Dataset Information

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

ABSTRACT: Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors-alterations (mutations and fusions), amplification and mRNA/protein overexpression-but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

SUBMITTER: Moes-Sosnowska J

PROVIDER: S-EPMC8991910 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Moes-Sosnowska Joanna J Chorostowska-Wynimko Joanna J

Frontiers in oncology 20220325

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors-alterations (mutations and fusions), amplification and mRNA/protein overexpression-but their predictive potential is unclear. Although FGFR1 amplification reli ...[more]

PMID: 35402233

Similar Datasets

Project description:BackgroundThe prevalence and types of fibroblast growth factor receptor (FGFR) mutations vary significantly among different ethnic groups. The optimal application of FGFR inhibitors depends on these variations being comprehensively understood. However, such an analysis has yet to be conducted in Chinese patients.MethodsWe retrospectively screened the genomic profiling results of 10,582 Chinese cancer patients across 16 cancer types to investigate the frequency and distribution of FGFR aberrations.ResultsFGFR aberrations were identified in 745 patients, equating to an overall prevalence of 7.0%. A majority of the aberrations occurred on FGFR1 (56.8%), which was followed by FGFR3 (17.7%), FGFR2 (14.4%), and FGFR4 (2.8%). Further, 8.5% of patients had aberrations of more than 1 FGFR gene. The most common types of aberrations were amplification (53.7%), other mutations (38.8%), and fusions (5.6%). FGFR fusion and amplification occurred concurrently in 1.9% of the patients. FGFR aberrations were detected in 12 of the 16 cancers, with the highest prevalence belonging to colorectal cancer (CRC) (31%). Other FGFR-aberrant cancer types included stomach (16.8%), breast (14.3%), and esophageal (12.7%) cancer. Breast tumors were also more likely than other cancer types to have concurrent FGFR rearrangements and amplifications (P<0.001). In comparison with the public dataset, our cohort had a significantly higher number of FGFR aberrations in colorectal (P<0.001) and breast cancer (P=0.05).ConclusionsAmong the Chinese cancer patients in our study, the overall prevalence of FGFR aberrations was 7.0%. FGFR1 amplification was the most common genetic alteration in CRC, breast cancer, and lung cancer; while FGFR2 amplification was more commonly observed in gastric cancer than in other cancers in our cohort. Our study advances the understanding of the distribution of FGFR aberrations in various cancer types in the Chinese population, which will facilitate the further development of FGFR inhibitors.

Project description:BackgroundS1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting.MethodsEligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR).ResultsNinety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%-17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4- 4.5 months) and 7.5 months (95% CI: 3.7-9.3 months).ConclusionsAZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3-amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

Project description:Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.

Dataset Information

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Publications

Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets