Fibroblast Growth Factor Receptor 1 Protein Expression Research Articles

High expression of FGFR3 predicts a better prognosis for patients with non-small cell lung cancer in a Chinese population.

This study sought to examine the expression and mutation status of fibroblast growth factor receptor 3 (FGFR3) in non-small cell lung cancer (NSCLC) tissues and explore the prognostic potential of FGFR3 in NSCLC. Immunohistochemistry (IHC) was used to evaluate the FGFR3 protein expression of 116 NSCLC tissues. Sanger sequencing was used to examine the mutation status of exons 7, 10, and 15 in FGFR3. A Kaplan‑Meier survival analysis was conducted to evaluate the association between the expression level of FGFR3 and the overall survival (OS) and disease-free survival (DFS) of NSCLC patients. Univariate and multivariate Cox analyses were conducted to examine the association between the risk score and clinical features. FGFR3 was immunoreactive in 26 of the 86 NSCLC cases. Further, FGFR3 was positively expressed in 84.6% of the lung adenocarcinoma (AC) cases and 15.4% of the lung squamous cell carcinoma (SCC) cases. FGFR3 mutations were detected in 2 NSCLC patients (2/72, 2.8%), who both harbored the T450M mutation, a novel mutation in exon 10 of FGFR3. In NSCLC, a high expression of FGFR3 was positively correlated with gender, smoking, histology type, T stage, and the epidermal growth factor receptor (EGFR) mutation (P<0.05). FGFR3 expression was also correlated with better OS and DFS. The multivariate analysis revealed that FGFR3 served as an independent prognostic factor (P=0.024) for the OS of NSCLC patients. This study showed that FGFR3 was highly expressed in NSCLC tissues, and the frequency rate for the FGFR3 mutation at T450 M in NSCLC tissues was low. The survival analysis suggested that FGFR3 may be a useful prognostic biomarker in NSCLC.

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123.The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.

Expression of fibroblast growth factor 9 and its receptors in the dentate gyrus of hippocampus in poststroke depression rats.

Studies have found that fibroblast growth factor 9 (FGF9) might have a negative effect in the psychiatric diseases, such as depression or anxiety, but its potential role in the pathophysiology of poststroke depression (PSD) remains uncertain. Here, we set out to investigate the expression changes of FGF9 and its receptors in PSD rats. Middle cerebral artery occlusion (MCAO) combined with chronic unpredictable mild stress was used to establish the PSD rat model. Then, the rats were randomly divided into four groups: control (sham-operation), MCAO, PSD and treated (fluoxetine injection by intraperitoneal). Weight measurement, sucrose preference test, open-field test and forced swim test were performed to evaluate the behavioral changes, and then Western blot and real-time quantitative PCR were used to detect the expression level of FGF9, fibroblast growth factor receptor 1 (FGFR1) and receptor 3 (FGFR3) in the dentate gyrus of rat hippocampus. We found that FGF9 protein and mRNA expression increased significantly in the MCAO and PSD groups; FGFR3 protein and mRNA expression decreased significantly in the MCAO and PSD groups; FGFR1 protein and mRNA expression decreased significantly in the PSD group, but increased in the treated group. Furthermore, the changes mentioned above were reversed obviously by fluoxetine. These results indicated that upregulated FGF9 expression and downregulated FGFR1 and FGFR3 expression may be involved in the pathogenesis of PSD, and the FGF9/FGFR signaling pathway may be considered as an attractive target for further study.

FGFR1 Is Associated With Tamoxifen Resistance and Poor Prognosis of ER-Positive Breast Cancers by Suppressing ER Protein Expression.

Fibroblast growth factor receptor 1 (FGFR1) is widely recognized as a key player in mammary carcinogenesis and associated with the prognosis and therapeutic response of breast cancers. With the aim of investigating the correlation between FGFR1 expression and estrogen receptor (ER) and exploring the effect of FGFR1 on endocrine therapy response and ER+ breast cancer prognosis, we examined the FGFR1 protein expression among 184 ER-positive breast cancers by the immunohistochemistry (IHC) method, analyzed the association between FGFR1 expression and disease characters using the Pearson’s chi-square test, and assessed the prognostic role of FGFR1 among breast cancers using Cox regression and Kaplan-Meier analyses. Moreover, in vitro assays were conducted to confirm the correlation between FGFR1 and ER expression and investigate the effect of FGFR1 on tamoxifen (TAM) sensitivity in ER+ breast cancer. The results showed that ER expression was negatively correlated with FGFR1 expression (P = 0.011, r = -0.221). Moreover, FGFR1 expression was one of the prognostic factors of ER-positive breast cancer (OR = 1.974, 95% CI = 1.043-3.633), and high FGFR1 expression was correlated with decreased breast cancer overall survival. In addition, knocking down FGFR1 inhibited cell proliferation and enhanced TAM sensitivity in TAM-resistant cells. In conclusion, we found that there was a significant negative correlation between FGFR1 and ER levels in ER+ breast cancers, high FGFR1 protein expression was associated with poor breast cancer prognosis, down-regulating FGFR1 could elevate ER expression and is associated with enhanced TAM sensitivity in ER+ breast cancers.

