The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

Helsten, Teresa; Elkin, Sheryl K.; Arthur, Elisa; Tomson, Brett N.; Carter, Jennifer; Kurzrock, Razelle

doi:10.1158/1078-0432.ccr-14-3212

Cited by 562 publications

(604 citation statements)

References 52 publications

(70 reference statements)

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“…The FGFR family alterations are more common in women than in men (17.6% vs 10.0%). This data is of great scientific value because it shows that an alteration of this pathway is the third most present after TP53 and KRAS anomalies (Harding and Nechiporuk, 2012;Helsten et al, 2015).…”

Section: Fgfr In Cancermentioning

confidence: 81%

“…FGFR alterations in cancer 3.1.1. Gene amplification Amplification of FGFR is reported to be present in 66% of cancers with an FGFRs alteration, with FGFR1 amplification being the most common (42%) (Helsten et al, 2015). Approximately 20% of the squamous cell carcinomas (SCC) of the lung present with FGFR1 amplification and this has been shown to be associated with smoking in a dose-dependent fashion (Rooney et al, 2016).…”

Section: Fgfr In Cancermentioning

confidence: 99%

“…In the last two decades, invasive breast cancer samples have been screened extensively for FGFR amplifications, as they account for 7.5-17% of all breast cancer and 16-27% of luminal B-type breast cancer, in both cases reducing the patients' outcome. Among 10-18% of the samples showed FGFR amplification, again with FGFR1 amplification being the most frequent (8-10%) (André and Cortés, 2015;Criscitiello et al, 2015;Helsten et al, 2015). In non-small cell lung cancer (NSCLC), the different histotypes are being screened for FGFR amplifications.…”

Section: Fgfr In Cancermentioning

confidence: 99%

“…In non-small cell lung cancer (NSCLC), the different histotypes are being screened for FGFR amplifications. It has been shown that FGFR1 amplifications are significantly correlated with tumor histotype: FGFR1 amplification is more common in SCC (20.7%) than in large cell carcinoma (LC) (13%) and adenocarcinoma (AC) (2.2%) (Helsten et al, 2015). Interestingly it has been shown that FGFR1 amplification is much more represented in early stages than in advanced stages, suggesting a key role of FGRF1 amplification during the initial phase of tumor development which may be clinically important for treatment purpose PLC-y pathway, PIK3-AKT pathway and the FRS2-Ras-MAPK pathway.…”

Section: Fgfr In Cancermentioning

confidence: 99%

“…FGF: fibroblast growth factor. (Cihoric et al, 2014;Helsten et al, 2015). Recently it has been discovered a high overexpression of FGFR1 in HNSCC (Head and neck squamous cell carcinoma) in particular, it was positive in 82% of human papillomavirus (HPV)-positive HNSCC and 75% of HPV-negative HNSCC and relates with poor outcome (Koole et al, 2016).…”

Section: Fgfr In Cancermentioning

confidence: 99%

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FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

167

152

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Section: Fgfr In Cancermentioning

confidence: 81%

Section: Fgfr In Cancermentioning

confidence: 99%

Section: Fgfr In Cancermentioning

confidence: 99%

Section: Fgfr In Cancermentioning

confidence: 99%

Section: Fgfr In Cancermentioning

confidence: 99%

See 3 more Smart Citations

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

167

152

View full text Add to dashboard Cite

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Estimation of Percentage of Patients With Fibroblast Growth Factor Receptor Alterations Eligible for Off-label Use of Erdafitinib

et al. 2019

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IMPORTANCE When a novel drug is granted accelerated approval, both its on-label and off-label uses must be taken into account. OBJECTIVES To estimate the potential upper bound of off-label use of erdafitinib to treat advanced cancer with fibroblast growth factor receptor gene (FGFR) alterations, compare it to the upper bound of on-label use in urothelial cancer, and to review studies that may support off-label use. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used frequency data on FGFR alterations by cancer type and the estimated number of deaths from all cancers for 2019 in the United States. Mortality statistics were used as surrogates for patients with advanced cancer. Analysis was conducted in May 2019. EXPOSURE Percentage of patients with an FGFR2 or FGFR3 alteration. MAIN OUTCOMES AND MEASURES Estimated number of patients with advanced cancer expressing an FGFR2 or FGFR3 alteration eligible for off-label use of erdafitinib by cancer type; number of studies investigating FGFR-targeting drugs for patients with cancer; and number of ongoing clinical trials on erdafitinib by cancer type. RESULTS A total of 15 cancer types had reported FGFR alterations. Of 455 440 estimated patients who died of cancer in 2019, 17 019 (3.7%) were estimated to have FGFR2 or FGFR3 alterations. Of these patients, 12 955 (76.1%) could be eligible for off-label treatment with erdafitinib. A total of 29 completed studies evaluated FGFR-targeting drugs in 11 cancer types, and 10 ongoing studies are studying erdafitinib for different oncological indications. CONCLUSIONS AND RELEVANCE This study indicates that the potential for off-label use of FGFR inhibitors such as erdafitinib spans a number of cancer types and a large patient population. Systematic trials exploring off-label uses may be desirable for drugs that target clear, identifiable molecular alterations because this may be more efficient than off-label use in identifying clinical scenarios where the agent has activity.

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Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

et al. 2020

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Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5–41% of breast cancers. Here, we investigated the genetic differences between HER2‐positive and HER2‐negative admixed breast cancer components. We performed an in‐depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin‐fixed, paraffin‐embedded breast cancer tissue of ten patients with at least one HER2‐negative and at least one HER2‐positive component was microdissected. Targeted next‐generation sequencing was performed using a customized 53‐gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2‐negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2‐negative tumour component. No common alternative drivers were identified in the HER2‐negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere ‘passenger’ molecular anomalies.

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The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

Cited by 562 publications

References 52 publications

FGFR a promising druggable target in cancer: Molecular biology and new drugs

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Estimation of Percentage of Patients With Fibroblast Growth Factor Receptor Alterations Eligible for Off-label Use of Erdafitinib

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

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