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

الوصول الحر: https://doaj.org/article/7c7a103652a4404eac1f649798184d56Test

المؤلفون: Paolo Tarantino, Hersh Gupta, Melissa E. Hughes, Janet Files, Sarah Strauss, Gregory Kirkner, Anne-Marie Feeney, Yvonne Li, Ana C. Garrido-Castro, Romualdo Barroso-Sousa, Brittany L. Bychkovsky, Simona DiLascio, Lynette Sholl, Laura MacConaill, Neal Lindeman, Bruce E. Johnson, Matthew Meyerson, Rinath Jeselsohn, Xintao Qiu, Rong Li, Henry Long, Eric P. Winer, Deborah Dillon, Giuseppe Curigliano, Andrew D. Cherniack, Sara M. Tolaney, Nancy U. Lin

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-10 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/5c5258c1093e4d42ab2f76c5fe3ba511Test

المؤلفون: R. C. Coombes, Sacha Howell, Simon R. Lord, Laura Kenny, Janine Mansi, Zahi Mitri, Carlo Palmieri, Linnea I. Chap, Paul Richards, William Gradishar, Sagar Sardesai, Jason Melear, Joyce O’Shaughnessy, Patrick Ward, Pavani Chalasani, Tobias Arkenau, Richard D. Baird, Rinath Jeselsohn, Simak Ali, Glen Clack, Ashwani Bahl, Stuart McIntosh, Matthew G. Krebs

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-10 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/b14be29b81754bafad04d4aa37714251Test

المؤلفون: Albert Grinshpun, Sara M. Tolaney, Harold J. Burstein, Rinath Jeselsohn, Erica L. Mayer

المصدر: npj Breast Cancer, Vol 9, Iss 1, Pp 1-4 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: The combination of an endocrine agent with a CDK4/6 inhibitor is the standard of care in the first-line setting for patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Randomized trials have demonstrated similar and significant improvements in progression-free survival using the three available CDK4/6 inhibitors and led to regulatory approval. However, mature overall survival data now suggest potential differences among the various agents, suggesting an evolution in selection preferences.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2374-4677Test

الوصول الحر: https://doaj.org/article/0064d50643924f538eaaf8da5ed4adbeTest

المؤلفون: Xiaoyong Fu, Resel Pereira, Chia-Chia Liu, Carmine De Angelis, Martin J. Shea, Sarmistha Nanda, Lanfang Qin, Tamika Mitchell, Maria L. Cataldo, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Mario Giuliano, Carolina Gutierrez, Balázs Győrffy, Meghana V. Trivedi, Ofir Cohen, Nikhil Wagle, Agostina Nardone, Rinath Jeselsohn, Mothaffar F. Rimawi, C. Kent Osborne, Rachel Schiff

المصدر: Cell Reports, Vol 42, Iss 8, Pp 112821- (2023)

مصطلحات موضوعية: CP: Cancer, Biology (General), QH301-705.5

الوصف: Summary: Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S221112472300832XTest; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/9ae29d74241a427e80d1e8022dc30c52Test

المؤلفون: Paolo Tarantino, Hersh Gupta, Melissa E. Hughes, Janet Files, Sarah Strauss, Gregory Kirkner, Anne-Marie Feeney, Yvonne Li, Ana C. Garrido-Castro, Romualdo Barroso-Sousa, Brittany L. Bychkovsky, Simona DiLascio, Lynette Sholl, Laura MacConaill, Neal Lindeman, Bruce E. Johnson, Matthew Meyerson, Rinath Jeselsohn, Xintao Qiu, Rong Li, Henry Long, Eric P. Winer, Deborah Dillon, Giuseppe Curigliano, Andrew D. Cherniack, Sara M. Tolaney, Nancy U. Lin

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-1 (2023)

مصطلحات موضوعية: Science

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/7fa2341e1b6d47c4bb97fd8b26758d3cTest

المؤلفون: Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: Frontiers in Oncology, Vol 13 (2023)

مصطلحات موضوعية: breast cancer, estrogen receptor, ESR1 fusion, endocrine therapy resistance, SERD, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2023.1155540/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/4cf1136085424b6eac26d3bb1f04eaaeTest

المؤلفون: R. C. Coombes, Sacha Howell, Simon R. Lord, Laura Kenny, Janine Mansi, Zahi Mitri, Carlo Palmieri, Linnea I. Chap, Paul Richards, William Gradishar, Sagar Sardesai, Jason Melear, Joyce O’Shaughnessy, Patrick Ward, Pavani Chalasani, Tobias Arkenau, Richard D. Baird, Rinath Jeselsohn, Simak Ali, Glen Clack, Ashwani Bahl, Stuart McIntosh, Matthew G. Krebs

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-1 (2023)

مصطلحات موضوعية: Science

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/4ff05e79a58f49b980db63215fe0a4b3Test

المؤلفون: Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: Frontiers in Oncology, Vol 12 (2023)

مصطلحات موضوعية: breast cancer, estrogen receptor, ESR1 fusion, endocrine therapy resistance, SERD, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Breast cancer is the most frequent female malignant tumor, and the leading cause of cancer death in women worldwide. The most common subtype of breast cancer is hormone receptor positive that expresses the estrogen receptor (ER). Targeting ER with endocrine therapy (ET) is the current standard of care for ER positive (ER+) breast cancer, reducing mortality by up to 40% in early- stage disease. However, resistance to ET represents a major clinical challenge for ER+ breast cancer patients leading to disease recurrence or progression of metastatic disease. Salient drivers of ET resistance are missense mutations in the ER gene (ESR1) leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly prominent and deleterious in metastatic breast cancer (MBC). In addition to activating ESR1 point mutations, emerging evidence imposes that chromosomal translocation involving the ESR1 gene can also drive ET resistance through the formation of chimeric transcription factors with constitutive transcriptional activity. Although these ESR1 gene fusions are relatively rare, they are enriched in ET resistant metastatic disease. This review discusses the characteristics of ER fusion proteins and their association with clinical outcomes in more aggressive and metastatic breast cancer. The structure and classification of ER fusion proteins based on function and clinical significance are also addressed. Finally, this review summarizes the metastatic phenotypes exhibited by the ER fusion proteins and their role in intrinsic ET resistance.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2022.1037531/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/edb23833f08c43a9ad4e7e6461d94908Test

المؤلفون: Tanya E. Keenan, Jennifer L. Guerriero, Romualdo Barroso-Sousa, Tianyu Li, Tess O’Meara, Anita Giobbie-Hurder, Nabihah Tayob, Jiani Hu, Mariano Severgnini, Judith Agudo, Ines Vaz-Luis, Leilani Anderson, Victoria Attaya, Jihye Park, Jake Conway, Meng Xiao He, Brendan Reardon, Erin Shannon, Gerburg Wulf, Laura M. Spring, Rinath Jeselsohn, Ian Krop, Nancy U. Lin, Ann Partridge, Eric P. Winer, Elizabeth A. Mittendorf, David Liu, Eliezer M. Van Allen, Sara M. Tolaney

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021)

مصطلحات موضوعية: Science

الوصف: A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/d25f24d7eb06482f96ec27595b0111bcTest