Fibroblast growth factor receptor 4 as a prognostic indicator in triple-negative breast cancer.

BackgroundTriple-negative breast cancer (TNBC) constitutes up to 15% of all breast cancers. It is one of the most aggressive breast cancers and is more prone to metastasize compared with other subtypes. Breast cancer patients with this subtype usually have a poor prognosis. Fibroblast growth factor receptor 4 (FGFR4) belongs to the receptor tyrosine kinase (RTK) family, and early analyses identified that FGFR4 was involved in breast cancer. However, the prognostic effect of FGFR4 on TNBC is unknown. In the present study, we investigated the association between FGFR4 and TNBC prognosis.MethodsA total of 282 TNBC patients were enrolled. FGFR4 protein expression was detected in these 282 TNBC patients using immunohistochemistry (IHC).ResultsIn the present study, FGFR4 was highly expressed in TNBC patients. Lymph node metastasis (LNM) (P=0.033) and p53 status (P=0.019) were associated with high FGFR4 expression. Univariate analysis identified high FGFR4 expression (P=0.016) as a prognostic predictor, and multivariate analysis found that high FGFR4 expression (P=0.016) was an independent prognostic factor. The Kaplan-Meier survival curve showed that high FGFR4 protein expression was correlated with poorer overall survival (OS).ConclusionsThe results of our present study show that FGFR4 protein expression is correlated with a worse prognosis in TNBC.

Abstract B23: FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment?

Abstract Objective: Fibroblast growth factor receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Overexpression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations and protein-expression of FGFR3 and p53 and assessed their prognostic value in a multicenter, multilaboratory setting. Methods: We included 1,000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uropathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expression were correlated to each other, clinicopathologic parameters, and disease-specific survival (DSS). Results: FGFR3 mutations were found in 107/1,000 RCs (11%), of which 67 were S249C. Overexpression of FGFR3 was found in 279/1,000 (28%) of tumors. p53 overexpression (cut-off&amp;gt;10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression. Among FGFR3 wild-type tumors, 22% had FGFR3 overexpression. FGFR3 mutations were associated with lower pT-stage (P&amp;lt;0.001), lower grade (G2-WHO 1973) (P&amp;lt;0.001), absence of CIS (P=0.009), pN0 (P&amp;lt;0.001), normal p53 (P&amp;lt;0.001), and prolonged DSS (Plog-rank=0.001). FGFR3 overexpression was associated with lower pT-stage (P&amp;lt;0.001) and G2 (P&amp;lt;0.001) but not with absence of CIS (P=0.860), pN0 (P=0.230), normal p53, (P=0.330) nor prolonged DSS (Plog-rank=0.204). We found no significant difference in DSS for patients with FGFR3 mutant tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.444). Furthermore, we also found no significant difference in DSS for patients with FGFR3 wild-type tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.754). Conclusions: FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 overexpression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only overexpression of FGFR3. Citation Format: Bas van Rhijn, Laura Mertens, Roman Mayr, Peter Bostrom, Mirari Marques, Geert van Leenders, Stefanie Gotz, Michiel van der Heijden, Michael Jewett, Francisco Real, Robert Stohr, Alexandre Zlotta, Markus Eckstein, Yanish Soorojebally, Max Burger, Wolfgang Otto, Francois Radvanyi, Damien Pouessel, Theo van der Kwast, Nuria Malats, Arndt Hartmann, Yves Allory, Deric van der Schoot, Ellen Zwarthoff, Tahlita Zuiverloon. FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B23.

FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment?†

Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. Patient summaryOncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.

Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer.

