FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations

Usón, Pedro Luiz Serrano; DeLeon, Thomas; Bogenberger, James M; Pai, Rish K.; Kosiorek, Heidi E.; Yin, Jun; Ahn, Daniel H.; Sonbol, Mohammad Bassam; Bekaii‐Saab, Tanios; Mansfield, Aaron S.; Buetow, Kenneth H.; Gores, Gregory J.; Smoot, Rory L.; Vasmatzis, George; Kipp, Benjamin R.; Mahipal, Amit; Baker, Alex; Babiker, Hani M.; Barro, Oumar; Dumbauld, Chelsae; Zhou, Yumei; Aslam, Faaiq; Barrett, Michael T.; Jacobs, Bertram L.; Meurice, Nathalie; Arora, Mansi; Petit, Joachim; Elliott, Natalie; Nagalo, Bolni Marius; Salomao, Marcela A.; Borad, Mitesh J.

doi:10.1007/s10620-021-07303-9

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…1 Furthermore, problems related to detection of FGFR2 genomic alterations are not observed in the case of IDH1 mutations. 8,23 In the largest cell-free tumor DNA (ctDNA) data, 2068 samples from 1671 patients were analyzed with next-generation sequencing. 8 Of patients with IDH1 mutations detected in tissue samples, 87% were also detected in ctDNA, showing a high concordance.…”

Section: Discussionmentioning

confidence: 99%

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date

Uson Junior,

Borad

2023

CMAR

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Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed.

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Section: Discussionmentioning

confidence: 99%

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date

Uson Junior,

Borad

2023

CMAR

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“…Second, first-line chemotherapy should be updated with Durvalumab in those trials [4]. Third, multiple limitations in detecting FGFR2 fusions, due to poor logistics in some centers, different methods of diagnosis and turnaround time, that can hinder recruitment in cancer centers located in low-and-middle-income countries [44]. Finally, for future trials evaluating FGFR inhibitors, data from co-occurring mutations would be necessary to be informed and included in the report of outcomes.…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

“…4 Third, multiple limitations in detecting FGFR2 fusions, due to poor logistics in some centers, different methods of diagnosis, and turnaround time, can hinder recruitment in cancer centers located in low-and middle-income countries. 44 Finally, for future trials evaluating FGFR inhibitors, data from cooccurring mutations would be necessary to be informed and included in the report of outcomes. Furthermore, ctDNA would need to be incorporated as the choice for detecting acquired mutations and cooccurring mutations related to primary and secondary resistance to FGFR inhibitors.…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond

Usón

Borad

2023

Semin Liver Dis

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FGFR2 Inhibitors are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma (CCA). Activation of the FGF-FGFR pathway is related to proliferation and tumor progression. Targeting the FGF-FGFR pathway is effective and can yield durable responses in patients with CCA harboring FGFR2 fusions or rearrangements. In this review article, we address molecules and clinical trials evaluating FGFR inhibitors in advanced CCA. We will further discuss identified mechanisms of resistance and the strategies to overcome it. The incorporation of next-generating sequencing in advanced CCA and circulating tumor DNA on disease progression will unveil mechanisms of resistance and improve the development of future clinical trials and more selective drugs and combinations.

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Expression of fibroblast growth factor receptor 2 (FGFR2) in combined hepatocellular-cholangiocarcinoma and intrahepatic cholangiocarcinoma: clinicopathological study

Sasaki,

Sato,

Nakanuma

2024

Virchows Arch

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Genetic alterations including fusions in fibroblast growth factor receptor 2 (FGFR2) are detected in 10–20% of intrahepatic cholangiocarcinoma (iCCA), and FGFR2 inhibitors are effective for the treatment of iCCA. We examined a prevalence of FGFR2 genetic alterations and their clinicopathological significance in combined hepatocellular–cholangiocarcinoma (cHCC-CCA). FGFR2 expression, which is a surrogate marker for FGFR2 genetic alterations, was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 35 with small duct-type iCCA, 30 with large duct-type iCCA, and 35 with hepatocellular carcinoma (HCC). FGFR2 genetic alterations were detected by reverse transcription-PCR and direct sequence. An association of FGFR2 expression with clinicopathological features was investigated in cHCC-CCAs. FGFR2 expression was detected in significantly more patients with cHCC-CCA (21.3%) and small duct-type iCCA (25.7%), compared to those with large duct-type iCCA (3.3%) and HCC (0%) (p < 0.05). FGFR2-positive cHCC-CCAs were significantly smaller size (p < 0.05), with more predominant cholangiolocarcinoma component (p < 0.01) and less nestin expression (p < 0.05). Genetic alterations of ARID1A and BAP1 and multiple genes were significantly more frequent in FGFR2-positive cHCC-CCAs (p < 0.05). 5′/3′ imbalance in FGFR2 genes indicating exon18-truncated FGFR2 was significantly more frequently detected in FGFR2-positive cHCC-CCAs and small duct iCCAs, compared to FGFR2-negative ones (p < 0.05). FGFR2::BICC fusion was detected in a case of cHCC-CCAs. FGFR2 genetic alterations may be prevalent in cHCC-CCAs as well as small duct-type iCCAs, which suggest cHCC-CCAs may also be a possible therapeutic target of FGFR2 inhibitors. Graphical Abstract

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FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations

Cited by 5 publications

References 24 publications

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond

Expression of fibroblast growth factor receptor 2 (FGFR2) in combined hepatocellular-cholangiocarcinoma and intrahepatic cholangiocarcinoma: clinicopathological study

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