Summary: prevalence of FGFR2 fusions or rearrangements in cholangiocarcinoma

Reported frequencies of FGFR2 fusions or rearrangements in intrahepatic cholangiocarcinoma are 13.6% (9 of 66) by reverse-transcriptase polymerase chain reaction, 13% (12 of 96) by fluorescence in situ hybridization, 14% in a sequenced institutional cohort, and 13.9% in a European routine-testing cohort. Central prescreening for FIGHT-202 confirmed FGFR2 fusions or rearrangements in 107 of 1,206 participants (9%), which the investigators describe as broadly consistent with the published range of 10% to 16%. In a comprehensive genomic profiling dataset of 6,802 cholangiocarcinoma samples, 9.2% had FGFR2 rearrangements, of which 76.1% were classified as fusions and 20.7% as other rearrangements, with BICC1 the most common partner (26.7%). In the FIGHT-202 prescreening cohort analysed for clinicogenomic correlates, 74 participants (6.1%) had FGFR2 rearrangements, 15.2% in the United States, 7.4% in Europe, and 2.2% in the rest of the world, which the investigators attribute partly to inclusion of extrahepatic cholangiocarcinoma. In a multicentre Italian cohort of 312 participants with advanced intrahepatic cholangiocarcinoma, FGFR2 fusions or rearrangements occurred in 10.6%. In a surgical FISH series, FGFR2 rearrangements were found in 12/96 intrahepatic, 0/25 perihilar, and 0/31 extrahepatic tumours. Frequency varied with the biopsy site sampled (9% of primary tumour biopsies, 6% and 4% of other sites) and was enriched 2.1-fold in participants with African ancestry. The FGFR2 cohort of FIGHT-202 contained greater proportions of women and of participants younger than 65 years than the other cohorts, and in a resected cohort FGFR2 fusion was more often present in younger (53 vs. 62 years) and female (83 vs. 49%) participants, whereas a European routine-testing cohort found no association between FGFR2 fusions and age or sex.

Overall prevalence of the underlying cancer is limited by short survival: SEER estimated 116,514 people living with liver and intrahepatic bile duct cancer in the United States in 2023, and the 16-year limited-duration prevalence of cholangiocarcinoma from 2001 to 2017 was reported as 5.92, higher for extrahepatic (4.23) than intrahepatic (1.69) disease. Nearly 40% of biliary tract cancers harbour a genetic alteration that is a potential target for precision medicine.

Prevalence: people living with liver and intrahepatic bile duct cancer in the United States

“In 2023, there were an estimated 116,514 people living with liver and intrahepatic bile duct cancer in the United States.” (opens the source at this quote in a new tab)
“Approximately 1.1 percent of men and women will be diagnosed with liver and intrahepatic bile duct cancer at some point during their lifetime, based on 2021–2023 data.” (opens the source at this quote in a new tab)

Prevalence: limited-duration prevalence of cholangiocarcinoma in SEER, 2001 to 2017

“From 2001 to 2017, the LDP of CCA was 5.92% (Table 3) and was higher for eCCA vs iCCA (4.23% vs 1.69%). The LDP of iCCA increased from 2001-2006 (0.60%) to 2007-2012 (0.98%) to 2013-2017 (1.37%), whereas the LDP for eCCA remained relatively stable.” (opens the source at this quote in a new tab)
“LDP is defined as the number of people alive on a certain day who had a diagnosis of the disease within the past 16 years; as of January 1, 2017.” (opens the source at this quote in a new tab)

FGFR2 fusion frequency in intrahepatic cholangiocarcinoma: FIGHT-202 prescreening

“FGFR2 fusions and rearrangements are found almost exclusively in intrahepatic cholangiocarcinoma, occurring in 10–16% of patients.” (opens the source at this quote in a new tab)
“107 (9%) of the 1206 prescreened patients had centrally confirmed FGFR2 fusions or rearrangements.” (opens the source at this quote in a new tab)
“Nevertheless, this prevalence is broadly consistent with that reported in the published scientific literature (10–16%),” (opens the source at this quote in a new tab)

FGFR2 rearrangement frequency by region in the FIGHT-202 prescreening cohort

“In the prescreening cohort, we identified 74 patients (6.1%) with FGFR2 rearrangements (Supplementary Table S1).” (opens the source at this quote in a new tab)
“The frequency of FGFR2 rearrangements varied among regions. In the United States, 21 patients (15.2%) were positive, whereas 42 (7.4%) were positive in Europe and 11 (2.2%) were identified in the rest of the world.” (opens the source at this quote in a new tab)
“For example, the frequency of FGFR2 rearrangements (6.1%) is lower than previously reported for pure intrahepatic cholangiocarcinoma populations (10–16%), likely due to the inclusion of patients with extrahepatic cholangiocarcinoma (typically negative for FGFR2 rearrangements) in the prescreening population.” (opens the source at this quote in a new tab)

FGFR2 fusion frequency in intrahepatic cholangiocarcinoma: RT-PCR discovery series