BackgroundTargeting fibroblast growth factor receptor 1 (FGFR1) is a potential treatment for squamous cell lung cancer (SQCLC). So far, treatment decision in clinical studies is based on gene amplification. However, only a minority of patients have shown durable response. Furthermore, former studies have revealed contrasting results regarding the impact of FGFR1 amplification and expression on patient's prognosis.AimsHere, we analyzed prevalence and correlation of FGFR1 gene amplification and protein expression in human lung cancer and their impact on overall survival.Materials & Methods FGFR1 gene amplification and protein expression were analyzed by fluorescence in situ hybridization and immunohistochemistry (IHC) in 208 SQCLC and 45 small cell lung cancers (SCLC). Furthermore, FGFR1 protein expression was analyzed in 121 pulmonary adenocarcinomas (ACs). Amplification and expression were correlated to each other, clinicopathological characteristics, and overall survival.Results FGFR1 was amplified in 23% of SQCLC and 8% of SCLC. Amplification was correlated to males (P = .027) but not to overall survival. Specificity of immunostaining was verified by cellular CRISPR/Cas9 FGFR1 knockout. FGFR1 was strongly expressed in 9% of SQCLC, 35% of AC, and 4% of SCLC. Expression was correlated to females (P = .0187) and to the absence of lymph node metastasis in SQCLC (P = .018) with no significant correlation to overall survival. Interestingly, no significant correlation between amplification and expression was detected.Discussion FGFR1 gene amplification does not seem to correlate to protein expression.ConclusionWe believe that patient selection for FGFR1 inhibitors in clinical studies should be reconsidered. Neither FGFR1 amplification nor expression influences patient's prognosis.

Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study.

Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated. The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1-not estimable [NE]), and 4.6 (95% CI 1.1-NE) months, respectively (p= 0.003). Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.

MRNA Expression of FGFR1 as Potential Marker for Predicting Prognosis of Surgical Resection of Small Cell Lung Cancer may be better than Protein Expression and Gene Amplification.

Purpose: Fibroblast growth factor receptor 1 (FGFR1) alterations have been described in many cancers, including lung cancer, but the role has not been elucidated specifically in small cell lung cancer (SCLC). The present study aimed to identify the frequency of FGFR1 alterations among Chinese patients with surgically resected SCLC and the association with the clinicopathological characteristics and the survival were also investigated.Methods: FGFR1 protein expression, FGFR1 amplification, FGFR1 mutations, and messenger RNA (mRNA) levels, were determined by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR), respectively in primary tumors from 33 patients with resected SCLC.Results: 7/33(21.2%) of the specimens were positive for FGFR1 protein expression. FGFR1 amplification was identified in 4/28 cases (14.3%). If the cut-off value was determined to be 3.5, FGFR1 mRNA positivity was considered in 7/33 cases (21.2%). However, no mutation was detected in the 33 SCLC postoperative tissue specimens. No significant association was observed between FGFR1 protein expression or amplification and clinicalcharacteristics or prognosis. There was a distinct trend for mRNA level and poor prognosis, including recurrence-free survival (RFS) (p = 0.07) and overall survival (OS) (p= 0.08), but they did not reach statistical significance.Conclusions: As novel FGFR1-targeted therapies are developed, FISH, IHC, especially mRNA were detected, which should be considered as biomarkers of FGFR1 pathway dysregulation in SCLC.

Prognostic implications of fibroblast growth factor receptor 4 polymorphisms in primary breast cancer.

Fibroblast growth factor receptor 4 (FGFR4) belongs to the receptor tyrosine kinase (RTK) family, and FGFR4 polymorphisms have been implicated in both normal development and cancer, including breast cancer. In the present study, we investigated correlations between polymorphisms in FGFR4 and breast cancer prognosis. The FGFR4 SNPs rs1966265 and rs351855 were genotyped in 747 breast cancer patients using the SNaPshot method. FGFR4 protein expression was detected by immunohistochemistry in 339 samples. SNP rs351855 was correlated with FGFR4 protein expression under dominant and co-dominant models. Lymph node metastasis (LNM), ER (estrogen receptor) status, and molecular subtype were associated with high FGFR4 expression. Univariate analysis revealed rs351855 (CC/CT: P = 0.027, CC/TT: P < 0.001, CC/CT + TT: P = 0.005) to be a prognostic predictor, and multivariate analysis indicated rs351855 (CC/TT: P = 0.005) to be an independent prognostic factor. Kaplan-Meier survival analysis showed that high FGFR4 protein expression was associated with a poor prognosis. SNP rs351855 was correlated with worse outcomes, with a dose-dependent effect. The results of this study show that FGFR4 SNP rs351855 is associated with up-regulation of FGFR4 protein expression and a worse prognosis in breast cancer.

Effects of FGFR1 Gene Polymorphisms on the Risk of Breast Cancer and FGFR1 Protein Expression

Background/Aims: Fibroblast growth factor receptor 1 (FGFR1) is widely considered to play an important role in mammary carcinogenesis. Some common variants in FGFR1 might be associated with its expression, and further affect breast cancer risk. The aim of this study was to investigate effects of single-nucleotide polymorphisms (SNPs) in FGFR1 on breast cancer susceptibility and FGFR1 protein expression. Methods: SNPs rs17182023, rs17175624 and rs10958704 in FGFR1 were genotyped in 747 breast cancer cases and 716 healthy controls by SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. Immunohistochemistry(IHC) was used to detect FGFR1 protein expression, and the association of FGFR1 polymorphisms with its protein expression was analyzed by Pearson’s chi-square test. Additionally, Cox regression and Kaplan-Meier analysis was used to evaluate the association between FGFR1 protein expression and breast cancer prognosis. Results: The minor allele of rs17182023 in FGFR1 was significantly associated with reduced breast cancer risk, with an odds ratio of 0.800 (95%CI = 0.684-0.935). No significant associations were detected between other SNPs and breast cancer. Moreover, rs17182023 was correlated to FGFR1 protein expression (P = 0.006), and patients with high FGFR1 protein expression tended to have poor outcomes. Conclusions: SNP rs17182023 was correlated to reduced breast cancer risk, and was associated with FGFR1 protein expression. High FGFR1 protein expression was an independent risk factor of breast cancer, and resulted in poor prognosis.

Combination of FGFR4 inhibitor Blu9931 and 5-fluorouracil effects on the biological characteristics of colorectal cancer cells.

The aim of this study was to explore the effects of single agent treatments and combination of Blu9931 and 5-fluorouracil (5-FU) on the biological characteristics of colorectal cancer cells and its mechanism. Blu9931 is the first selective small molecule inhibitor of the fibroblast growth factor receptor4 (FGFR4) and exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. The colorectal cancer cells HCT116 and SW620 with high expression of FGFR4 were selected for a series of functional tests including cell viability, cell proliferation, apoptosis and cell cycle detection. Western blotting was used to detect the expression of related molecules including signal pathway (STAT3), apoptosis (cleaved caspase‑3), cell cycle (cyclinD1 and P27kip1) and epithelial-mesenchymal transition (E-cadherin and vimentin) in HCT116 and SW620 cells used as single and combination treatments of 5‑FU and Blu9931. The cell viability gradually decreased when the concentration of 5‑FU and Blu9931 increased. Blu9931 can inhibit FGFR4 protein expression while 5‑FU cannot, as assessed by western blot analysis. The single agent treatment and combinations of 5‑FU and Blu9931 arrest cell cycle (P<0.05), increased p27kip1 expression and reduced cyclinD1 expression. The single agent treatment and combinations of 5‑FU and Blu9931 inhibited EMT. Furthermore, the combination of 5‑FU and Blu9931 has a synergistic effect in reducing colorectal cancer cell proliferation and preventing cell cycle. Taken together, this study provides the first evidence that Blu9931 functions as a FGFR4-selective inhibitor in colorectal cancer (CRC) cells, and Blu9931 may be a new targeted drug.

FGFR1 as a prognostic biomarker and potential therapeutic target in head and neck squamous cell carcinoma.

6057Background: FGFR1 (fibroblast growth factor receptor 1) is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. Methods: Immunohistochemistry and fluorescence in situ hybridization were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy-numbers in 452 HNSCC. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with gefitinib, was assessed using long-term colony formation assays and biochemical analysis. Results: FGFR1 protein overexpression occurred in 82% (36/44) of HPV-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival a...

Amplification of FGFR1 gene and expression of FGFR1 protein is found in different histological types of lung carcinoma

Although lung cancer continues to be the leading cause of cancer-related death, accurate diagnosis followed by personalized treatment is expected to raise the 5-year survival rate. Targeted therapies are now in routine clinical use, in particular for lung adenocarcinoma (ADC). Fibroblast growth factor receptor 1 (FGFR1) has recently emerged as a molecular target, especially in squamous cell/epidermoid carcinoma (SQC) of the lung. This paper evaluates FGFR1 expression and gene copy number in adenocarcinomas, squamous cell carcinomas, pleomorphic carcinomas (PLEOMC) and adenosquamous carcinomas (ADSQC) of the lung and also explores the epithelial-mesenchymal transition (EMT) pathway. We studied 76 lung carcinomas: 34 ADC, 24 SQC, 10 PLEOMC and 8 ADSQC. FGFR1 expression was evaluated by immunohistochemistry and gene amplification by fluorescence in situ hybridization (FISH). Higher FGFR1 protein expression was observed in all tumour types compared to non-tumour tissue. FGFR1 expression was higher in ADC and PLEOMC than in SQC. We found a tendency to higher expression in ADC than in SQC and significantly higher expression in PLEOMC than in other histological subtypes. FISH-based amplification of FGFR1 was identified in 15 (20%) lung carcinomas: 5 (15%) ADC, 5 (21%) SQC, 3 (30%) PLEOMC and 2 (25%) ADSQC. Amplification was more frequent in SQC without significant differences. FGFR1 protein is expressed in the majority of lung carcinomas, though it is higher in ADC and PLEOMC (the latter may reflect the importance of FGFR1 control of the EMT pathway). FGFR1 amplification was identified in all types of lung carcinoma. Although FGFR1 is most frequently amplified in SQC, other histological types merit assessment of FGFR1 amplification, in order to select patients that might benefit from targeted therapy.

Evaluation of FGFR3 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma.

Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC. FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment. Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398. Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.

Fibroblast growth factor receptor-1 protein expression is associated with prognosis in estrogen receptor-positive/human epidermal growth factor receptor-2-negative primary breast cancer.

Recently, research into the development of new targeted therapies has focused on specific genetic alterations to create advanced, more personalized treatment. One of the target genes, fibroblast growth factor receptor‐1 (FGFR1), has been reported to be amplified in estrogen receptor (ER)‐positive subtype breast cancer, and is considered one possible mechanism of endocrine resistance through cross‐talk between ER and growth factor receptor signaling. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, transcript and protein expression, and examined the relationships between FGFR1 status and clinicopathological parameters, including prognosis in 307 ER‐positive/HER2‐negative primary breast cancer patients treated with standard care at our institute. Most notably, a high level of FGFR1 protein expression was observed in 85 patients (27.7%), and was positively associated with invasive tumor size (P = 0.039). Furthermore, univariate analysis revealed that high FGFR1 protein expression was significantly correlated with poor relapse‐free survival rate (P = 0.0019, HR: 2.63, 95% confidence interval: 1.17–5.98), and showed a tendency towards an increase in recurrent events if the observation period extended beyond the 5 years of the standard endocrine treatment term. FGFR1 gain/amplification was found in 43 (14.0%) patients, which was only associated with higher nuclear grade (P = 0.010). No correlation was found between FGFR1 mRNA expression levels and any clinicopathological factors. Overall, the level of FGFR1 protein expression may be a biomarker of ER‐positive/HER2‐negative primary breast cancer with possible resistance to standard treatment, and may be a useful tool to identify more specific patients who would benefit from FGFR‐1 targeted therapy.

Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy-numbers in a single well-documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin-fixed paraffin-embedded tissues were immunohistochemically stained with an anti-FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease-free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64-1.39; P=0.77, HR: 0.94; 95% CI: 0.65-1.36; P=0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81-1.80; P=0.36, HR: 0.42; 95% CI: 0.79-1.77; P=0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3-directed therapies in oral and oropharyngeal squamous cell carcinoma.

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

Objective: The aim of this study was to investigate whether fibroblast growth factor receptor 4 (FGFR4) could serve as a potential therapeutic target, prognostic biomarker or biomarker predicting radiotherapy sensitivity in oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC). Methods: FGFR4 immunohistochemistry and FGFR4/CEN5q FISH were performed on tissue microarrays from 212 OSCC and 238 OPSCC patients. FGFR4 genotypes were determined by PCR and DNA sequencing in 76 random OPSCC samples. The response to radiotherapy was evaluated 3 months after the last radiotherapy treatment session by a head and neck radiation oncologist and/or surgeon during clinic visits. The results were correlated to overall survival and response to radiotherapy. Results: The FGFR4 protein was overexpressed in 64% (153/238) of OPSCCs and 41% (87/212) of OSCCs. The FGFR4 gene was amplified in 0.47% (1/212) of OSCCs and 0.42% (1/238) of OPSCCs, and the FGFR4 Gly388Arg polymorphism was detected in 62% (47/76) of OPSCCs. FGFR4 protein expression, FGFR4 gene copy numbers and FGFR4 genotypes were not related to overall survival or response to radiotherapy in OSCC or OPSCC. Conclusion: FGFR4 is frequently overexpressed in OSCC and OPSCC in the absence of gene amplification, and may serve as a potential predictive marker for FGFR4-directed targeted therapy in OSCC and OPSCC.

Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer

Introduction:Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non–small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples.Methods:FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number.Results:FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression.Conclusions:A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy.