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ZusammenfassungDie CT(Computertomographie)-Koronarangiographie (cCTA) ist bei Patienten mit niedriger und mittlerer Vortestwahrscheinlichkeit für eine koronare Herzkrankheit (KHK) eine sichere Möglichkeit zum nicht-invasiven Ausschluss signifikanter Koronarstenosen und ermöglicht darüber hinaus auch deren funktionelle und morphologische Beurteilung. Der Stellenwert der cCTA wurde durch die 2019 publizierte ESC(European Society of Cardiology)-Leitlinie zu Diagnose und Management des chronischen Koronarsyndroms gestärkt und hat dadurch eine erhebliche Aufwertung erfahren. Die Bestimmung des Agatston-Scores ist eine klinisch etablierte Methodik zur Quantifizierung des Koronarkalks und hat Einfluss auf die Einleitung einer medikamentösen Therapie. Durch Technologien wie die Einführung der EKG-kontrollierten Dosismodulation und der iterativen Bildrekonstruktion kann die cCTA mit hoher Bildqualität und niedriger Strahlendosis durchgeführt werden. Die alleinige anatomische Darstellung von Koronarstenosen wird derzeit um innovative Techniken wie die myokardiale CT-Perfusion oder CT-FFR (fraktionelle Flussreserve) erweitert, jedoch ist der klinische Stellenwert dieser Methoden noch nicht abschließend geklärt. Die cCTA könnte sich zu einem Weichensteller hinsichtlich der Indikationsstellung für eine invasive Koronardiagnostik/-intervention entwickeln.

Funding Acknowledgements Type of funding sources: None. Background/Introduction The extent of myocardial injury is strongly associated with adverse outcome after acute myocardial infarction (AMI). Contrast-enhanced magnetic resonance imaging (CE-MRI) is the preferred technique for myocardial imaging. Its use in daily clinical practise, however, is restricted due to limited availability and high costs. High-sensitivity cardiac troponin T (hs-cTnT) correlates well with the extent of myocardial injury and may therefore be a cost effective and widely available surrogate for the estimation of infarct size. Purpose To validate correlations between CE-MRI infarct mass and hs-cTnT values at different time points in patients with confirmed AMI. Methods Patients presenting with AMI and with available CE-MRI between January 1, 2018 and December 31, 2020 were included. Correlation coefficients between hs-cTnT on admission, after 24h, 48h, 72h, 96h and peak hs-cTnT values and CE-MRI infarct mass were calculated. Correlations between hs-cTnT and CE-MRI infarct mass were compared to those of a 3rd generation cTnT assay from a previously published study of our group. Results 137 patients were included for the present analysis. Median CE-MRI infarct mass was 12,5 g (95%CI: 9.8-16.2 g). Hs-cTnT values and infarct mass correlated well at all time points including admission (r=0.474, [95%CI: 0.331-0.560], p Conclusions Hs-cTnT values at different time points correlate well with CE-MRI infarct mass. Correlations of admission hs-cTnT values are superior to those of a 3rd generation assay.

Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.

Aerogels are high surface area, low density, low thermal mass, nanoporous materials that are stable at high temperatures. This unique combination of physical characteristics makes them promising for use in three-way catalyst systems. Their high surface area has the potential to result in more active sites and improved gas/solid interaction. Their high temperature stability may reduce active site diffusion/sintering and allow for close coupling, which combined with the low thermal inertia may lead to a reduced time to light-off. It is relatively easy to incorporate a variety of metals, including non-precious group metals, into an aerogel backbone. We have developed a series of copper-alumina (CuAl) aerogels via sol-gel synthesis and rapid supercritical extraction drying. Different amounts of copper were incorporated into the alumina gel, resulting in materials with 20% to 40% copper by mass. Scanning electron microscopy imaging shows copper-containing particles distributed in the material, and powder X-ray diffraction indicates that the copper may be in the copper aluminate spinel phase after heat treatment. The materials were tested in the Union Catalytic Aerogel Testbed (UCAT), which evaluates catalytic material performance for conversion of NO, HCs, and CO over a range of temperatures from 200 to 700 °C using a simulated exhaust gas mixture with and without air. UCAT test results indicate that adding more copper to the aerogel lowers the light-off temperature from 350 to 225–250 °C for the conversion of CO and from 500 to 425–450 °C for the conversion of HCs (in the presence of air) and from 425 to 325 °C for NO (without air).

In 2016, the Universite de Rennes 1 officially joined the CNES pedagogical project PERSEUS in order to stimulate interest in innovative research and entrepreneurship. On-campus activities undertaken without the stress of formal examinations help build self-confidence in students as they are encouraged to propose their own solutions under the supervision of teachers who act more like coaches. Projects are carefully designed to suit a wide range of levels and backgrounds, allowing students to take risks, fail and persevere and thus acquire soft skills that are decisive in professional life but difficult to learn through traditional education. The hands-on approach of PERSEUS paradoxically brings out the importance of academic knowledge when solving complex issues, much more convincingly than classes and textbooks. To facilitate interactions between students, all PERSEUS projects of the Universite de Rennes 1 were grouped together in 2021 at the Pole de Mecanique et Technologies on the Campus de Beaulieu. The Project Lab is a new facility set up with financial supports from CNES, Region Bretagne, Rennes Metropole and Universite de Rennes 1, where participants have easy access to a whole range of prototyping, CNC milling, 3D-printing and additive manufacturing machines. The room is equipped with computers, a large interactive touch screen for brainstorming sessions and video-conferences, high top desks and stools as well as a cosy corner for free-flowing discussions and business lunches. The Rennes team is involved in several projects: SERA, Astreos, MiniApterros and SmartCatcher. The latter is a ground active landing system proposed by ArianeWorks to securely catch a reusable rocket stage equipped with grid-fins, by means of 4 mobile cables whose positions are accurately determined during the last seconds of descent through a frame equipped with detectors. The first 1/10 scale prototype was commissioned by ArianeWorks to myCTO, now Sparkmate, and delivered to the University of Rennes 1 in autumn 2019. Over the last two years, it has been improved by students, mainly from the Masters degree in Mechanics and Mechatronics. The first step consisted in constructing mathematical and FEM models capable of simulating the behaviour of the system depending on physical parameters such as dimensions, stage mass, velocity, etc. Modifications to the initial prototype were studied, designed and implemented, in particular to make it easily dismountable and transportable, using limited machined parts and more on-theshelf components for easy manufacturing and maintenance. Simulations of the catching scenarios were programmed in a Python code. Two students from the Masters degree in Mathematics, Computational Science and Modelling further developed and implemented the detection and catching of a model rocket, first using a Python code, then a faster version in C, able to control in real time the 1/10 SmartCatcher mobile cables. Details of the work realized by the students under the joint supervision of the teaching staff, as well as current developments, will be presented at the EUCASS 2022 conference.

International audience; Background: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinibresistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. Patients and methods: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. Results: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n ¼ 2 FGFR3-TACC3, n ¼ 1 KIF5B-RET, n ¼ 1 STRN-ALK fusions; n ¼ 2 BRAF V600E , n ¼ 1 KRAS G12V , n ¼ 1 KRAS G12R , n ¼ 1 KRAS G12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. Conclusions: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

This handbook describes the nature, uses, and limitations of the Modern Language Association of America (MLA) language proficiency tests for teachers and advanced students. The proficiency tests are examined in seven areas of language teaching competence: listening comprehension, speaking, reading, writing, applied linguistics, civilization and culture, and professional preparation. Several articles examine the validity of the tests and discuss related research. The final section focuses on the potential and limitation of the tests. Appendixes contain information concerning the MLA teacher qualifications, test scores and NDEA Institute ratings, MLA Proficiency and MLA Cooperative Tests, Foreign Service Institute rating scale, comparative test scores of Institute and native speakers, and NDEA Institute norms for the MLA Proficiency Tests, 1961-67. (RL)

This survey of profession-wide accomplishments and failures in foreign language instruction, characteristic of the last two decades, is complemented by suggestions intended to spur teachers and educational institutions into initiating improvements in curriculum development considered to be vital to the survival of the foreign language profession. Specific references to programs and publications, characteristic of the period under consideration, are outlined in four categories: (1) professional statements, (2) professional programs with specific objectives, (3) selected publications, and (4) new means for professional communiction. Concluding remarks predict that unless the language teaching profession recovers the "boldness" of the early 1950's the profession shall be nothing more than a "paper tiger" in an academic jungle. (RL)

