Association between FGFR2b Positivity and Survival Outcomes of Patients with Gastric Cancer Treated with First-Line Nivolumab Plus Chemotherapy.

Background: Fibroblast growth factor receptor 2 (FGFR2) amplification is associated with tumorigenesis of gastric cancer and can be a promising molecular target for the treatment of FGFR2-amplified gastric cancer. So far, the most optimal single method to screen patients with FGFR2 amplification has not been determined. To screen patients with gastric cancer harboring FGFR2 amplification, we aim to investigate whether qPCR can replace the FISH method which is the golden standard but less sensitive and much more expensive than qPCR. Methods: FISH (Abnova, #FG0018) and qPCR (Applied Biosystems, HS05182482_cn) method for FGFR2 amplification were performed with formalin-fixed paraffin-embedded (FFPE) tissues of patients with gastric cancer who were diagnosed from 2007 to 2012 in Asan Medical Center, Seoul, Korea, and whose FFPE tissues contained at least 70% of tumor cells. qPCR was conducted initially in 26 patients who had both endoscopic biopsy and surgical tissues in the diagnosis to figure out which samples are better between biopsy and surgical tissues. According to the results, 182 patients with endoscopic biopsy tissues were further included. FISH was defined as positive in case of FGFR2 to CEP10 ratio > 2.0. Results: In 26 patients who had paired endoscopic biopsy and surgical samples, the qPCR-based copy number assay for FGFR2 amplification was more sensitive in biopsy samples; i.e., FGFR2 copy number by qPCR was higher in biopsy samples in 13 (50%) patients, while it was higher in surgical samples only in 3 (11.5%) patients. In a total of 208 endoscopic biopsy FFPE samples including 182 patients with biopsy tissues, copy number of FGFR2 ranged from 0.8 to 399.0 (median 15.9) by qPCR and from 0.7 to 166.9 (median 6.1) by FISH. 16 biopsy samples showing FGFR2 copy number > 10 by qPCR were all FISH-positive, while 192 biopsy samples showing FGFR2 copy number < 10 by qPCR were all FISH-negative. In cases of FGFR2 copy number > 10 in biopsy tissues by qPCR, the copy numbers were very well correlated between qPCR and FISH in all patients, and were also over 10 in surgical tissues regardless of methods in 26 patients. The positive rate of FGFR2 amplification was 7.7% with a cut-off value of 10 by qPCR. Conclusion: This study suggests that it is better to use biopsy samples than surgical tissues to detect FGFR2 amplification by qPCR; and for patient screening in gastric cancer, the optimal cut-off value for definite FGFR2 amplification by qPCR is 10 in comparison with the results of FISH. Clinical relevance of intermediate FGFR2 copy number elevation < 10 by qPCR needs to be addressed in future clinical trials using FGFR2 inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B211. Citation Format: Young-Soon Na, Young Soo Park, Min-Hee Ryu, Chae-Won Lee, Hye Jin Park, Ju-Kyung Lee, Sook Ryun Park, Baek-Yeol Ryoo, Yoon-Koo Kang. Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B211.

Background/Aims: Fibroblast growth factor receptor 2 (FGFR2) has attracted considerable interest as a therapeutic target in gastric cancer (GC). There is growing evidence to suggest that the bioavailability of the potent pro-tumor function of FGFR2 is associated with thrombospondins (TSPs). As a follow-on from our previous study, here we evaluated the potential clinical significance and mechanism of the relationship between FGFR2 and TSP4 in GC. Methods: Expression levels of FGFR2 and TSP4 were detected by immunohistochemistry in GC tissue microarray slides. SGC7901 and MKN28 cell lines were used to confirm the relationship between FGFR2 and TSP4. In vitro cell viability, colony formation, and invasion and migration assays were performed to evaluate the effect of FGFR2-TSP4 axis on tumor cell activities. The mechanism of TSP4 regulated by FGFG2 was explored via small molecular inhibitors in vitro and a xenograft model. Results: FGFR2 was shown to be markedly overexpressed in GC tissues and was correlated with a high risk of lymph node metastasis, late clinical stage, and poor prognosis. Low TSP4 expression was associated with shorter overall survival (OS) and advanced stage in GC patients. Interestingly, correlation analysis indicated that FGFR2 was negatively associated with TSP4. Indeed, in vitro and in vivo experiments suggested FGFR2 activation could downregulate TSP4 expression, which played an important role in the proliferation, invasion and migration of GC cells. We also found involvement of the PI3K-AKT-mTOR pathway in the FGFR2-TSP4 axis. Conclusion: The FGFR2 signal promotes human GC progression through the downregulation of TSP4 via PI3K-AKT-mTOR pathway. Our findings provide a foundation for further investigating promising therapeutic strategies for GC overexpressing FGFR2.

Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule, Allosteric Inhibitor of FGF Receptor Signaling

The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan-Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2-positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).

The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan–Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2–positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).

We are developing a novel fibroblast growth factor receptor 2 (FGFR2) directed antibody (BAY 1179470) as well as an FGFR2-antibody drug conjugate (FGFR2-ADC) for cancer therapy. FGFR2 is expressed in a range of tumor types such as gastric, breast, HNSCC, pancreatic and ovarian cancers. FGFR2 has been described to promote tumor growth and survival and play a role in chemotherapy resistance. In this study, we aim to identify stratification and pharmacodynamic biomarkers for two antibody-based anti-FGFR2 therapies in preclinical models. As potential biomarkers, FGFR2 antigen expression levels were investigated in tumors by FGFR2 immunohistochemistry (IHC), FGFR2 gene amplification by FISH, FGFR2 mRNA by RNAscope, and FGFR2 protein by mass spectrometry. Furthermore, FGFR2 levels in xenograft tumors were compared to those in clinical samples of human tumors. Efficacy of BAY 1179470 in gastric cancer tumor models with high FGFR2 expression levels was generally higher compared to models with low FGFR2 expression. SNU-16 and GC10-0608, which are characterized by high expression levels of FGFR2, had T/C values of 0.13 and 0.55 when treated with 5 mg/kg BAY 1179470. Tumor growth was not inhibited by BAY 1179470 in MKN-45 and T47D, which had no detectable FGFR2 expression. MFM-223 and NCI-H716 with high FGFR2 expression levels did not respond to BAY1179470 suggesting that they were not dependent on FGFR2 signaling. In contrast, all three established tumor models SNU-16, MFM-223, and NCI-H716 were highly responsive to FGFR2-ADC. Analysis and scoring of FGFR2 expression by IHC using human tumor samples (gastric, breast, HNSCC, pancreatic and ovarian cancer, respectively) demonstrated that tumor cell FGFR2 expression varied both within and between tumor types. IHC scoring revealed that 54% of gastric cancers, 73% of triple negative breast cancers, 90% of HNSCC, 43% of pancreatic cancers, and 43% of ovarian cancer investigated were FGFR2 positive. Within the tumor indications investigated patients showed FGFR2 expression of score 0, 1, 2 or 3 respectively.In the SNU-16 gastric cancer xenograft model, total and phospho-FGFR2 were reduced upon treatment with BAY 1179470. Depending on dose, total FGFR2 levels showed the lowest level 1-4 days after treatment and returned to baseline after 21 days. Suppression of the downstream signaling pathway component phospho-RPS6 signaling was also shown. In summary, these results demonstrate that FGFR2-directed therapies are effective in xenograft models with high FGFR2 expression. FGFR2 expression as assessed by IHC and FGFR2 gene amplifications are therefore candidate biomarkers for stratification of the FGFR2-directed studies. The anti-FGFR2 antibody BAY 1179470 is currently in Phase I testing (NCT01881217). Citation Format: Christoph A. Schatz, Charlotte Kopitz, Sabine Wittemer-Rump, Anette Sommer, Lars Lindbom, Motonobu Osada, Hiroshi Yamanouchi, Hung Huynh, Thomas Krahn, Khusru Asadullah. Pharmacodynamic and stratification biomarker for the anti-FGFR2 antibody (BAY1179470) and the FGFR2-ADC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2014-4766

Gastric cancer is the 3rd most common cause of cancer-related mortality worldwide, thus new treatment options are urgently needed. In gastric cancer, over-expression of the tumor-promoting tyrosine kinase receptor fibroblast growth factor receptor 2 (FGFR2) has been described, representing a potential therapeutic target. FGFR2 expression in gastric cancer has been reported to be heterogeneous. Most methods for detection of RNA in FFPE (formalin fixed paraffin embedded) do not provide spatial resolution for assessment of tumor heterogeneity. Here we used a novel RNA in situ technique called RNAscope. The technology allows visual investigation of FGFR2 transcription on FFPE slides. Samples from 1036 gastric adenocarcinoma patients who underwent surgery in National Cancer Center Hospital East (Chiba, Japan) were assembled in tissue micro-arrays and analyzed by RNAscope. A total of 578 samples were also analyzed by DISH to determine gene amplification. Using these tissue based methods we were able to assess the localization and heterogeneity of both FGFR2 gene amplification and RNA expression. Strong FGFR2 gene amplification (FGFR2:CEN10 >10) was detected in 2% of 578 samples. Moderate FGFR2 gene amplification (FGFR2:CEN10 between 2 and 10) was seen in 8% of the samples. High FGFR2 RNA expression (score 4+) was seen in 4% of 718 evaluable samples. Gene amplification and RNA expression were closely correlated. All samples with dense clusters of score 4+ RNA showed FGFR2:CEN10 ratios >10. The identical tumor areas showed high gene amplification and RNA expression. FGFR2 RNA and gene amplification was highly heterogeneous in the tissue. Only 0.4% of the samples showed homogeneous FGFR2 expression in >80% of the tumor cells. High RNA expression intensity was associated with a more homogeneous expression pattern compared to moderate FGFR2 expression. In early stage I/II gastric cancer samples with score 4+ RNA expression are mostly of the differentiated type. RNA score 4+ patients of grade III/IV gastric cancer were mostly of undifferentiated histology. In a subset of 195 samples with available data cMet IHC 3+ and Her2 positivity status were not mutually exclusive with regards to FGFR2 RNA Score 4+ expression. In a multivariant analysis FGFR2 RNA expression was associated with patient outcome. Gastric cancer patients with score 4+ RNA expression had a shorter progression free survival compared to patients with score 0-3. Interestingly, there was a trend for patients with homogeneous score 3+ RNA expression, but not heterogeneous score 3+ expression, to show shorter PFS and OS suggesting that patients with high intensity or homogeneous FGFR2 RNA expression may define a subgroup of patients with gastric cancer. Patients with homogenous or strong focal FGFR2 expression might therefore be candidates for FGFR2 directed therapies in gastric cancer. Citation Format: Yasutoshi Kuboki, Christoph A. Schatz, Sabine Jabusch, Karl Koechert, Janine Feng, Sabine Wittemer-Rump, Karl Ziegelbauer, Thomas Krahn, Akiko Nagatsuma, Atsushi Ochiai. In Situ analysis of FGFR2 RNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4933.

