The advent of targeted inhibitors that work on the fibroblast growth factor receptor (FGFR) pathway may alter the disease course and outcomes in intrahepatic cholangiocarcinoma, suggests data from a four-center retrospective study. Lead investigator Apurva Jain, MD, of the University of Texas MD Anderson Cancer Center presented the findings at the 2016 ASCO Annual Meeting.
This patient pool was drawn from a database of 377 biliary tract cancer patients who had next-generation sequencing (NGS). The investigators reviewed the records of 95 cholangiocarcinoma patients with FGFR pathway genetic aberrations identified on NGS. Of these, FGFR2 genetic aberrations were by far the most common, occurring in 74 patients (77%). The next most frequently seen was FGFR19, with 11 patients (12%). “However, we must note that the incidence of FGFR genetic aberrations was higher than previously reported by others, reflecting a referral bias in our study,” Jain said.
Among the 74 FGFR2 patients, 62 had genetic fusions (59 with intrahepatic cholangiocarcinoma, 2 with gallbladder cancer, and 1 with extrahepatic cholangiocarcinoma). One had genetic amplification and the remaining 9 had genetic mutation.
The study patient population (n = 95) displayed several notable demographic characteristics. Nearly two-thirds (n = 60, 63%) were female. The overall mean age was 54 (range 22 to 82), but an unexpectedly high number were aged 40 or younger (n = 19, 20%). Eighty-three patients (87%) had intrahepatic cholangiocarcinoma. Regarding treatment history, 86 patients (91%) had received standard chemotherapy, 40 (42%) had received surgery and 26 (27%) had been treated with radiation.
The investigators observed that patients who had FGFR genetic aberrations (n = 83) had an overall survival (OS) of 40 months (95% CI, 19.41 - 60.59), while those who did not (n = 190) had OS of 22 months (95% CI, 16.18 27.82). ThePvalue was <0.0001. “As a matter of fact, this survival improvement remained significant even after we excluded 33 patients who had been treated with FGFR-specific targeted therapy,” Jain said. “Furthermore, the FGFR pathway was significant in a multivariate analysis [hazard ratio (HR) = .478,P=.03], indicating that cholangiocarcinomas with FGFR pathway genetic aberrations may have an indolent course.”
Of the 62 patients who had genetic fusions, the most common FGFR2 fusion partner was BICC1 (n = 8). One notable observation was that, among other coexisting mutations and pathways (n = 95), KRAS was rarely seen (n = 2, 2%), “it was seen in 2 only cases where it coexisted with FGF19 ligand genetic aberrations and not with FGFR2 genetic fusions, where it may be mutually exclusive,” Jain said.
Of the 36 patients who had been treated with FGFR-specific targeted therapy, 23 (64%) received BGJ398, 8 (22%) received ponatinib, 3 (8%) received TAS-120, and 1 (3%) received dovitinib.
The investigators noted that patients with genetic aberrations (n = 86) had an improvement in OS when they were treated with FGFR-targeted therapy versus standard care. Those with genetic aberrations (n = 36) had an OS of 44 months (95% CI, 33.11 - 54.89). Those without genetic aberrations (n = 50) had an OS of 24 months (95% CI, 16.86 31.15). ThePvalue was .01.
Jain and colleagues also constructed a multivariate Cox model of FGFR genetic aberrations. Variables included radiation, surgery, FGFR-directed treatment and TP53 mutations. Of these, FGFR treatment was statistically significant, with a coefficient of -1.6436, estimated risk of .1933, and aPvalue of .00293.
The investigators additionally concluded that biliary tract cancer patients with FGFR pathway genetic aberrations “represent a unique subtype” and coexisting mutations (like TP53) may have important prognostic implications.
Jain A, Shroff RT, Kelley RK, et al. FGFR pathway genetic aberrations in cholangiocarcinoma: Demographics and experience with targeted therapy.J Clin Oncol34, 2016 (suppl; abstr 109).