollment practices. Further research is warranted to determine if the pathogenesis of FGFR2 structural alterations are driven by female biology including the involvement of sex hormones and the potential impact on the development of acquired resistance to FGFR2 kinase inhibitors.