9 To date, no molecular predictive biomarker for sorafenib response

in HCC treatment has been validated and accepted in clinical practice. Efforts in such a direction were performed 5-Fluoracil solubility dmso during the SHARP molecular biomarker program, but were of limited success.10 Furthermore in the same trial, 10 plasma biomarkers implicated in hepatocarcinogenesis were measured serially in 305 patients, and only high s-c-KIT or low hepatocyte growth factor showed trends toward enhanced survival. In addition, exploratory subset analyses of the Asia-Pacific trial also failed to identify markers associated with superior response to sorafenib.5 Working along this line of research, currently, Arao et al. have successfully identified a novel potential molecular biomarker: fibroblast growth factors 3 and 4 (FGF3/FGF4) amplification in a patient with partial response and long-term survival under sorafenib. Based on this finding and by employing copy number polymerase chain reaction, fluorescence in situ hybridization, and gene-expression analysis,

the investigators buy GDC-0449 extended their investigation and retrospectively identified FGF3/FGF4 amplification in 30% of sorafenib responders (3 of 1011). This frequency is significantly increased, compared with the overall reported rate of FGF3/FGF4 amplification, amounting to 2.4% in unselected patients with HCC. Therefore, the investigators conclude that FGF3/FGF4 amplification with consecutive up-regulation of gene expression seems to be associated with a substantially increased likelihood and degree of response to sorafenib. These findings were functionally confirmed by the screening of various

cancer cell lines for FGF3/FGF4 up-regulation and by its correlation with in vitro response to sorafenib. In addition, enhanced proliferation in a cell clone expressing FGF4 was reversed by sorafenib in a nude mouse assay. Although elegantly performed and scientifically sound, the study by Arao et al. is somewhat hampered by several limitations. First, a small cohort of patients is studied and retrospective analyses may lead to a selection bias. Second, an unbiased genome-wide evaluation was performed only in the index patient, and the finding in this patient (FGF3/FGF4 gene amplification) was confirmed in 3 click here of 10 other patients, but without genome-wide assessment in this population. Therefore, it remains unclear whether the proposed amplification is a driving genetic alteration rendering the affected cells particularly susceptible to sorafenib treatment and, if so, by which mechanism. Alternatively, the finding could represent a secondary bystander phenomenon. Based on clinical and molecular data, up-regulated signaling through FGF family receptors (FGFRs) has been identified as a promising therapeutic target in patients with HCC.