PurposeClaudin 18.2 (CLDN18.2) and fibroblast growth factor receptor 2b (FGFR2b) have recently emerged as promising therapeutic targets for advanced gastric cancer (GC). Before integrating CLDN18.2 and FGFR2b into routine practice, for optimal treatment planning, it is important to consider whether there exists an overlap between these biomarkers.Materials and MethodsWe evaluated CLDN18.2 expression in many patients with GC (n=1,538) using tissue microarrays that had been previously used to evaluate FGFR2b overexpression. We investigated the overlap between CLDN18.2 and FGFR2b expression and evaluated the clinicopathological features and prognostic implications of CLDN18.2 expression.ResultsThe CLDN18.2 positivity rates at 50% and 75% cutoffs were 34.7% and 24.4%, respectively. Heterogeneous expression was identified in 335 (23.5%) of 1426 cases with multiple tissue microarray cores. FGFR2b positivity at >0% cutoff was identified in 47 (3.1%) patients with more marked intratumoral heterogeneity than that observed with CLDN18.2. CLDN18.2 positivity (59.6%) in FGFR2b-positive GCs was significantly higher than that (33.9%) in FGFR2b-negative GCs (P<0.001). Concurrent FGFR2b- and CLDN18.2-positive GCs accounted for 1.8% of all patients, and FGFR2b-positive tumor cells were also positive for CLDN18.2 in approximately 75% of these cases. CLDN18.2 positivity was associated with poorly differentiated histology (P<0.001) and advanced pT and pN stages (P<0.03), but not with overall survival.ConclusionsCLDN18.2 and FGFR2b were significantly associated with each other, suggesting a considerable overlap. This finding may have important clinical implications on the optimal treatment strategy for CLDN18.2-positive GC.

Background: Gastric cancer currently has the third highest mortality rate worldwide among cancer types. Despite gradual declines in mortality rates attributed to improvements in early detection and treatment, outcomes for advanced-stage disease are still poor. The identification of new biomarkers such as fibroblast growth factor receptor 2 (FGFR2) has opened new pathways for directed therapy in gastric cancer. Objective: This review aims to synthesize the current evidence on the role of FGFR2 in gastric cancer, focusing on its biological function and oncogenic mechanisms, diagnostic and prognostic modification, therapeutic targeting, and possible roadblocks in clinical application. Methods: A comprehensive literature search was conducted, selecting studies published between 2015 and 2025 using the MeSH terms “FGFR2 protein, human” [Supplementary Concept]) AND “Stomach Neoplasms”. Articles were screened based on relevance to gastric cancer, language (English), and availability of full text, yielding a final selection of 75 studies, including preclinical research, clinical trials, and reviews. Findings: We compiled and reported the evidence on FGFR2 detection methods, intra-tumoral heterogeneity of FGFR2 expression, effects of FGFR2 expression on prognosis, current therapy options targeting FGFR2, and challenges in pursuing this modality of treatment. Conclusion: FGFR2 represents a promising biomarker and therapeutic target in gastric cancer.

Introduction: Fibroblast growth factors (FGFs) are potent mitogens and inducers of angiogenesis. FGF signalling pathway is closely associated with cancer development and progression. Fibroblast growth factor receptor 2 (FGFR2) gene, located at human chromosome 10q26, encodes FGFR2b and FGFR2c isoforms functioning as distinct FGF receptors. Gene amplification or missense mutation of FGFR2 occurs in gastric cancer (GC). Genetic alterations of FGFR2 may induce aberrant activation of FGFR2 signalling pathway, thereafter induce proliferation and survival of GC cells. FGFR2 plays an important role in gastric carcinogenesis. Patients and Methods: A total of 33 gastric cancer tissues with formalin-fixed, paraffin-embedded tumor slides were investigated by immunohistochemical staining with primary antibody against FGFR2. By Lauren's classification, there are 9 diffuse-type, 23 intestinal-type, and 1 mixed-type GC patients, respectively. Results: The FGFR2 immunohistochemical staining was classified as 0, 1+, 2+, and 3+ according to percentage of immunoreactive positive-staining FGFR2 cells in &amp;lt;10%, 10-25%, 25-50%, and &amp;gt;50% tumor cells, respectively. The relationship between the FGFR2 expression and the clinicopathological characteristics were analyzed. Among 33 GC patients, 13 patients (39.4%; 23-57%, 95% C.I.) had FGFR2 expression (1+, 2+, and 3+), and 11 patients (33.3%; 17-52%, 95% C.I.) had FGFR2 overexpression (2+ and 3+), respectively. FGFR2 expression was not correlated with diffuse-type versus intestinal-type GC patients (p=0.427, Fisher exact test). Conclusions: Overexpression of FGFR2 in gastric cancer forms the basis of the rational clinical application of future FGFR2-targeted cancer therapy for treatment of advanced GC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1770.