This handbook is the culmination of an examination of problems encountered in the articulation of foreign language programs from secondary schools to college. The report contains the results of discussions with the chairmen of language departments at the college level and the examining committee, the findings obtained from on-campus interviews, and written responses to direct solicitation for advice. Sections include: (1) introduction: project background and rationale; (2) description of project activities; (3) fifteen case studies: some common assumptions; (4) publications and position papers: a summary of observations and recommendations; (5) a new approach to college language placement; and (6) several appendixes relating to this project. Included among these papers are several selected publications, position papers, and "The Foreign Language Program in Washoe County and the University of Nevada," by C.W.F. Melz. (RL)

The survey of foreign language testing described in this paper resulted in the issuing of three handbooks and a special validation report, encompassing the results of research, consultation with professional committees, and significant position statements in four major areas of foreign language testing: placement of incoming students in foreign languages at the college level, the use of standardized achievement tests in foreign languages and the preparation of teacher made tests, interpretation of the results of the MLA Foreign Language Proficiency Tests for Teachers and Advanced Students, and validation of the Proficiency Tests in terms of the native speaker. The paper includes a detailed outline of the objectives of the survey, the background of the survey, the methods and procedures used, and the results, findings, and conclusions. (Author/HW)

Five position papers resulting from a conference on the teaching of FLES discuss recent theory about elementary education and are intended to initiate a dialogue among teachers of foreign languages directed toward the exploration of ways and means of managing educational change. The report suggests how a broader rationale and a new curriculum base for FLES might be evolved. Papers include: (1) "Psychological and Educational Considerations in Early Language Learning", (2) "The Emerging Elementary School as a Setting for Foreign Language Instruction", (3) "Trends in Two Elementary School Subject-Matter Areas", (4) "Goals and Trends of Administration, Organization, and Supervision in Elementary Education", and (5) "Managing Change". The appendix contains background notes on the conference, the conference program, and a list of participants. (RL)

This handbook illustrates how the classroom teacher can make efficient use of tests, discusses the main purposes tests can serve, treats principal kinds of testing devices especially useful in language instruction, and includes a section on the interpretation of test results. Chapters include: (1) the importance and place of testing in the foreign language program, (2) planning the classroom test, (3) construction of test items, (4) preparing test items in French, German, Italian, Russian, and Spanish, and (5) test interpretation. A glossary of technical terms used in the handbook and an annotated bibliography on testing are included. (RL)

INFORMATION IS PRESENTED BASED ON RESPONSES OF 203 DEPARTMENT CHAIRMEN TO A QUESTIONNAIRE STUDYING THE TRAINING OF FOREIGN LANGUAGE TEACHERS AT THE UNDERGRADUATE LEVEL. SUBJECTS SURVEYED WERE COURSE REQUIREMENTS, PROFICIENCY TESTS, METHODS COURSES, PRACTICE TEACHING, NUMBER OF FOREIGN LANGUAGE GRADUATES, AND PLANS FOR CHANGES IN THE TEACHER TRAINING PROGRAM. SEVEN CHARTS ARE INCLUDED TO FURTHER CLARIFY THIS REPORT, AND COMPARISONS ARE MADE WITH DATA ACCUMULATED IN OTHER STUDIES. THIS ARTICLE IS A REPRINT FROM "THE MODERN LANGUAGE JOURNAL," VOLUME 49, NUMBER 7, NOVEMBER 1965, PAGES 414-421. (AF)

UNDERGRADUATE TEACHER-TRAINING IN LIBERAL ARTS COLLEGES WITH HIGH MODERN LANGUAGE ENROLLMENTS AND GOOD GEOGRAPHICAL DISTRIBUTION WAS SURVEYED WITH REGARD TO COURSE REQUIREMENTS, PRACTICE TEACHING, AND FUTURE TEACHER-TRAINING PLANS. RESPONSES WERE RECEIVED FROM THE CHAIRMEN OF 335 FOREIGN LANGUAGE DEPARTMENTS IN 244 COLLEGES. SEVENTY PERCENT OF THE DEPARTMENTS HAVE EQUAL SEMESTER HOUR REQUIREMENTS FOR MAJORS WHO DO AND DO NOT INTEND TO TEACH. FIGURES ON SPECIFIC COURSE AND COURSE SEQUENCE REQUIREMENTS ARE INCLUDED. FIGURES ARE SUPPLIED ON NUMBERS OF GRADUATES AND CERTIFIED GRADUATES. TYPES OF PROGRAM CHANGES MOST FREQUENTLY CONSIDERED ALSO ARE REPORTED. COURSE CREDIT INFORMATION IS GIVEN, AND THE SURVEY IS COMPARED WITH OTHERS OF ITS TYPE. RECOMMENDATIONS ARE MADE. THIS ARTICLE WAS PUBLISHED IN "THE MODERN LANGUAGE JOURNAL," VOLUME 48, NUMBER 7, NOVEMBER 1964, PAGES 424-431. (AF)

Three hundred thirty-seven entries treat language, language teaching, language learning, linguistics, education, and related topics. Books are listed in alphabetical order by author. Most are in English, but a few are written in Spanish or French. (JH)

THIS STUDY, CONDUCTED BY THE MODERN LANGUAGE ASSOCIATION (MLA) WITH THE ASSISTANCE OF THE EDUCATIONAL TESTING SERVICE, WAS DESIGNED TO DETERMINE WHETHER THE FRENCH, GERMAN, AND SPANISH SKILL TESTS OF THE MLA COOPERATIVE FOREIGN LANGUAGE TESTS AND THE MLA PROFICIENCY TESTS FOR TEACHERS AND ADVANCED STUDENTS MEASURE ALONG A CONTINUUM OR WHETHER THERE IS A SERIOUS GAP BETWEEN THE TWO SETS OF TESTS. THE RESULTS OF THE STUDY, SUMMARIZED IN A SERIES OF 44 GRAPHS AND TABLES COMPRISING THE BULK OF THE DOCUMENT, SHOW THAT THE TWO SETS OF TESTS DO MEASURE ALONG A CONTINUUM AND THAT THERE IS NO NEED FOR A TEST OF INTERMEDIATE DIFFICULTY. THE OVERLAP IS NOT SO GREAT, HOWEVER, AS TO PREVENT THE COMBINED SETS OF TESTS FROM MEASURING STUDENTS AT ALL LEVELS OF ACHIEVEMENT. BRIEF BUT INCLUSIVE DISCUSSIONS OF TEST ADMINISTRATION AT THE UNIVERSITY OF ILLINOIS AND HOFSTRA UNIVERSITY AND OF STUDY DESIGN AND RESULTS ARE INCLUDED. (ST)

A PLAN IS PRESENTED FOR REDESIGNING THE FOREIGN LANGUAGE CURRICULUM IN THE SECONDARY SCHOOLS, BASED PRIMARILY ON THE USE OF FLEXIBLE SCHEDULING, THE REVISION OF COURSE CONTENT AND ACTIVITIES, AND THE ESTABLISHMENT OF MINIMUM SEQUENCES OF 6 YEARS IN MODERN LANGUAGES AND 4 YEARS IN LATIN. TOPICS DISCUSSED ARE (1) THE VALUES OF FOREIGN LANGUAGE STUDY, (2) GENERAL AND SPECIFIC OBJECTIVES, (3) THE PROGRAM SCHEDULE, (4) TESTING, AND (5) THE SUPERVISION OF THE PROGRAM. THE TOPIC RECEIVING MAJOR EMPHASIS IS THE DIVISION OF CONTENT AND LEARNING ACTIVITIES FOR SMALL GROUP, LARGE GROUP, AND INDIVIDUAL INSTRUCTION. CHARTS ARE GIVEN SHOWING THESE DIVISIONS FOR EACH OF THE FOUR SKILLS OF LISTENING, SPEAKING, READING, AND WRITING IN THE FIRST LEVEL OF MODERN LANGUAGE INSTRUCTION IN GRADES 7 AND 8, AND FOR THE COURSE ACTIVITIES FOR THE FIRST LEVEL OF LATIN INSTRUCTION IN GRADES 9 AND 10. AN EXTENSIVE LIST OF CRITERIA FOR THE EVALUATION OF 16 TYPES OF INSTRUCTIONAL MATERIALS IS GIVEN IN AN APPENDIX. (AM)

PD-L1 checkpoint inhibitor; Atezolizumab; Solid tumors Inhibidor del punto de control PD-L1; Atezolizumab; Tumores sólidos Inhibidor del punt de control PD-L1; Atezolizumab; Tumors sòlids Background The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. Patients and methods This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. Results Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. Conclusions Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings. This study was supported by F. Hoffmann-La Roche (no grant number) who provided financial support for the conduct of study and were involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. They also funded assistance with manuscript writing by a professional medical writer.

Cardiovascular magnetic resonance imaging is one of the most important diagnostic modalities in the evaluation of cardiomyopathies. However, significant limitations are the complex and time-consuming workflows and the need of contrast agents. The aim of this multi-center retrospective study was to assess workflows and diagnostic value of a short, contrast agent-free cardiac magnetic resonance protocol. 160 patients from Heidelberg, Germany and 119 patients from Montreal, Canada with suspected cardiomyopathy and 20 healthy volunteers have been enrolled. Scans were performed at a 1.5Tesla or 3Tesla scanner in Heidelberg and at a 3Tesla scanner in Montreal. We used single-slice T1 map only. A stepwise analysis of images has been performed. The possible differential diagnosis after each step has been defined. T1-values and color-encoded T1 maps significantly contributed to the differential diagnosis in 54% of the cases (161/299); the final diagnosis has been done without late gadolinium enhancement images in 83% of healthy individuals, in 99% of patients with dilated cardiomyopathy, in 93% of amyloidosis patients, in 94% of patients with hypertrophic cardiomyopathy and in 85% of patients with hypertensive heart disease, respectively. Comparing the scan time with (48 ± 7 min) vs. without contrast agent (23 ± 5 min), significant time saving could be reached by the short protocol. Subgroup analysis showed the most additional diagnostic value of T1 maps in amyloidosis and hypertrophic cardiomyopathy or in confirmation of normal findings. In patients with unclear left ventricular hypertrophy, a short, non-contrast protocol can be used for diagnostic decision-making, if the quality of the T1 map is diagnostic, even if only one slice is available.

Background: The incidence of breast cancer (BC) increases with age. However, there appears to be a trend that elderly patients with BC receive less than the standard treatment compared to younger ones and this leads to poorer outcomes. The aim of this work was to assess whether chemotherapy has a differential impact on the health related quality of life (HRQOL) of elderly patients with BC, compared to younger ones. Methods: CANTO (NCT 01993498) is a multicenter prospective observational study (26 centers in France) whose main objective is to study the chronic toxicities of anticancer treatments in 12,000 women with localized stages I to III BC. HRQOL was assessed at baseline and at the end of acute treatments (surgery +/- radiotherapy +/- chemotherapy) using the EORTC-QLQ-C30 questionnaire and its BC specific module, the EORTC-QLQ-BR23. HRQOL at the end of acute treatments of patients aged 70 and over treated by chemotherapy was compared to that of the youngest ones. Multivariable mixed linear model was used to assess the determinants of HRQOL for the dimensions with minimal clinically important differences; defined as a mean difference of at least 5 points in HRQOL scores; between younger and older patients. Results: 3079 patients were included in the CANTO cohort from March 2012 to December 2014 and treated by chemotherapy. The mean age at diagnosis was 53 years and 7.3% of this population was ≥70 years old. Older and younger patients treated by chemotherapy were similar for the disease stage at diagnosis (p=0.7869), the tumor histology (p=0.07), the SBR grade (p=0.2350) and the HER2 status (p=0.4268). However, elderly patients treated by chemotherapy were more likely to be overweight (p Citation Format: Sandrine Dabakuyo Yonli, Oumar Billa, Olivia Dialla, Florence Joly, Sarah Dauchy, Charles Cecile, Cedric Lemogne, Patrick Soulie, Marie-Ange Mouret-Reynier, Carole Tarpin, Mario Campone, Sophie Guillermet, Jean-Marc Ferrero, Sylvie Giacchetti, Florence Lerebours, Suzette Delaloge, Anne-Laure Martin, Sibille Everhard, Charles Coutant, Fabrice Andre, Patrick Arveux. Impact of chemotherapy on the health related quality of life among elderly patients with localized breast cancer: Findings from the prospective CANTO cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-07.

Computed tomography coronary angiography (cCTA) is a safe option for the noninvasive exclusion of significant coronary stenoses in patients with a low or moderate pretest probability for coronary artery disease (CAD). Furthermore, it also allows functional and morphological assessment of coronary stenoses. The European Society of Cardiology (ESC) guidelines on the diagnosis and management of chronic coronary syndrome published in 2019 have strengthened the importance of cCTA in this context and for this reason it has experienced a considerable upgrade. The determination of the Agatston score is a clinically established method for quantifying coronary calcification and influences the initiation of drug treatment. With technologies, such as the introduction of electrocardiography (ECG)-controlled dose modulation and iterative image reconstruction, cCTA can be performed with high image quality and low radiation exposure. Anatomic imaging of coronary stenoses alone is currently being augmented by innovative techniques, such as myocardial CT perfusion imaging or CT-fractional flow reserve (FFR) but the clinical value of these methods merits further investigation. The cCTA could therefore develop into a gatekeeper with respect to the indications for invasive coronary diagnostics and interventions.Die CT(Computertomographie)-Koronarangiographie (cCTA) ist bei Patienten mit niedriger und mittlerer Vortestwahrscheinlichkeit für eine koronare Herzkrankheit (KHK) eine sichere Möglichkeit zum nicht-invasiven Ausschluss signifikanter Koronarstenosen und ermöglicht darüber hinaus auch deren funktionelle und morphologische Beurteilung. Der Stellenwert der cCTA wurde durch die 2019 publizierte ESC(European Society of Cardiology)-Leitlinie zu Diagnose und Management des chronischen Koronarsyndroms gestärkt und hat dadurch eine erhebliche Aufwertung erfahren. Die Bestimmung des Agatston-Scores ist eine klinisch etablierte Methodik zur Quantifizierung des Koronarkalks und hat Einfluss auf die Einleitung einer medikamentösen Therapie. Durch Technologien wie die Einführung der EKG-kontrollierten Dosismodulation und der iterativen Bildrekonstruktion kann die cCTA mit hoher Bildqualität und niedriger Strahlendosis durchgeführt werden. Die alleinige anatomische Darstellung von Koronarstenosen wird derzeit um innovative Techniken wie die myokardiale CT-Perfusion oder CT-FFR (fraktionelle Flussreserve) erweitert, jedoch ist der klinische Stellenwert dieser Methoden noch nicht abschließend geklärt. Die cCTA könnte sich zu einem Weichensteller hinsichtlich der Indikationsstellung für eine invasive Koronardiagnostik/-intervention entwickeln.

Rationale: while large efforts have been done to characterize early breast cancer, little is known about the genomic landscape of metastatic breast cancer. In the present study, we performed whole exome sequencing of 800 metastatic breast cancers, in order to identify new candidate targets and better stratify patients eligible for innovative therapies. Patients and Methods: Patients were selected to present a metastatic breast cancer and to have received a biopsy in the context of precision medicine trials (SAFIR01, SAFIR02, PERMED, MOSCATO, SHIVA). Samples with >30% cancer cells, and normal DNA, were sequenced using Hiseq and Novaseq. Drivers were identified using MutSigCV. Actionability of somatic genetic alterations was determined based on OncoKB. Decomposition of mutational signatures was performed using deconstructSigs. Prognostic value was assessed using a cox model. TCGA database was used as comparator to identify gene alterations enriched in metastatic samples. Results: results presented in the current abstract are based on the first 629 patients analyzed.Sequencing was performed in 387 patients with HR+/Her2- breast cancer, 186 triple negative breast cancers, and 32 Her2-overexpressing breast cancers. only 9 patients received a pretreatment with a CDK4 inhibitor. 24 driver genes were significantly mutated. In patients with HR+/Her2- breast cancer, 11 genes were found more frequently mutated in the metastatic setting as compared to early stage breast cancer. This includes TP53 (29%), KMT2C (13%), NCOR1 (8%), NF1 (7%), RB1 (4%), C16orf3 (2%), FRG1 (6%), ESR1 (21%), RIC8A (4%), AKT1 (7%), PLSCR5 (2%). In addition, in the whole population, KRAS was found mutated in 3% of samples (G12A/C/R/V) while its frequency of mutation in early breast cancer is We further assessed the mutational signatures in order to better understand which mutational processes could drive cancer progression. Metastatic HR+/Her2- mBC presented an increase in APOBEC, S3 (HRD), S10 (POLE-associated signature), S17 signatures as compared to early HR+/Her2- BC. Conclusion: the present study, based on 629 patients, identifies 11 driver gene alterations and four mutational processes enriched in HR+/Her2- metastatic breast cancers. Final results on 800 patients will be presented. Citation Format: Andre F, Filleron T, Ng C, Bertucci F, Letourneau C, Jacquet A, Piscuoglio S, Jimenez M, Bachelot T. Genomic characterisation of metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-08.

Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts. Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3. Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET. Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-03.

Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose >250mg/dL; 37% for ALP+FUL vs Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast cancer; PI3K; alpelisib; endocrine therapy Citation Format: Juric D, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu Y-S, Inoue K, Takahashi M, Pápai Z, Longin A-S, Mills D, Wilke C, Sellami D, Andre F. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-08.