“In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212).” (opens the source at this quote in a new tab)
“FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma.” (opens the source at this quote in a new tab)

FGFR2 fusion frequency by fusion type and tumour type in an RT-PCR screening series

“RT-PCR and Sanger sequencing analysis of 102 cholangiocarcinoma specimens (66 ICCs and 36 ECCs) from Japanese individuals, including eight who had been subjected to whole transcriptome sequencing, identified seven FGFR2-AHCYL1-positive and two FGFR2-BICC1-positive cases (Table 1; Supporting Table 4).” (opens the source at this quote in a new tab)
“The nine FGFR2-fusion-positive cases were ICC type tumors (9/66, 13.6%).” (opens the source at this quote in a new tab)
“The FGFR2-BICC1 fusion gene was detected in one colorectal cancer (0.7%) and one hepatocellular carcinoma (1.0%). These fusion-positive non-ICC cases were also hepatitis virus-positive (Table 1).” (opens the source at this quote in a new tab)
“However, fusion positive cases had a propensity for hepatitis virus infection (Table 2).” (opens the source at this quote in a new tab)

FGFR2 translocation frequency by fluorescence in situ hybridization

“Thirteen (10 women, 3 men; 8%) of 156 biliary tumors harbored FGFR2 translocations, including 12 intrahepatic cholangiocarcinomas (12/96; 13%) and 1 intraductal papillary neoplasm of the bile duct.” (opens the source at this quote in a new tab)

FGFR2 translocation frequency by anatomic location in a surgical FISH series

“Using FISH, FGFR2 translocations were identified in 12 cholangiocarcinomas and 1 IPNB for an overall frequency of 8% (13/156; Figs. 1 and 2). All specimens with FGFR2 translocation were intrahepatic, with a frequency of 13% (12/96) for intrahepatic cholangiocarcinomas.” (opens the source at this quote in a new tab)
“None of the FGFR2-translocated tumors occurred in patients with primary sclerosing cholangitis.” (opens the source at this quote in a new tab)
“The patients with FGFR2-rearranged tumors had a median age of 52 years (range, 36-83 years), which was 11 years younger than the median age for the biliary tumors without FGFR2 rearrangement, but this difference was not statistically significant (P = .121).” (opens the source at this quote in a new tab)

Anatomic location	FGFR2 rearrangements by FISH, n/N (%)
Intrahepatic	“12/96 (13)”
Perihilar	“0/25 (0)”
Extrahepatic	“0/31 (0)”

FGFR2 fusion frequency by anatomic subtype in a sequenced cholangiocarcinoma cohort

“The most commonly altered genes in intrahepatic cholangiocarcinoma (IHC) were IDH1 (30%), ARID1A (23%) BAP1 (20%), TP53 (20%) and FGFR2 gene fusions (14%).” (opens the source at this quote in a new tab)
“BAP1 mutations and FGFR2 gene fusions were identified exclusively in patients with intrahepatic cholangiocarcinoma.” (opens the source at this quote in a new tab)

FGFR2 rearrangement frequency in a comprehensive genomic profiling dataset of cholangiocarcinoma

“Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements.” (opens the source at this quote in a new tab)

FGFR2 rearrangement classes and fusion partners in a comprehensive genomic profiling dataset

“Of the 6802 samples tested, 629 (9.2%) had a total of 632 FGFR2 rearrangement events. These events were further classified as fusions (n = 481; 76.1%), rearrangements (n = 131; 20.7%), truncations (n = 18; 2.8%), and duplications (n = 2; 0.3%) (Figure 1A).” (opens the source at this quote in a new tab)
“The most common fusion partner was BICC1 (n = 169; 26.7%), followed by AHCYL1 (n = 19; 3.0%), TACC2 (n = 17; 2.7%), and CCDC6 (n = 16; 2.5%); 126 (19.9%) rearrangement events had a partner gene that was unique to a single patient (N-of-One), and 35 (11.1%) for which the partner was observed in only two patients (N-of-Two) (Figure 1B and Supplemental Table S5).” (opens the source at this quote in a new tab)
“Most FGFR2 rearrangements (54.4%) involved intrachromosomal rearrangements on chromosome 10, with BICC1, CCDC6, and TACC2 being the most common rearrangement partners.” (opens the source at this quote in a new tab)
“The frequency of FGFR2 rearrangements observed in our real-world data set of 6802 patients with CCA was 9.2%, which is slightly lower than estimates for iCCA of 10% to 15%.” (opens the source at this quote in a new tab)
“Given the lack of detailed clinical information in this data set, the cohort is likely not strictly iCCA and may include eCCA, perihilar CCA, and cancers of unknown primary, as the genomic test may have been ordered before the physician received the results of a full diagnostic assessment.” (opens the source at this quote in a new tab)

FGFR2 rearrangement frequency by biopsy site and ancestry in intrahepatic cholangiocarcinoma

