FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355

Gatekeeping and trailblazing: The role of biomarkers in novel guidelines for diagnosing Alzheimer’s disease

In innovation policy discourse, clinical practice guidelines are often viewed as gatekeepers: they select which novel technologies may enter clinical practice. Earlier research has pointed out, however, that in biomedical innovation a ‘regime of hope’ and a ‘regime of truth’ interact. High expectations of future developments can feed into clinical guidelines by changing assessment criteria, thus co-shaping the ‘gate’ innovations have to pass. This paper shows how diagnostic guidelines can embody hope in yet another way, by introducing a novel disease vocabulary that paves the way for emerging diagnostic technologies. I discuss two sets of guidelines for diagnosing Alzheimer’s disease: the guidelines issued by the American National Institute on Aging and the Alzheimer’s Association (2011), and the parts of the DSM-5 related to diagnosing AD (2013). Both function as gatekeepers in that they explicitly discourage the use of biomarker testing in clinical practice. However, they also act as ‘trailblazers’, transforming the conceptualization of Alzheimer’s disease in such a way that biomarker tests can be easily fitted in later on. The paper ends with some reflections on the potential presence of such ‘trailblazing’ in other diagnostic guidelines, and its acceptability from an ethical and societal point of view