FGFR3 amplification

P1, N=35, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Dec 2023 --> Sep 2024

Actionable molecular alterations were frequently observed in patients with ICC. Detection of actionable alterations was associated with improved OS. The role of targeted therapy needs further exploration in prospective multi-center studies.

Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.

FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas.

Conclusions In our cohort, FGFR3 alterations are neither predictive nor prognostic for 1st-line platinum or 2nd-line IO. Further investigation is needed.

The combination of anlotinib and osimertinib might be an efficacy and safety treatment option for patients with EGFR T790M mutation who have failed prior EGFR-TKI. Dynamic changes of ctDNA could be used to monitor treatment response and to explore mechanisms of acquired resistance to therapy.

In this study, we report preliminary results of potential molecular mechanisms underlying disease progression in patients treated with neoadjuvant nivolumab plus chemotherapy using plasma samples from NADIM and NADIM II cohorts. A total of 10 plasma samples collected upon disease progression from patients included in NADIM or NADIM II trials were analyzed... Acquisition of somatic-copy number alterations in RET, EGFR and FGFR was found in the plasma samples collected upon disease progression in patients treated with neoadjuvant chemoimmunotherapy (NADIM I and II cohorts) which may have important implications for subsequent treatment selection.

Whole exome sequence showed ESCA and its subtypes, tissue block shared similar single nucleotide variants, such as TP53, ARHGAP35, CDH3 mutations, while relatively large difference in copy number variations on the basis of some common variants, such as amplification of FGFR3 (chr.4) and BCL9L (chr.11) genes.Conclusion ESCA cell line is the very first cell line of UCS until now, which showed infinite multiplication and tumorigenicity in vivo. ESCA harbored TP53, ARHGAP35, CDH3 mutations and amplification of FGFR3 and BCL9L genes, which would probably be a good model for exploring the molecular mechanism of UCS.

Our results highlight the clinical potential of personalized genome-wide mutation integration as an ultra-sensitive, non-invasive method for MRD detection and treatment response monitoring.

Activating FGFR fusions, which occur across tumor types with marked diversity in fusion partners, present opportunities for future drug development. Non-target FGFR alterations in iCCA and UC, particularly those that cluster with target FGFR alterations, may be candidates for future FGFR-targeted strategies.

In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations.

FGFR3 :: TACC3 fusions may occur de-novo or as a secondary treatment resistance mechanism in NSCLC. These fusions appear to be enriched in smokers or former smokers and more frequently occur with squamous cell carcinoma histology and may demonstrate clear cell morphology by light microscopy. Identification of FGFR alterations is of particular importance given the lack of targeted therapeutic options for patients with squamous cell carcinoma.

Histologic features correlate with FGFR alterations in IGs. FGFR3-TACC3 fusion and FGFR3 amplification are the most common FGFR alterations in IGs. FGFR alterations are a rare, but potentially viable, therapeutic target in asubset of IGs.

Variant histology was appreciated in 76% of FGFR mutated cases, with the micropapillary pattern being the most prevalent (n=12 | 32%). The FGFR pathway is classically associated with low-grade papillary tumors, which, through additional mutations, can cause invasive, high-grade disease. It is speculated that the initial papillary architecture present in FGFR mutated lesions may be preserved, manifesting as the micropapillary pattern appreciated in some invasive lesions.

In conclusion, PSC-CCA exhibit a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early whereas mutations in ERBB2, TP53, and KRAS appear later in the development of CCA. These findings are promising for the development of NGS-guided diagnostic strategies in PSC-CCA.

NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.

Our data provide insight into the presence of various molecular aberrations simultaneously on DNA and RNA level alongside with the FGFR1 amplification and protein expression. TP53 mutations approved to be most common in analysed Sq-NSCLC tumors, while the FGFR fusions and pathogenic variants were rare. Our results highlight the necessity of detailed and extended molecular analysis (i.e.

We found no association between FGFR1-3 aberrations and PT PD-L1 expression (p=0.379). Our data emphasize the need for further studies in predictive biomarkers.

Novel acquired secondary KRAS mutations within the adagrasib-binding pocket such as Y96C, H95D/Q/R, R68S, 2... Our analysis results indicate about 15% KRAS G12C-mutant Chinese CRC were probable resistant to KRASG12C inhibitor. One-third of these patients had co-existed oncogenic fusions and higher TMB levels, suggesting possibilities for other therapeutic choices.

Surprisingly, a significant response to SOC (cisplatin alone or in combination with gemcitabine) was observed in 8 out of 17 analyzed samples and the non-SOC drugs were effective in few samples...For example, Docetaxel sensitivity was associated to copy number gain in TUBB1 and MIBC organoids were significantly more sensitive to a low dose of cisplatin than NMIBC organoids...Conclusions : To conclude, the genetic and phenotypic profiles of PDOs and parental tumor were very similar, supporting that PDOs are preserving tumor heterogeneity and are therefore a good model of BLCa. This indicates that PDOs can represent a tool to predict drug sensitivity in a personalized manner.

At current, erdafitinib, an inhibitor of FGFR1-4, is the only approved targeted therapy in metastatic UC following the BLC2001 study, which demonstrated a 49% overall response rate in patients with UC harboring an FGFR3 mutation. Additional FGFR-directed agents also continue to be investigated across multiple disease stages in FGFR-mutated UC including infigratinib, rogaratinib, and AZD4547, among others. Ongoing trials are combining these agents with immune checkpoint inhibitors and chemotherapy regimens. The precision medicine revolution has begun in UC, and FGFR3 inhibitors are leading the charge toward a more personalized, biomarker-driven treatment paradigm.

NSR-SCCUB has potentially actionable genomic alterations with anticancer agents and many of these aberrations are also seen in UC. The recruitment of NSR-SCCUB patients harboring such mutations should be considered in biomarker driven urinary bladder cancer studies.

At a median follow-up of 68 months (2-147 months) for 15 patients, all were alive without disease. Oncocytic renal tumors with diffuse keratin 7 labeling show frequent alterations in the TSC/MTOR pathway, despite more oncocytoma-like morphology than initially described in LOT, likely expanding the morphologic spectrum of the latter.

Tailored therapy with FGFRi in molecularly-selected metastatic BC based on high FGFR1-4 mRNA levels warrants prospective validation in luminal BC CDK4/6i-resistant patients and in TNBC patients without targeted therapeutic options.

This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

Frequency of FGFR fusions Fusions Fusion region N (%) FGFR3-TACC3 EX18E:EX11 3(7.14%) EX17:EX8 3(7.14%) EX17:EX10 2(4.76%) EX18E:EX13 1(2.38%) EX8:EX9 1(2.38%) FGFR3-LETM1 EX8:Promoter 1(2.38%) FGFR3-SZT2 EX7:EX61 1(2.38%) FGFR3-PCDH7(intergenic) EX8:intergenic 1(2.38%) FAM53A(intergenic)-FGFR3 intergenic:EX18E,intergenic:EX8 2(4.76%) FGFR3-chr20 55284041 EX18E:chr20 55284041 1(2.38%) FGFR2-FAM184B EX17:EX8 1(2.38%) FGFR2-GRK5 EX17:EX1 1(2.38%) FGFR2-SORBS1 EX17:EX24 1(2.38%) FGFR2-PROM1 EX18:EX11 1(2.38%) FGFR2-chr10 122732846 EX17:chr10 122732846 1(2.38%) FGFR2-NPVF(intergenic) EX14:intergenic 1(2.38%) OPALIN-FGFR2 EX6E:EX2 1(2.38%) ATE1-FGFR2 EX11:EX2,EX5:EX17 2(4.76%) chr10 123156582-FGFR2 chr10 123156582:EX18 1(2.38%) DEC1(intergenic)-FGFR2 intergenic:EX6 1(2.38%) FGFR1-TACC1 EX1:EX2 1(2.38%) FGFR1-STAU1 EX1:EX7 1(2.38%) FGFR1-LETM2 EX12:EX8 1(2.38%) FGFR1-KCNU1(intergenic) EX3:intergenic 1(2.38%) FGFR1-SLC22A23 EX13:EX10 1(2.38%) FGFR1-ISL1(intergenic) EX8:intergenic,EX4:intergenic 2(4.76%) DDHD2-FGFR1 EX5:EX2 1(2.38%) ZMAT4-FGFR1 EX2:EX2 1(2.38%) HELZ-FGFR1 EX33E:EX6 1(2.38%) chr8 76149982-FGFR1 EX0:EX2 1(2.38%) chr8 138590655-FGFR1 EX0:EX2 1(2.38%) UNC5D(intergenic)-FGFR1 intergenic:EX2 1(2.38%) LOC100996508-FGFR1 EX1:EX2 1(2.38%) TACC1(intergenic)-FGFR1 intergenic:EX2 1(2.38%) Total 42(100%) Conclusion We report the prevalence of FGFR aberrations in a large lung cancer pts, including mutations, gene amplifications, gene deletion and one novel FGFR fusion. Our results revealed the potential therapeutic strategies with FGFR inhibitors for Chinese patients with lung cancer.

Interestingly, we observed a significant response to SOC (cisplatin in combination with gemcitabine) only in 4 out of 14 cases. In conclusion, our data support that PDOs are a reliable in vitro model of BLCa heterogeneity. The general low sensitivity to SOC observed in our PDOs highlights the need for novel therapies and the high genomic concordance between PT and derived organoids supports the use of organoids as a tool for this purpose.

Clinical benefit in OS was observed in pts with pretreated EGFR T790M-positive advanced NSCLC receiving aumolertinib. The common mechanisms of resistance to aumolertinib were EGFR C797S mutation and aberrations in bypass tracks.

FGFR3 IHC is a useful screening tool for the detection of FGFR3 alterations and could be included in the workflow for isocitrate dehydrogenase (IDH) wild-type glioma diagnostics. Samples with positive FGFR3 staining could then be selected for NGS-based diagnostic tools.

In April 2020, the Food and Drug Administration (FDA) approved the first targeted FGFR therapy, erdafitinib, in patients with locally advanced or metastatic bladder cancer who have progressed on platinum-based chemotherapy. Herein, we reviewed the normal structure and function of FGFR We also explored its role in the development of urothelial carcinoma and major developments in the FGFR-targeted therapy.

Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.

Furthermore, the discovery of FGFR inhibitors revealed how these biological compounds improve the neoplastic condition by demonstrating efficacy and safety. On this basis, this review focuses on the role and involvement of FGFRs in brain tumors such as astrocytoma and glioblastoma.

These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.

High CEP78 expression was found to be correlated with non-papillary histological type, luminal, basal-squamous and neuronal molecular subtypes, TP53 mutation, RB1 mutation, wild-type FGFR3, PPARG fusion and amplification, high total number of single-nucleotide variants, and high neoantigen load, but it was not associated with tumor stages or overall survival. CONCLUSIONS The results of this study suggest that CEP78 plays in a role in promoting the development of MIBC and could be a novel diagnostic and therapeutic target.

Finally, malignant Brenner tumors had overall distinct genomic signatures compared to FGFR-mutated ovarian serous, endometrioid, and clear cell carcinoma subtypes. This study provides insights into the molecular pathogenesis of malignant Brenner tumors, contrasts the extent of FGFR1/2/3 alterations in ovarian serous, clear cell and endometrioid carcinomas and emphasizes the potential value of novel and FDA-approved, anti-FGFR inhibitors, such as erdafitinib and pemigatinib, in refractory, FGFR3-mutated malignant Brenner tumors.

To our knowledge, this is the first time an FGFR inhibitor has been tested in combination with ET and CDK4/6i in patients with MBC harboring FGFR alterations. Erdafitinib-related side effects appeared to be on target, leading to treatment discontinuation in several patients despite optimal medical treatment. Clinical activity was seen in heavily pre-treated patients with molecular evidence of high FGFR amplification despite 100% prior exposure to ET and CDK4/6i.