[Background] Amplification of the fibroblast growth factor receptor 2 (FGFR2) is reportedly identified in 3-10% of primary gastric cancers (GCs). We found that FGFR2 overexpression was closely associated with poor prognosis of patients with gastric cancer. Recently, FGFR signaling inhibitors have been considered a key drug in the treatment of GCs with FGFR2 overexpression. FGFR2 overexpression can be assessed by immunohistochemical staining of primary tumors; however, this method does not sufficiently reflect FGFR2 expression in recurrent tumors owing to the heterogeneity of tumor cells between primary and recurrent tumors. Circulating tumor cells (CTCs) might overcome this issue of “temporal” and “spatial” heterogeneity. This study aimed to assess the significance of the detection of FGFR2-positive CTCs in patients with gastric cancer. [Methods] Seventy-eight patients with gastric cancer who underwent gastrectomy in our hospital were enrolled in this study. A total volume of 10 ml of peripheral blood was collected prior to surgery from each patient, and mononuclear cells were enriched by Ficol density gradient centrifugation. These cells were immunostained with PI/CD45/EpCAM/FGFR2 and PI/CD45/EpCAM/CK. The number of cells in each sample was enumerated depending on the positivity of EpCAM, FGFR2, and CK by fluorescence-activated cell sorting (FACS). FGFR2 expression was assessed by immunohistochemical staining of resected specimens. Patients were categorized into four groups as follows: group IHC-0 (n=32), no staining; group IHC-1+ (n=24), cytoplasmic staining in 1-19% or membranous staining in 1-5%; group IHC-2+ (n=16), cytoplasmic staining in 80-100% or membranous staining in 5-19%; group IHC-3+ (n=6), membranous staining in 20-100%. [Results] FGFR2+ cells were detected in 43 (55%) of 78 cases. Among these cases, CK+ cells or EpCAM+ cells were detected in 35 (81%) of 43 cases. By group, the proportions of FGFR2+ cells were 44% in group IHC-0, 52% in group IHC-1+, 69% in group IHC-2+, and 100% in group IHC-3+. The mean number of FGFR2+ cells from patient samples in the IHC-0, IHC-1+, IHC-2+, and IHC-3+ groups were 12, 11, 16, and 54 (per 10 ml peripheral blood), respectively, with a significant difference between group IHC-0 and group IHC-3+, group IHC-1+ and group IHC-3+, and group IHC-0 and group IHC-2+ (p=0.001, p=0.008 and p=0.034, respectively, by Mann-Whitney U test). Among 68 patients with R0 and pStage I-III, the recurrence-free survival of patients with an FGFR2+ cell count ≧10 cells / 10 ml was significantly poorer than that of patients with an FGFR2+ cell count &amp;lt;10 cells / 10 ml (p = 0.018, by logrank test). [Conclusion] Detection of CTCs with FGFR2 expression by FACScan might be a useful approach to identify gastric cancer patients who would benefit the most from FGFR inhibitor treatment. Citation Format: Kenji Kuroda. Significance of circulating tumor cells (CTCs) with fibroblast growth factor 2 expression in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1366.

Intratumoral heterogeneity in gastric cancer: a new challenge to face

Background: The fibroblast growth factor (FGF) and FGF receptor pathway has been implicated in several cancers. Inhibition of this pathway has led to the attenuation of tumor growth in preclinical models1. This phase I, first in human dose (FIH) study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of LY2874455, an oral FGF receptor inhibitor. Methods: This study had 2 open-label parts. Part A: standard 3+3 patient dose escalation study, identified 16 mg BID as the recommended dose2. Part B: dose expansion study, evaluated 16 mg BID dose in patients (pts) with pretreated advanced gastric cancer (GC) or non-small cell lung carcinoma (NSCLC), who also had ECOG performance status 0-2 and adequate organ function. Treatment continued until disease progression or intolerability. We report here results from Part B of the study. Results: Overall 27 pts in the NSCLC cohort and 31 pts in the GC cohort were treated. Median age was 58.5 years: majority of pts were Asian (89.7%). Pts had received a median of 4 previous lines of chemotherapy. FGFR1 amplification status in the NSCLC group: 29.6% were negative, 7.4% were positive, and status was unknown in 63.0%. For GC pts: 80.6% negative for FGFR2 amplification, 6.5% positive, and status unknown in 12.9%. Both cohorts each received a median of 2 cycles. All 58 pts experienced at least 1 treatment emergent adverse event (TEAE) possibly related to study drug, with 39 pts (67.2%) experiencing at least 1 Grade 3 or 4 TEAE possibly related to study drug. The most common drug-related AEs included: hyperphosphatemia (79.3%), diarrhea (77.6%), anorexia (72.4%), and fatigue (51.7%). Eighteen pts (31.0%) experienced at least 1 serious adverse event (SAE), and 9 pts had SAE possibly related to study drug related. SAEs possibly related to study drug were: fatigue (n = 4), anorexia (n = 3), heamoptysis, central serous retinopathy, keratoconjunctivitis sicca, diarrhea, and hyponatremia. Eleven pts discontinued due to AE or SAE. In the GC cohort, 1 patient, who was FGFR2 amplification negative, had a partial response, and 6 FGFR2 negative pts had stable disease (SD), with 1 patient on treatment for 9 cycles. None of the NSCLC pts responded, but 4 pts had SD (FGFR1 positive n = 2; FGFR1 negative n = 2). Conclusion: Treatment with LY2874455 had a manageable toxicity profile, and preliminary findings suggest anti-tumor activity in gastric cancer. 1. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 1996;2:1373-81. 2. Tie, J., et al. “A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cancer.” Proceedings of the 105th annual meeting of the American Association for Cancer Research 2014;74(19 Suppl):Abstract nr CT215. Citation Format: Jeanne Tie, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, David Monteith, Kimberly Hartsock, Oday Hamid, Donald E. Thornton, Michael Michael. Phase I study of LY2874455, a fibroblast growth factor (FGF) receptor inhibitor, in patients with advanced cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT058.

Fibroblast growth factor receptor 1 (FGFR1) has been reported in gastric cancer to be a prognostic factor. However, miR-497-targeted FGFR1 has not been explored in the carcinogenesis of gastric cancer. The present study intended to revalidate the prognostic significance of FGFR1 in patients with gastric cancer, and the mechanism of miR-497-regulated FGFR1 was investigated in gastric cancer cell proliferation and apoptosis. The messenger RNA (mRNA) and protein levels were assayed by RT-qPCR and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell proliferation was analyzed by CCK-8 assay. Annexin V-FITC/PI staining was used to evaluate the apoptosis in AGS and SGC-7901 cells. FGFR1 was frequently up-regulated in gastric cancer tissues and associated with poor overall survival in patients with gastric cancer. Interestingly, FGFR1 loss-of-function resulted in a significant growth inhibition and apoptosis in AGS and SGC-7901 cells. In addition, we found that miR-497 was inhibited in gastric cancer tissues and cell lines, while overexpression of miR-497 could suppress proliferation and induce apoptosis in AGS and SGC-7901 cells. Importantly, bioinformatics analysis and experimental data suggested that FGFR1 was a direct target of miR-497, which could inhibit FGFR1 expression when transfected with miR-497 mimics. Furthermore, we found that overexpression of FGFR1 reversed the growth inhibition and apoptosis of miR-497 mimics in AGS and SGC-7901 cells. These findings suggested that overexpression of miR-497 inhibited proliferation and induced apoptosis in gastric cancer through the suppression of FGFR1.

A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification