FGFR Inhibitors: Clinical Activity and Development in the Treatment of Cholangiocarcinoma

King, Gentry Teng; Javle, Milind

doi:10.1007/s11912-021-01100-3

Cited by 27 publications

(23 citation statements)

References 79 publications

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“…Basturk et al described four patients with this type of alteration, 55 which appeared to be enriched in ITPN compared with that in PDAC/IPMN. Since there is a growing body of evidence regarding the sensitivity of neoplastic cells harboring such fusions to FGFR inhibitors, 91,92 this alteration should be taken into account during the molecular diagnosis of ITPN and when developing tailored therapeutic approaches. A final consideration of the genetic landscape of pancreatic ITPN should be reserved for chromatin remodelers, such as MLL genes and BAP1, which seemed to be more altered in this type of lesion compared with that in conventional PDAC (although the comparison with existing datasets did not show statistical significance).…”

Section: O L E C U L a R L A N D S C A P Ementioning

confidence: 99%

Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors

et al. 2022

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Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumorsAims: Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a recently recognized pancreatic tumor entity. Here we aimed to determine the most important features with a systematic review coupled with an integrated statistical approach. Methods and results: PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic ITPN. The clinicopathological, immunohistochemical, and molecular data were summarized. Then a comprehensive survival analysis and a comparative analysis of the molecular alterations of ITPN with those of pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) from reference cohorts (including the International Cancer Genome Consortium-ICGC dataset and The Cancer Genome Atlas, TCGA program) were conducted. The core findings of 128 patients were as follows: (i) Clinicopathological parameters: pancreatic head is the most common site; presence of an associated adenocarcinoma was reported in 60% of cases, but with rare nodal metastasis. (ii) Immunohistochemistry: MUC1 (>90%) and MUC6 (70%) were the most frequently expressed mucins. ITPN lacked the intestinal marker MUC2; unlike IPMN, it did not express MUC5AC. (iii) Molecular landscape: Compared with PDAC/IPMN, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, GNAS, and RNF43 were less altered in ITPN (P < 0.001), whereas MCL amplifications, FGFR2 fusions, and PI3KCA mutations were commonly altered (P < 0.001). (iv) Survival analysis: ITPN with a "pure" branch duct involvement showed the lowest risk of recurrence. Conclusion: ITPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for the enrichment of potential targets for precision oncology.

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Section: O L E C U L a R L A N D S C A P Ementioning

confidence: 99%

Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors

et al. 2022

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“…TST170 constitutes a hybrid capture-based assays, which captures targeted RNA molecules regardless of the neighbouring nucleotide sequence and is thus also able to detect unknown partner genes. These technical considerations have particular relevance for the evaluation of FGFR2 fusions, for which more than 150 partner genes have been reported in the literature until now [ 24 ]. In this study, AMP, OCAv3, and TST170 panels were applied in 78% ( n = 79/101), 21% ( n = 21/101), and 15% ( n = 15/101) of patients, respectively (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Precision oncology for intrahepatic cholangiocarcinoma in clinical practice

et al. 2022

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Background Advanced cholangiocarcinoma has a poor prognosis. Molecular targeted approaches have been proposed for patients after progression under first-line chemotherapy treatment. Here, molecular profiling of intrahepatic cholangiocarcinoma in combination with a comprehensive umbrella concept was applied in a real-world setting. Methods In total, 101 patients received molecular profiling and matched treatment based on interdisciplinary tumour board decisions in a tertiary care setting. Parallel DNA and RNA sequencing of formalin-fixed paraffin-embedded tumour tissue was performed using large panels. Results Genetic alterations were detected in 77% of patients and included gene fusions in 21 patients. The latter recurrently involved the FGFR2 and the NRG1 gene loci. The most commonly altered genes were BAP1, ARID1A, FGFR2, IDH1, CDKN2A, CDKN2B, PIK3CA, TP53, ATM, IDH2, BRAF, SMARCA4 and FGFR3. Molecular targets were detected in 59% of patients. Of these, 32% received targeted therapy. The most relevant reason for not initiating therapy was the deterioration of performance status. Patients receiving a molecular-matched therapy showed a significantly higher survival probability compared to patients receiving conventional chemotherapy only (HR: 2.059, 95% CI: 0.9817–4.320, P < 0.01). Conclusions Molecular profiling can be successfully translated into clinical treatment of intrahepatic cholangiocarcinoma patients and is associated with prolonged survival of patients receiving a molecular-matched treatment.

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“…Other mechanisms of resistance include gatekeeper mutations, activation of alternate signaling pathways, polyclonal secondary FGFR mutations, cooccurring tumor suppressor gene alterations such as BAP1, CDKN2A/B, PBRM1, TP53 etc. [22][23][24] A number of FGFR2-point mutations (N549H, N549K, E565A, K641R, or K659M) and gatekeeper mutation (V565F and V565I) were seen in patients who developed progression on reversible ATP-competitive FGFR inhibitor. King et al and Goyal et al suggested combination therapy with mTOR/PI3K targeted therapy, immune checkpoint inhibitor, vascular endothelial growth factor (VEGF) inhibitor, chemotherapy or sequential FGFR targeted therapy as a possible direction towards overcoming resistance.…”

Section: Discussionmentioning

confidence: 99%

Sustained response on sequential anti-FGFR therapy in metastatic gall bladder cancer: a case report and literature review

Sheth

Limaye

Kumar³

et al. 2022

J Cancer Res Clin Oncol

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Advanced gall bladder cancer (aGBC) is an aggressive disease with no consensus on treatment options beyond rst line chemotherapy. We report a case of an elderly male with FGFR2 altered advanced adenocarcinoma of the gallbladder who failed two prior lines of chemotherapy but had sustained response and stable disease on sequential FGFR directed targeted therapy. This treatment was based on comprehensive genomic pro ling by next-generation sequencing revealed FGR2 alteration. Sequential anti-FGFR tyrosine kinase inhibitors was initiated as a treatment of choice. The patient tolerated the sequential targeted therapy very well and had a sustained response and stable disease with 5 years of survival. Our study demonstrates that aGBC with FGFR alteration can be managed on anti-FGFR therapy for prolonged periods of time, with improved survival. The study revealed a FGFR-directed therapeutic as a viable treatment option in these patients.

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FGFR Inhibitors: Clinical Activity and Development in the Treatment of Cholangiocarcinoma

Cited by 27 publications

References 79 publications

Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors

Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors

Precision oncology for intrahepatic cholangiocarcinoma in clinical practice

Sustained response on sequential anti-FGFR therapy in metastatic gall bladder cancer: a case report and literature review

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