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1دورية أكاديمية
المؤلفون: Albert Grinshpun, Douglas Russo, Wen Ma, Ana Verma, Francisco Hermida-Prado, Shira Sherman, Giorgio Gaglia, Sheheryar Kabraji, Gregory Kirkner, Melissa E. Hughes, Nancy U. Lin, Zachary Sandusky, Agostina Nardone, Cristina Guarducci, Quang-De Nguyen, Sandro Santagata, Zsuzsanna Nagy, Rinath Jeselsohn
المصدر: npj Breast Cancer, Vol 10, Iss 1, Pp 1-12 (2024)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2374-4677Test
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2دورية أكاديمية
المؤلفون: Francesca Galardi, Francesca De Luca, Chiara Biagioni, Ilenia Migliaccio, Giuseppe Curigliano, Alessandro M. Minisini, Martina Bonechi, Erica Moretti, Emanuela Risi, Amelia McCartney, Matteo Benelli, Dario Romagnoli, Silvia Cappadona, Stefano Gabellini, Cristina Guarducci, Valerio Conti, Laura Biganzoli, Angelo Di Leo, Luca Malorni
المصدر: Breast Cancer Research, Vol 23, Iss 1, Pp 1-12 (2021)
مصطلحات موضوعية: Liquid biopsy, CTCs, Luminal breast cancer, Metastatic, Palbociclib, CDK4/6 inhibitor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. Methods Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. Results All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. Conclusions CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1465-542XTest
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3دورية أكاديمية
المؤلفون: Emanuela Risi, Chiara Biagioni, Matteo Benelli, Ilenia Migliaccio, Amelia McCartney, Martina Bonechi, Cristina Guarducci, Florentine Hilbers, Serena Di Cosimo, Jens Huober, Dario Romagnoli, Giulia Boccalini, Stefania Vitale, Christos Sotiriou, Laura Biganzoli, Angelo Di Leo, Luca Malorni
المصدر: Therapeutic Advances in Medical Oncology, Vol 11 (2019)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Background: Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial. Methods: We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported p values resulted from Fisher’s exact test. Results: Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ n = 129; HR− n = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% versus 18% respectively; p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52–0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients versus 28% in HR+/RBsig High. Conclusions: These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1758-8359Test
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4دورية أكاديمية
المؤلفون: Ilenia Migliaccio, Angela Leo, Francesca Galardi, Cristina Guarducci, Giulio Maria Fusco, Matteo Benelli, Angelo Di Leo, Laura Biganzoli, Luca Malorni
المصدر: Cancers, Vol 13, Iss 11, p 2640 (2021)
مصطلحات موضوعية: CDK4/6 inhibitors, circulating biomarkers, liquid biopsy, therapy resistance, breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are the standard treatment for patients with hormone receptor-positive and HER2 negative (HR+/HER2−) metastatic breast cancer. Patients might show intrinsic and acquired resistance, which leads to treatment failure and progression. Circulating biomarkers have the potential advantages of recognizing patients who might not respond to treatment, monitoring treatment effects and identifying markers of acquired resistance during tumor progression with a simple withdrawal of peripheral blood. Genomic alterations on circulating tumor DNA and serum thymidine kinase activity, but also circulating tumor cells, epigenetic or exosome markers are currently being tested as markers of CDK4/6i treatment response, even though none of these have been integrated into clinical practice. In this review, we discuss the recent advancements in the development of circulating biomarkers of CDK4/6i response in patients with HR+/HER2−breast cancer.
وصف الملف: electronic resource
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5دورية أكاديمية
المؤلفون: Yu-Chen Cheng, Shayna Stein, Agostina Nardone, Weihan Liu, Wen Ma, Gabriella Cohen, Cristina Guarducci, Thomas O. McDonald, Rinath Jeselsohn, Franziska Michor
مصطلحات موضوعية: Cancer, Tumor Biology, Molecular and Cellular Biology, Therapeutic Research and Development, Methods and Technology, Computational Methods, Mathematical modeling, Tumor Evolution, Breast Cancer, Small Molecule Agents, Endocrinology, Hormone signaling and inhibitors, Cell Cycle, CDKs and CDK inhibitors
الوصف: Supplementary Table S3 shows ratio of each schedule to the standard schedule at day 100 for simulated cell lines
الإتاحة: https://doi.org/10.1158/2767-9764.24574045.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_Table_S3_from_Mathematical_Modeling_Identifies_Optimum_Palbociclib-fulvestrant_Dose_Administration_Schedules_for_the_Treatment_of_Patients_with_Estrogen_Receptor_positive_Breast_Cancer/24574045Test -
6دورية أكاديمية
المؤلفون: Yu-Chen Cheng, Shayna Stein, Agostina Nardone, Weihan Liu, Wen Ma, Gabriella Cohen, Cristina Guarducci, Thomas O. McDonald, Rinath Jeselsohn, Franziska Michor
مصطلحات موضوعية: Cancer, Tumor Biology, Molecular and Cellular Biology, Therapeutic Research and Development, Methods and Technology, Computational Methods, Mathematical modeling, Tumor Evolution, Breast Cancer, Small Molecule Agents, Endocrinology, Hormone signaling and inhibitors, Cell Cycle, CDKs and CDK inhibitors
الوصف: Supplementary Fig. S4 shows using LOOIC to determine number of stages m
الإتاحة: https://doi.org/10.1158/2767-9764.24574069.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_Fig_S4_from_Mathematical_Modeling_Identifies_Optimum_Palbociclib-fulvestrant_Dose_Administration_Schedules_for_the_Treatment_of_Patients_with_Estrogen_Receptor_positive_Breast_Cancer/24574069Test -
7دورية أكاديمية
المؤلفون: Yu-Chen Cheng, Shayna Stein, Agostina Nardone, Weihan Liu, Wen Ma, Gabriella Cohen, Cristina Guarducci, Thomas O. McDonald, Rinath Jeselsohn, Franziska Michor
مصطلحات موضوعية: Cancer, Tumor Biology, Molecular and Cellular Biology, Therapeutic Research and Development, Methods and Technology, Computational Methods, Mathematical modeling, Tumor Evolution, Breast Cancer, Small Molecule Agents, Endocrinology, Hormone signaling and inhibitors, Cell Cycle, CDKs and CDK inhibitors
الوصف: Supplementary Appendix S2 shows Bayesian estimation of model parameters
الإتاحة: https://doi.org/10.1158/2767-9764.24574105.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_Appendix_S2_from_Mathematical_Modeling_Identifies_Optimum_Palbociclib-fulvestrant_Dose_Administration_Schedules_for_the_Treatment_of_Patients_with_Estrogen_Receptor_positive_Breast_Cancer/24574105Test -
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المؤلفون: Cristina Guarducci, Simona Cristea, Avery Feit, Sergey Naumenko, Agostina Nardone, Wen Ma, Douglas Russo, Gabriella Cohen Feit, Ariel Feiglin, Francisco Hermida-Prado, Shira Sherman, Myles Brown, Franziska Michor, Rinath Jeselsohn
المصدر: Cancer Research. 83:GS3-07
مصطلحات موضوعية: Cancer Research, Oncology
الوصف: Background Despite the remarkable activity of CDK4/6 inhibitors (CDK4/6i) in the treatment of estrogen receptor positive (ER+) metastatic breast cancer (BC), most patients eventually develop resistance to these drugs. The ctDNA analysis of the PALOMA-3 trial showed that the estrogen receptor (ER) mutation Y537S is a potential mechanism of acquired resistance to the combination of endocrine therapy (ET) with CDK4/6i. To date, the role of the ER mutations in the clonal evolution and the mechanisms of acquired resistance to CDK4/6i is unknown. Moreover, it is not known if the development of resistance to CDK4/6i in the presence or absence of ER mutations is due to the expansion of pre-existing resistant clones or to the de novo acquisition of resistance mechanisms. Methods To explore the clonal evolution and the mechanisms of resistance to CDK4/6i in ER-wild type (ER-WT) and ER-mutant (ER-Mut) BC, we transduced doxycycline (DOX)-inducible Y537S ER-Mut MCF7 cells with the ClonTracer library, a high-complexity DNA barcode library, and cultured the barcoded cells without DOX (MCF7), or with DOX to induce the expression of the Y537S ER mutation (MCF7-YS). To develop Palbociclib (Palbo)-resistant (PDR) and Abemaciclib (Abema)-resistant (ABR) cell models, the barcoded MCF7 and MCF7-YS cells were passaged in culture with increasing concentrations of Palbo and Abema until the acquisition of resistance. The clonal dynamics and the molecular characteristics of the PDR and ABR models were investigated by barcode sequencing, whole-exome sequencing (WES), bulk and single cell RNA sequencing (RNAseq) and protein analyses. Finally, using an ER-Mut barcoded mice model, we compared the in vitro clonal evolution of ER-Mut CDK4/6i-resistant cells with the in vivo clonal evolution of ER-Mut metastases. Results The analysis of the barcodes revealed that during the acquisition of resistance to either Palbo or Abema there is a strong clonal selection of pre-existing resistant clones. The PDR clones were different in the presence of the Y537S mutation versus WT-ER. In contrast, the clones enriched in the ABR cells were comparable between WT and mutant ER. Furthermore, the ER mutations led to decreased diversity of the enriched clones in the PDR but not in the ABR cells. Interestingly, the barcodes enriched in the PDR and ABR models did not overlap. Unsupervised analyses showed that the samples clustering based on the barcodes fractions and the mutations were similar, suggesting that the clonal selection was driven by cellular populations with specific mutational landscapes. All the ER-WT and ER-Mut resistant models had different transcriptional profiles and by single-cell RNAseq showed various degrees of intra-sample heterogeneity. At the protein level, the PDR and the ABR cells displayed downregulation of ER, Rb and p27 and upregulation of p21. In the ER-Mut conditions Cyclin D1 was upregulated in the PDR cells, while Cyclin E was upregulated in the ABR cells. Finally, the barcode sequencing of the mice metastases revealed that the clonal selection in ER-Mut metastases and in ER-Mut CDK4/6i-resistant cells is different. Conclusion Our study suggests that the development of resistance to CDK4/6i is due to the selection of pre-existing resistant clones. We also demonstrate that the expression of the Y537S ER mutation impacts the clonal evolution and the mechanisms of acquired resistance to Palbo but not to Abema. Finally, we show that the clonal evolution and mechanisms are disparate in Palbo and Abema resistance. These results support the addition of a third drug to CDK4/6i and ET, early in treatment, to delay the selection of pre-existing resistant clones and prolong the response to treatment and highlight differences between Palbo and Abema. Citation Format: Cristina Guarducci, Simona Cristea, Avery Feit, Sergey Naumenko, Agostina Nardone, Wen Ma, Douglas Russo, Gabriella Cohen Feit, Ariel Feiglin, Francisco Hermida-Prado, Shira Sherman, Myles Brown, Franziska Michor, Rinath Jeselsohn. GS3-07 Clonal evolution and mechanisms of acquired resistance to CDK4/6 inhibitors in ER-wild type and ER-mutant breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-07.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::db8d5a2fcd983f93aa03bb004d3f5efeTest
https://doi.org/10.1158/1538-7445.sabcs22-gs3-07Test -
9دورية أكاديمية
المؤلفون: Francesca Galardi (10433289), Francesca De Luca (7213424), Chiara Biagioni (6116525), Ilenia Migliaccio (6116537), Giuseppe Curigliano (7911845), Alessandro M. Minisini (10433292), Martina Bonechi (6116522), Erica Moretti (10433295), Emanuela Risi (3148563), Amelia McCartney (8118398), Matteo Benelli (155415), Dario Romagnoli (6116516), Silvia Cappadona (10433298), Stefano Gabellini (10433301), Cristina Guarducci (8118401), Valerio Conti (10433304), Laura Biganzoli (7641635), Angelo Di Leo (410260), Luca Malorni (10433307)
مصطلحات موضوعية: Medicine, Immunology, Cancer, Space Science, Biological Sciences not elsewhere classified, Liquid biopsy, CTCs, Luminal breast cancer, Metastatic, Palbociclib, CDK4/6 inhibitor, ddPCR, Biomarker
الوصف: Additional file 2: Figure S2. T47D set up of ddPCR assay. A, B-2D plot of T47D PDS and PDR, C, D- concentration plot of T47D PDS and PDR; PDS: sensitive to palbociclib, PDR resistant to palbociclib.
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10دورية أكاديمية
المؤلفون: Francesca Galardi (10433289), Francesca De Luca (7213424), Chiara Biagioni (6116525), Ilenia Migliaccio (6116537), Giuseppe Curigliano (7911845), Alessandro M. Minisini (10433292), Martina Bonechi (6116522), Erica Moretti (10433295), Emanuela Risi (3148563), Amelia McCartney (8118398), Matteo Benelli (155415), Dario Romagnoli (6116516), Silvia Cappadona (10433298), Stefano Gabellini (10433301), Cristina Guarducci (8118401), Valerio Conti (10433304), Laura Biganzoli (7641635), Angelo Di Leo (410260), Luca Malorni (10433307)
مصطلحات موضوعية: Medicine, Immunology, Cancer, Space Science, Biological Sciences not elsewhere classified, Liquid biopsy, CTCs, Luminal breast cancer, Metastatic, Palbociclib, CDK4/6 inhibitor, ddPCR, Biomarker
الوصف: Additional file 5: Figure S5. RB1 and GAPDH gene expression analysis. A) distribution of GAPDH and RB1 copies number in single CTCs, B) distribution of mean number of copies of GAPDH and RB1 (tot n copies/n cells).
النص الكامل