FGFR4 is a regulator of tumor subtype differentiation in luminal breast cancer and metastatic disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145326 | GEO | 2020/07/30
REPOSITORIES: GEO
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Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We observed that a subset of Luminal A primary breast tumors give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 drives this subtype switching. To evaluate this, we developed two FGFR4 signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-29 | GSE126037 | GEO
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We observed that a subset of Luminal A primary breast tumors give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 drives this subtype switching. To evaluate this, we developed two FGFR4 signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-29 | GSE126036 | GEO
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that fibroblast growth factor receptor 4 (FGFR4) likely participates in this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Bulk tumor gene expression analysis, and single cell RNAseq demonstrated that the inhibition of FGFR4 signaling caused molecular switching. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.
2020-08-31 | GSE147322 | GEO
Project description:Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (P<0.001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.
2024-11-08 | GSE262860 | GEO
Project description:Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ as well as the IFN-γ signature for metastasis-free survival (MFS) were examined using Kaplan Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. Kaplan Meier curves and univariate Cox regression analyses showed that the prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (P=0.033). In contrast, the IFN-γ associated gene signature was a significant prognostic factor in the whole cohort (HR 1.554; 95%CI 1.1099-2.199; P=0.013) as well as in the luminal B (P=0.007) and HER2-positive (P=0.033) molecular subtype with borderline significance in basal-like breast cancer(P=0.050). In multivariate analysis, the IFN-γ signature retained its independent prognostic significance (HR 2.287; 95% CI: 1.410-3.633;P<0.001) in the entire cohort. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.
2020-09-22 | GSE158309 | GEO
Project description:Introduction In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed. Methods We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusion We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
2023-01-26 | GSE223700 | GEO
Project description:Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2+ circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employed preclinical models of bone metastasis (BM) to validate the role of Her2+ CTCs in multi-organ metastases. While Her2+ expression was higher in patients with bone metastasis, experimental analyses revealed that a majority of these Her2+ CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 treatment. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2+ CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.
2024-12-05 | GSE230612 | GEO
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124647 | GEO
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SETER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SETER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SETER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SETER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124648 | GEO
Project description:Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Keywords: clinical outcome
2008-08-22 | GSE12417 | GEO