scholarly journals Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

2015 ◽  
Vol 61 (7) ◽  
pp. 974-982 ◽  
Author(s):  
David S Guttery ◽  
Karen Page ◽  
Allison Hills ◽  
Laura Woodley ◽  
Stephanie D Marchese ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Fibroblast Growth Factor Receptor ◽  
Hot Spot ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Fibroblast Growth ◽  
Activating Mutations ◽  
Esr1 Mutations ◽  
Esr1 Mutation ◽  
Estrogen Receptor 1

Abstract BACKGROUND Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a “liquid biopsy.” METHODS We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α–positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR). RESULTS Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans. CONCLUSIONS Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.

Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3521-3528 ◽  
Author(s):  
Suzanne Trudel ◽  
Scott Ely ◽  
Yildiz Farooqi ◽  
Maurizio Affer ◽  
Davide F. Robbiani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Myeloma Cell ◽  
Fibroblast Growth ◽  
Genetic Changes ◽  
Functional Changes ◽  
Activating Mutations ◽  
Molecule Inhibitor

Abstract We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor, PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further, morphologic, phenotypic, and functional changes typical of plasma cell (PC) differentiation, including increase in light-chain secretion and expression of CD31, were observed and this was followed by apoptosis. Finally, using a mouse model of FGFR3 myeloma, we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3, even in advanced disease associated with multiple genetic changes, may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition, this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments. (Blood. 2004;103:3521-3528)

scholarly journals Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 76 ◽  
Author(s):  
Navid Sobhani ◽  
Anna Ianza ◽  
Alberto D’Angelo ◽  
Giandomenico Roviello ◽  
Fabiola Giudici ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Tumor Formation ◽  
Current Status ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Receptors

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

scholarly journals A single droplet digital PCR for ESR1 activating mutations detection in plasma

2019 ◽  
Author(s):  
Emmanuelle Jeannot ◽  
Lauren Darrigues ◽  
Marc Michel ◽  
Marc-Henri Stern ◽  
Jean-Yves Pierga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Limit Of Detection ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Plasma Samples ◽  
Activating Mutations

AbstractBackgroundActivating mutations in the estrogen receptor 1 (ESR1) gene are recurrent mechanisms of acquired resistance to aromatase inhibitors (AI), and may be the target of other selective estrogen receptor down-regulators. To assess the clinical utility of monitoring ESR1 resistant mutations, a droplet digital PCR (ddPCR)-based assay compatible with body fluids is ideal due to its cost-effectiveness and quick turnaround.MethodsWe designed a multiplex ddPCR, which combines a drop-off assay, targeting the clustered hotspot mutations found in exon 8, with another pair of probes interrogating the E380Q mutation in exon 5. We assessed its sensitivity in vitro using synthetic oligonucleotides, harboring E380Q, L536R, Y537C, Y537N, Y537S or D538G mutations. Validation of the assay was performed on plasma samples from a prospective study and compared to next generation sequencing (NGS) data.ResultsThe multiplex ESR1-ddPCR showed a high sensitivity with a limit of detection ranging from 0.07 to 0.19% in mutant allele frequency depending on the mutation tested. The screening of plasma samples from patients with AI-resistant metastatic breast cancer identified ESR1 mutations in 29% of them with perfect concordance (and higher sensitivity) to NGS data obtained in parallel. Additionally, this test identifies patients harboring polyclonal alterations. Furthermore, the monitoring of ctDNA using this technique during treatment follow-up predicts the radiological response to palbociclib-fulvestrant.ConclusionThe multiplex ESR1-ddPCR detects, in a single reaction, the most frequent ESR1 activating mutations and is compatible with plasma samples. This method is thus suitable for real-time ESR1 mutation monitoring in large cohorts of patients.Statement of translational relevanceExons 5 and 8 mutations in ESR1 are recurrent mechanisms of resistance to aromatase inhibitors (AI) in estrogen receptor (ER)-positive metastatic breast cancer and may be targeted by selective ER down-regulators. We implemented a novel droplet digital PCR, which allows for the detection of the most frequent ESR1 mutations in circulating cell-free DNA. In prospectively collected plasma samples, ESR1 mutations were found in 29% of AI-resistant patients, with excellent concordance and higher sensitivity to next generation sequencing. Moreover, circulating ESR1 mutations appear to be reliable markers for ctDNA monitoring in order to predict treatment response. Ultimately, the short turnaround time, high sensitivity and limited cost of the ESR1-ddPCR are compatible with repeated samplings to detect the onset of resistance to AI before the radiological progression. This opens a window of opportunity to develop new clinical strategies for breast cancer hormone therapy, as tested in an ongoing phase 3 trial.List of abbreviationsAIAromatase InhibitorcfDNACell-free DNActDNACirculating tumor DNAddPCRDroplet digital PCRER+ HER2-MBCER+ HER2-negative Metastatic Breast CancerEREstrogen ReceptorER+Estrogen Receptor positiveLOBLimit of blankLODLimit of detectionMAFMutant Allele FrequencyPBMCPeripheral blood mononuclear cellsPDProgressive diseaseSDStandard deviationToPTime of progressionWTWild typeHuman genesESR1: Estrogen Receptor 1HER2: Human Epidermal Growth Factor Receptor 2EGFR: Epithelial Growth Factor ReceptorKRAS: KRAS proto-oncogene, GTPaseBRAF: B-Raf Proto-Oncogene, Serine/Threonine kinase

Phase I/II study of SAR439859, an oral selective estrogen receptor degrader (SERD), in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1070-1070
Author(s):  
Mario Campone ◽  
Aditya Bardia ◽  
Gary A. Ulaner ◽  
Sarat Chandarlapaty ◽  
Alice Gosselin ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Targeted Therapy ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Hot Flush ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutation ◽  
Ecog Ps

1070 Background: SERDs competitively antagonize and degrade the ER and can block signaling in ER-dependent tumors resistant to standard endocrine therapy (ET). This study (NCT03284957) investigates SAR439859, a potent oral SERD, in ER+/HER2- mBC. We present pooled dose escalation/expansion (Part A/B) data for SAR439859. Methods: Postmenopausal patients (pts) with ER+/HER2- mBC treated for ≥ 6 mos with prior ET received SAR439859 ≥ 150 mg QD (Part A) or 400 mg QD (Part B). Chemotherapy and targeted therapy in the advanced setting were allowed. Objective response rate (ORR; RECIST v1.1), clinical benefit rate (CBR; complete or partial response [PR] or stable disease [SD] ≥ 24 weeks), safety, and pharmacokinetics (PK) were assessed. Results: Pts (n = 62; Part A, 13; Part B, 49) had a median age of 63 yrs (range 37–88) and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral disease. All had prior ET, 74.2% had prior targeted therapy and 48.4% had ≥ 3 prior lines in the advanced setting. 61.3% of pts had treatment-related adverse events (TRAEs), all grade 1–2. Most frequent: hot flush (16.1%), constipation, arthralgia (both 9.7%), decreased appetite, vomiting, diarrhea, nausea (all 8.1%), fatigue (6.5%). No pts discontinued due to AEs. CBR was 35.6% overall, with antitumor activity irrespective of ESR1 mutation status (Table). In pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14), ORR was 21.4% and CBR 64.3%. PK data for Part B and ESR1 mutation data will be provided. Conclusions: SAR439859 had a favorable safety profile with limited TRAEs. In these heavily pre-treated pts (prior targeted therapy in 74.2%), ORR and CBR were similar to historical fulvestrant performance in pts with no prior targeted therapy. Encouraging ORR and CBR in pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14; ORR 21.4%; CBR 64.3%) supports SAR439859 development in earlier lines of therapy. Clinical trial information: NCT03284957 . [Table: see text]

Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 729-736 ◽  
Author(s):  
Marta Chesi ◽  
Leslie A. Brents ◽  
Sarah A. Ely ◽  
Carlos Bais ◽  
Davide F. Robbiani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Tumor Progression ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Myeloma Cells ◽  
Activating Mutations ◽  
Nih 3T3

Abstract The t(4;14) translocation occurs frequently in multiple myeloma (MM) and results in the simultaneous dysregulated expression of 2 potential oncogenes, FGFR3 (fibroblast growth factor receptor 3) from der(14) and multiple myeloma SET domain protein/Wolf-Hirschhorn syndrome candidate gene 1 from der(4). It is now shown that myeloma cells carrying a t(4;14) translocation express a functional FGFR3 that in some cases is constitutively activated by the same mutations that cause thanatophoric dysplasia. As with activating mutations of K-ras and N-ras, which are reported in approximately 40% of patients with MM, activating mutations ofFGFR3 occur during tumor progression. However, the constitutive activation of ras and FGFR3 does not occur in the same myeloma cells. Thus the activated forms of these proteins appear to share an overlapping role in tumor progression, suggesting that they also share the signaling cascade. Consistent with this prediction, it is shown that activated FGFR3—when expressed at levels similar to those seen in t(4;14) myeloma—is an oncogene that acts through the MAP kinase pathway to transform NIH 3T3 cells, which can then generate tumors in nude mice. Thus,FGFR3, when overexpressed in MM, may be not only oncogenic when stimulated by FGF ligands in the bone marrow microenvironment, but is also a target for activating mutations that enable FGFR3to play a ras-like role in tumor progression.

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