“In Pbx, Mbx, and Lbx, FGFR2 rearrangements were found in 9%, 6%, and 4%, and IDH1 mutations were identified in 16%, 5%, and 9% patients, respectively.” (opens the source at this quote in a new tab)
“Moreover, alterations in FGFR2 and IDH1 were significantly associated with distinct ancestries, including 2.1‐fold enrichment for FGFR2 rearrangements in patients with African ancestry and 1.5‐fold enrichment for IDH1 mutations in patients with admixed American (Hispanic) ancestry.” (opens the source at this quote in a new tab)
“The Pbx cohort of 1,048 patients was 51% female and had a median age of 65 years.” (opens the source at this quote in a new tab)

FGFR2 fusion frequency across biliary tract cancer subtypes in a European routine-testing cohort

“IDH1 mutations (17.3%) and FGFR2 fusions (13.9%) were exclusively observed in intrahepatic cholangiocarcinoma, KRAS mutations were most prevalent in extrahepatic cholangiocarcinoma (42.9%), and ERBB2 amplification was enriched in gallbladder cancer (16.7%).” (opens the source at this quote in a new tab)

FGFR2 alteration frequency in the full cohort and in intrahepatic disease in a European routine-testing cohort

“Of the 224 included BTC cases, molecular alterations were identified in 133 (59.4%).” (opens the source at this quote in a new tab)
“The five most frequently observed alterations in the general cohort included KRAS mutations (20.4%), IDH1 mutations (11.3%), FGFR2 fusions (9.3%), ERBB2 amplification (8.8%), and BRAF mutations (5.7%).” (opens the source at this quote in a new tab)
“Notably, FGFR2 fusions, IDH1 mutations and IDH2 mutations were found exclusively in iCCAs and never co-occurred.” (opens the source at this quote in a new tab)
“iCCA was molecularly defined by IDH1/2 mutations (17.3% IDH1, 5.8% IDH2) and FGFR2 alterations (13.9% fusions, 2.9% mutations, 0.9% amplifications), which were nearly exclusive to this subgroup (excepting one FGFR2-mutant CCA NOS case).” (opens the source at this quote in a new tab)
“While FGFR2 alterations were mainly represented by fusions, a number of point mutations were also detected, with Y375C being the most frequently observed variant (40.0%; Figure 2B).” (opens the source at this quote in a new tab)

FGFR2 fusion or rearrangement frequency in a multicentre Italian real-world cholangiocarcinoma cohort

“Molecular profiling among the 312 patients with advanced iCCA revealed IDH1 mutation as the most common druggable alteration, with a prevalence of 15.1% (47), followed by FGFR2 fusions/rearrangements (33, 10.6%), IDH2 mutation (10, 3.2%), MSI-high/deficient MMR status (6, 1.9%), and BRAF V600E mutations (4, 1.3%).” (opens the source at this quote in a new tab)
“The ANITA dataset comprised 42 patients with FGFR2-fused/rearranged disease and 59 patients with IDH1-mutated CCA, accounting for 11.4% and 15.2% of the profiled population, respectively. In both cases, iCCA was the most common site of origin (FGFR2: 95.2%; IDH1: 94.9%).” (opens the source at this quote in a new tab)
“Of the EMP-profiled tumors, 139 (28.6%) presented an ESCAT I-III alteration; this was significantly more frequent in iCCA (115, 36.9%) compared to pCCA (13, 15.3%) and dCCA (11, 12.4%), p < 0.001).” (opens the source at this quote in a new tab)

Demographic features of participants with FGFR2 fusions or rearrangements

“This cohort included greater proportions of women, patients aged younger than 65 years, and patients with disease confined to the liver, and included a smaller proportion of patients with an ECOG performance status of 2 than patients in the other cohorts (table 1).” (opens the source at this quote in a new tab)

“In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001)” (opens the source at this quote in a new tab)

Age and sex associations of FGFR2 fusions in resected and routine-testing cohorts

“Twelve (13%) patients with iCCA were found to have an FGFR2 fusion based on FISH break-apart probe testing (Fig. 1). FGFR2 fusion was not found in any patients with pCCA or dCCA consistent with previously published reports.” (opens the source at this quote in a new tab)
“FGFR2 fusion was more often present in younger (53 vs. 62 years, p = 0.012) female (83 vs. 49%, p = 0.033) patients. Additionally, those diagnosed with CCA before the age of 40 years were more likely to be characterized by FGFR2 fusion (p = 0.01).” (opens the source at this quote in a new tab)

“No association between FGFR2 fusions and age or sex was observed in our cohort, despite reports of enrichment in younger female iCCA patients” (opens the source at this quote in a new tab)

Prevalence: share of biliary tract cancers with a potentially targetable genetic alteration

“Nearly 40% of patients with BTC harbour genetic alterations which are potential targets for precision medicine.” (opens the source at this quote in a new tab)
“There remains, therefore, an urgent need to develop new therapies, particularly for patients who lack a targetable genomic alteration.” (opens the source at this quote in a new tab)

Lirafugratinib (Lyrfigtu)

Prevalence of Previously treated FGFR2 fusion or rearrangement-positive cholangiocarcinoma