FGFR2 Identified as Rare Target in Fluke-Associated Cholangiocarcinoma

FGFR2 fusions are significantly less common in endemic fluke-associated cholangiocarcinoma compared with non—fluke-associated cholangiocarcinoma, demonstrating that distinct etiologies could affect the molecular landscape of cholangiocarcinoma tumors, according to findings from a study published in the Journal of Clinical Oncology Global Oncology.

According to anchored multiplex polymerase (AMP) chain reaction target enrichment RNA sequencing, FGFR2 fusions were identified in 0.8% and 11.6% of fluke-associated cholangiocarcinoma and non—fluke-associated cholangiocarcinoma, respectively (P = .0006).

"Collectively, our findings illustrate the importance of conducting genomic studies in diverse populations [with cancer] to enable the molecular dissection of specific cancer types for translational benefit," Sarinya Kongpetch, PhD, and coinvestigators wrote.

These findings, which were validated by florescence in situ hybridization (FISH) and Sanger sequencing, highlight the need to discover actionable genomic alterations in this patient population, as well as in more diverse patient populations.

"The same cancer in fluke-endemic Thailand not only suffers from worse prognosis, it unfortunately also presents with a profound lack of actionable targets, therefore representing an area of unmet clinical need that requires novel therapeutic strategies," Kongpetch and coinvestigators wrote.

FGFR fusions have been shown to be functionally relevant and druggable in cholangiocarcinoma. Moreover, as these alterations contribute to tumorigenesis and progression, they could serve as an ideal target for antikinase therapy. Additionally, patients with FGFR fusions tend to respond more effectively to FGFR inhibitors compared with standard chemotherapy.

In the study, investigators evaluated whether these alterations were present in fluke-associated cholangiocarcinoma in endemic countries, specifically northeast Thailand, through AMP and targeted sequencing. One hundred twenty-one fluke-associated tumors from northeast Thailand and 95 non—fluke-associated tumors from Romania and Singapore were screened for FGFR fusions.

Among FGFR1/2/3 fusions, FGFR2 fusions were identified with the highest frequency. These fusions were found in 15.7% (n = 51) of samples from Singapore, 6.8% (n = 44) of samples from Romania, and 0.8% (n = 121) of samples from Thailand, demonstrating the disparity of FGFR2 fusions in fluke-associated and non—fluke-associated cholangiocarcinoma.

Risk factors including geography and etiology appeared to be associated with cholangiocarcinoma. In areas such as northeastern Thailand, Laos, and Cambodia, the chronic infection Opisthorchis viverrini is associated with a liver fluke and often results in cholangiocarcinoma carcinogenesis. However, in western countries like the United States, the most common risk factors for cholangiocarcinoma are primary sclerosing cholangitis, hepatobiliary duct stones, inflammatory bowel disease, alcohol use, smoking, and fatty liver disease.

Clinicopathologic information from each specimen, including age, sex, and tumor subtype was reviewed retrospectively. These features were classified in categorical variables—total counts and frequencies—and continuous variables.

The retrospective analyses regarding baseline demographic and clinicopathologic characteristics showed that 59.7% and 40.3% of samples came from male and female patients, respectively (P = .551). Slightly more than half (52.3%) of samples came from patients 58 years of age or older (P = .043).

More intrahepatic cholangiocarcinoma samples (n = 124) were tested compared with extrahepatic samples (n = 89; P = .009). The histologic differentiation spread was categorized as well (n = 94), moderate (n = 53), poor (n = 7), and papillary (n = 51; P = .016). Additionally, 29 patients had stage 1 disease, 35 had stage 2 disease, 60 had stage 3 disease, and 77 had stage 4 disease (P = .049).

FGFR mutations were detected exclusively in intrahepatic disease and were mutually exclusive with other somatic mutations, including KRAS, ERBB2, BRAF, and FGFR, confirming that FGFR fusions are oncogenic drivers in cholangiocarcinoma.

Notably, 56% of samples were fluke-associated compared with 44% which were non—fluke-associated (P = .003).

Upon clinicopathologic analyses, FGFR2/3 fusion-positive tumors were predominately present in younger patients (P = .043, Fisher’s exact test). Moreover, these genetic alterations had a significantly higher association with intrahepatic disease (P = .009) and tumors with moderate differentiation histology (P = .016).

Notably, these tumors suggested a trend toward improved overall survival compared with fusion-negative tumors, according to Kongpetch and coinvestigators. However, this difference was not found to be statistically significant.

"We comprehensively analyzed fusions involving FGFR family genes using a targeted RNA sequencing approach," Kongpetch and coinvestigators wrote. "By comparing between cholangiocarcinoma tumors with different etiologies, we found that FGFR2 fusions were almost exclusively associated with non—fluke-associated cholangiocarcinoma. For endemic fluke-associated cholangiocarcinoma, which carries a poorer prognosis compared with its non–fluke-associated counterpart, there is an urgent need to identify specific targets that are druggable. The current study also highlights the importance to conduct genomic and other studies on cancer in diverse populations," concluded Kongpetch and coinvestigators.

Kongpetch S, Jusakul A, Lim JQ, et al. Lack of targetable FGFR2 fusions in endemic fluke-associated cholangiocarcinoma. JCO Global Oncology. 2020;6:628-638. doi:10.1200/GO.20.00030