Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial

Elacestrant; Càncer de mamaElacestrant; Cáncer de mamaElacestrant; Breast cancerPURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial.

Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable mutations. Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; = .002) and patients with mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory

The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and administrative staff in Malargue. We are very grateful to the following agencies and organizations for financial support: Argentina-Comision Nacional de Energia Atomica, Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Gobierno de la Provincia de Mendoza, Municipalidad de Malargue, NDM Holdings and Valle Las Lenas; in gratitude for their continuing cooperation over land access; Australia-the Australian Research Council; BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacao de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ), Sao Paulo Research Foundation (FAPESP) Grants No. 2019/10151-2, No. 2010/07359-6, and No. 1999/05404-3, Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC); Ministry of Education, Youth and Sports of the Czech RepublicGrants No. MSMT CR LTT18004, No. LM2015038, No. LM2018102, No. CZ.02.1.01/0.0/0.0/16_013/0001402, No. CZ.02.1.01/0.0/0.0/18_046/0016010, and No. CZ.02.1.01/0.0/0.0/17_049/0008422; France-Centre de Calcul IN2P3/CNRS, Centre National de la Recherche Scientifique (CNRS), Conseil Regional Ile-de-France, Departement Physique Nucl ' eaire et Corpusculaire (PNC-IN2P3/CNRS), Departement Sciences de l'Univers (SDU-INSU/CNRS), Institut Lagrange de Paris (ILP) Grant No. LABEX ANR-10-LABX-63 within the Investissements d'Avenir Programme Grant No. ANR11-IDEX-0004-02; Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministerium Baden-Wurttemberg, Helmholtz Alliance for Astroparticle Physics (HAP), Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Ministerium fur Wissenschaft, Forschung und Kunst des Landes Baden-Wurttemberg; Italy-Istituto Nazionale di Fisica Nucleare (INFN), Istituto Nazionale di Astrofisica (INAF), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), CETEMPS Center of Excellence, Ministero degli Affari Esteri (MAE); Mexico-Consejo Nacional de Ciencia y Tecnologia (CONACYT) Grant No. 167733, Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAM; The Netherlands-Ministry of Education, Culture and Science, Netherlands Organisation for Scientific Research (NWO), Dutch national e-infrastructure with the support of SURF Cooperative; Poland-Ministry of Science and Higher Education, Grant No. DIR/WK/2018/11, National Science Centre, Grants No. 2013/08/M/ST9/00322, No. 2016/23/B/ST9/01635, and No. HARMONIA 5-2013/10/M/ST9/00062, UMO-2016/22/M/ST9/00198; Portugal -Portuguese national funds and FEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE); Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI (PN19150201/16N/2019 and PN19060102), and project PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018 within PNCDI III; Slovenia-Slovenian Research Agency, Grants No. P1-0031, No. P1-0385, No. I00033, No. N1-0111; Spain-Ministerio de Economia, Industria y Competitividad (FPA2017-85114-P and FPA2017-85197-P), Xunta de Galicia (ED431C 2017/07), Junta de Andalucia (SOMM17/6104/UGR), Feder Funds, RENATA Red Nacional Tematica de Astroparticulas (FPA2015-68783-REDT), and Maria de Maeztu Unit of Excellence (MDM-2016-0692); U.S.Department of Energy, Awards No. DE-AC0207CH11359, No. DE-FR02-04ER41300, No. DE-FG0299ER41107, and No. DE-SC0011689, National Science Foundation, Grant No. 0450696, The Grainger Foundation, Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, and UNESCO.We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.Argentina-Comision Nacional de Energia AtomicaANPCyTConsejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)Gobierno de la Provincia de MendozaMunicipalidad de MalargueNDM HoldingsValle Las LenasAustralian Research CouncilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF)Financiadora de Inovacao e Pesquisa (Finep)Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2019/10151-2 2010/07359-6 1999/05404-3Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC)Ministry of Education, Youth & Sports - Czech Republic MSMT CR LTT18004 LM2015038 LM2018102 CZ.02.1.01/0.0/0.0/16_013/0001402 CZ.02.1.01/0.0/0.0/18_046/0016010 CZ.02.1.01/0.0/0.0/17_049/0008422France-Centre de Calcul IN2P3/CNRSCentre National de la Recherche Scientifique (CNRS)Region Ile-de-FranceCentre National de la Recherche Scientifique (CNRS)Departement Sciences de l'Univers (SDU-INSU/CNRS)French National Research Agency (ANR) LABEX ANR-10-LABX-63 ANR11-IDEX-0004-02Federal Ministry of Education & Research (BMBF)German Research Foundation (DFG)Finanzministerium Baden-WurttembergHelmholtz Alliance for Astroparticle Physics (HAP)Helmholtz AssociationMinisterium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMinisterium fur Wissenschaft, Forschung und Kunst des Landes Baden-WurttembergItaly-Istituto Nazionale di Fisica Nucleare (INFN)Istituto Nazionale Astrofisica (INAF)Ministry of Education, Universities and Research (MIUR)CETEMPS Center of ExcellenceMinistry of Foreign Affairs and International Cooperation (Italy)Consejo Nacional de Ciencia y Tecnologia (CONACyT) 167733Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAMNetherlands-Ministry of Education, Culture and ScienceNetherlands Organization for Scientific Research (NWO)Dutch national e-infrastructureSURF CooperativePoland-Ministry of Science and Higher Education DIR/WK/2018/11National Science Centre, Poland 2013/08/M/ST9/00322 2016/23/B/ST9/01635 HARMONIA 5-2013/10/M/ST9/00062 UMO-2016/22/M/ST9/00198Portugal -Portuguese national fundsFEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE)Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI PN19150201/16N/2019 PN19060102Romania-Romanian Ministry of Educatio n and Research, the Program Nucleu within PNCDI III PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018Slovenian Research Agency - Slovenia P1-0031 P1-0385 I00033 N1-0111Spain-Ministerio de Economia, Industria y Competitividad FPA2017-85114-P FPA2017-85197-PXunta de Galicia European Commission ED431C 2017/07Junta de Andalucia SOMM17/6104/UGREuropean CommissionRENATA Red Nacional Tematica de Astroparticulas FPA2015-68783-REDTMaria de Maeztu Unit of Excellence MDM-2016-0692United States Department of Energy (DOE) DE-AC0207CH11359 DE-FR02-04ER41300 DE-FG0299ER41107 DE-SC0011689National Science Foundation (NSF) 0450696Grainger FoundationMarie Curie-IRSES/EPLANETEuropean Particle Physics Latin American NetworkUNESC

Observation of inclined EeV air showers with the radio detector of the Pierre Auger Observatory

International audienceWith the Auger Engineering Radio Array (AERA) of the Pierre Auger Observatory, we have observed the radio emission from 561 extensive air showers with zenith angles between 60o and 84o. In contrast to air showers with more vertical incidence, these inclined air showers illuminate large ground areas of several km2 with radio signals detectable in the 30 to 80 MHz band. A comparison of the measured radio-signal amplitudes with Monte Carlo simulations of a subset of 50 events for which we reconstruct the energy using the Auger surface detector shows agreement within the uncertainties of the current analysis. As expected for forward-beamed radio emission undergoing no significant absorption or scattering in the atmosphere, the area illuminated by radio signals grows with the zenith angle of the air shower. Inclined air showers with EeV energies are thus measurable with sparse radio-antenna arrays with grid sizes of a km or more. This is particularly attractive as radio detection provides direct access to the energy in the electromagnetic cascade of an air shower, which in case of inclined air showers is not accessible by arrays of particle detectors on the ground

Reconstruction of events recorded with the surface detector of the Pierre Auger Observatory

International audienceCosmic rays arriving at Earth collide with the upper parts of the atmosphere, thereby inducing extensive air showers. When secondary particles from the cascade arrive at the ground, they are measured by surface detector arrays. We describe the methods applied to the measurements of the surface detector of the Pierre Auger Observatory to reconstruct events with zenith angles less than 60ˆ using the timing and signal information recorded using the water-Cherenkov detector stations. In addition, we assess the accuracy of these methods in reconstructing the arrival directions of the primary cosmic ray particles and the sizes of the induced showers

Cosmic-Ray Anisotropies in Right Ascension Measured by the Pierre Auger Observatory

We present measurements of the large-scale cosmic-ray (CR) anisotropies in R.A., using data collected by the surface detector array of the Pierre Auger Observatory over more than 14 yr. We determine the equatorial dipole component, through a Fourier analysis in R.A. that includes weights for each event so as to account for the main detector-induced systematic effects. For the energies at which the trigger efficiency of the array is small, the "east-west" method is employed. Besides using the data from the array with detectors separated by 1500 m, we also include data from the smaller but denser subarray of detectors with 750 m separation, which allows us to extend the analysis down to ∼0.03 EeV. The most significant equatorial dipole amplitude obtained is that in the cumulative bin above 8 EeV, %, which is inconsistent with isotropy at the 6σ level. In the bins below 8 EeV, we obtain 99% CL upper bounds on d ⊥ at the level of 1%-3%. At energies below 1 EeV, even though the amplitudes are not significant, the phases determined in most of the bins are not far from the R.A. of the Galactic center, at GC =-94°, suggesting a predominantly Galactic origin for anisotropies at these energies. The reconstructed dipole phases in the energy bins above 4 EeV point instead to R.A. that are almost opposite to the Galactic center one, indicative of an extragalactic CR origin. © 2020. The American Astronomical Society. All rights reserved.

Spectral Calibration of the Fluorescence Telescopes of the Pierre Auger Observatory

International audienceWe present a novel method to measure precisely the relative spectral response of the fluorescence telescopes of the Pierre Auger Observatory. We used a portable light source based on a xenon flasher and a monochromator to measure the relative spectral efficiencies of eight telescopes in steps of 5 nm from 280 nm to 440 nm. Each point in a scan had approximately 2 nm FWHM out of the monochromator. Different sets of telescopes in the observatory have different optical components, and the eight telescopes measured represent two each of the four combinations of components represented in the observatory. We made an end-to-end measurement of the response from different combinations of optical components, and the monochromator setup allowed for more precise and complete measurements than our previous multi-wavelength calibrations. We find an overall uncertainty in the calibration of the spectral response of most of the telescopes of 1.5% for all wavelengths; the six oldest telescopes have larger overall uncertainties of about 2.2%. We also report changes in physics measurables due to the change in calibration, which are generally small