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Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or > 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p < 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to >48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Benoîte Mery,1,2,&ast; Christine Ménétrier-Caux,2,3,&ast; Laure Montané,4 Pierre-Etienne Heudel,1 Isabelle Ray-Coquard,1 Thomas Bachelot,1 Olfa Derbel,5 Paule Augereau,6 Isabelle Treilleux,2,7 Justine Berthet,2,3 Axelle Nkodia,3 Christine Bardin-Dit-Courageot,3 Valery Attignon,8 Anthony Ferrari,9 Gwenaele Garin,4 David Perol,4 Christophe Caux,2,3 Bertrand Dubois,2,3,&ast; Olivier Trédan1,2,&ast; 1Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 2Inserm U1052, CNRS 5286, Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, Lyon, France; 3Laboratory of Cancer Immunotherapy of LYON (LICL), Centre Léon Bérard, Lyon, France; 4Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France; 5Department of Medical Oncology, Hôpital Privé Jean-Mermoz, Lyon, France; 6Department of Medical Oncology, Institut de Cancérologie de L’ouest- Paul Papin, Angers, France; 7Biopathology Department, Centre Léon Bérard, Lyon, France; 8Genomic of Cancer Platform, Centre Léon Bérard, Lyon, France; 9Gilles Thomas Bioinformatics Platform, Synergie Lyon Cancer Foundation, Centre Léon Bérard, Lyon, France&ast;These authors contributed equally to this workCorrespondence: Benoîte Mery, Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laennec, Lyon, 69008, France, Tel +33 4 78 78 26 44, Fax +33 4 78 78 27 15, Email Benoite.mery@lyon.unicancer.frPurpose: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide.Experimental Design: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon’s minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS).Results: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4+ T cells and higher CD8+ T cells to macrophage ratios in the tumor. This impact on CD4+ and CD8+ T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4+ and CD8+ memory T cells was observed in other patients.Conclusion: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.Keywords: metastatic breast cancer, lymphopenia, immunotherapy, chemotherapy, immunomonitoring

Cabozantinib is an inhibitor of multiple tyrosine kinases, including AXL, MET and VEGF receptors. Here, we describe the rationale and design for the phase II CaboPoint trial (ClinicalTrials.gov identifier: NCT03945773), which will evaluate the efficacy and safety of cabozantinib as a second-line treatment in patients with unresectable, locally advanced or metastatic renal cell carcinoma whose disease has progressed despite checkpoint inhibitor therapy. Patients will be recruited into two cohorts: prior ipilimumab plus nivolumab (cohort A) or prior checkpoint inhibitor-VEGF-targeted therapy (cohort B). All patients will receive once-daily oral cabozantinib 60 mg for up to 18 months. The primary end point is objective response rate. Secondary end points include overall survival, progression-free survival and safety.Most patients diagnosed with kidney cancer have a type of tumor called renal cell carcinoma (RCC). Most cases of RCC are described as ‘clear cell’ because the tumor cells appear clear when viewed under a microscope. Cabozantinib is an oral treatment approved for use in some patients with advanced RCC, including those with clear cell disease. Cabozantinib slows RCC progression by targeting pathways that help tumors grow, including inhibition of VEGF. The ongoing CaboPoint study will assess the efficacy and safety of cabozantinib in patients with clear cell RCC that has progressed despite previous anticancer treatment involving an immune checkpoint inhibitor (CPI). CPI therapy helps the body to detect tumors and to launch its own anticancer response. Patients included in CaboPoint must be adults with clear cell RCC that is not suitable for surgery and has either spread within the kidney or to other organs, despite previous CPI-based therapy. In total, 250 patients will be recruited: 125 who received previous combination CPI treatment (ipilimumab plus nivolumab; group A) and 125 who received previous CPI treatment plus anti-VEGF therapy (group B). Patients will start cabozantinib at a dose of 60 mg/day and continue treatment for up to 18 months. The main outcome to be studied will be the number of patients with a reduction in tumor size (objective response rate). The length of time patients live with their disease, the effect of treatment on symptoms and patient safety will also be evaluated. Clinical trial registration: NCT03945773 (ClinicalTrials.gov).

Patients with cancer are at high risk of severe or lethal COVID-19. The impact of SARS-COV-2 vaccination on the risk of developing COVID-19 was investigated in an exhaustive series of patients from a comprehensive cancer center.This is a study of the exhaustive population of 2391 cancer patients who were prescribed SARS-COV-2 vaccination until 09/21. Patient characteristics, documented SARS-COV-2 infection with RT-PCR, and survival were collected. The primary endpoint was the rate of COVID-19 after vaccination. Secondary endpoints included risk factors to develop COVID-19 after vaccination, with a comparison with the cohort of vaccinated health care workers (HCW), and risk factors for death.From January to September 2021, among 2391 patients with cancer under active treatment in whom a SARS-COV-2 vaccine was prescribed, 659 (28%), 1498 (63%) and 139 (6%) received 1, 2, and 3 doses, respectively. Ninety five patients received a single dose of vaccine after a previous COVID-19. Two thousand two hundred eighty five health care workers (HCW) received one (N = 17, 0.7%), 2-3 (N = 2026, 88.7%) vaccine doses and one dose after COVID-19 (N = 242, 10.6%). With a median follow-up of 142 and 199 days for patients and HCW, respectively. Thirty nine (1.6%) patients and 35 (1.5%) HCW developed COVID-19 after vaccination. Six of 39 cancer patients and no HCW died because ofCOVID-19 within 50 days after diagnosis. Independent risk factors for COVID-19 in vaccinated patients were age, single dose of vaccine without previous COVID-19 and anti-CD20 treatment in the last three months. Independent risk factors for death included metastatic disease, gender, cancer type, but also documented COVID-19 before vaccination.Patients receiving two or more doses of COVID-19 vaccine have reduced risk of COVID-19. The risk of death of vaccinated cancer patients presenting COVID-19 remains high. COVID-19 before vaccination is associated with an increased overall risk of death.

La médecine moléculaire du cancer s’appuie sur l’identification d’anomalies génomique de l’ADN des cellules tumorales, permettant de guider le traitement des patients, en choisissant des inhibiteurs agissant sur les protéines mutées codées par les gènes mutés. Cependant, on assiste depuis 10 ans à l’émergence très rapide d’un nouveau corpus de connaissance décrivant les anomalies génomiques des cellules cancéreuses au sein des programmes internationaux comme ICGC ou TCGA, permettant de déboucher sur de nouvelles classifications nosologiques mais démontrant aussi l’extrème complexité et variabilité clonale des cellules cancéreuses chez le patient humain. Il s’agit désormais d’utiliser ces données nouvelles de manière efficace. Ceci requiert la constitution de plateformes de diagnostic explorant progressivement avec une plus grande profondeur les anomalies moléculaire de chaque patient individuel, et l’organisation de réunions de concertation pluridisciplinaires moléculaire permettant d’intégrer ces données au contexte clinique et global du patient, et requérant la contribution croissante des bio-informaticiens. Ce court article fait le point sur l’évolution de cette médecine moléculaire.

Background: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of NCL and whether NCL stratified cancer patients. Here, we have investigated for the first time the association of NCL with clinical characteristics in breast cancers independently of the different subtypes. Methods: Using two independent series (n = 216; n = 661), we evaluated the prognostic value of NCL in non-metastatic breast cancers using univariate and/or multivariate Cox-regression analyses. Results: We reported that NCL mRNA expression levels are markers of poor survivals independently of tumour size and lymph node invasion status (n = 216). In addition, an association of NCL expression levels with poor survival was observed in TNBC (n = 40, overall survival (OS) p = 0.0287, disease-free survival (DFS) p = 0.0194). Transcriptomic analyses issued from The Cancer Genome Atlas (TCGA) database (n = 661) revealed that breast tumours expressing either low or high NCL mRNA expression levels exhibit different gene expression profiles. These data suggest that tumours expressing high NCL mRNA levels are different from those expressing low NCL mRNA levels. Conclusions: NCL is an independent marker of prognosis in breast cancers. We anticipated that anti-NCL is a promising therapeutic strategy that could rapidly be evaluated in high NCL-expressing tumours to improve breast cancer management.

Introduction Les donnees de vraie vie (RWD) ont un role important pour l’evaluation de l’efficience des medicaments et des strategies therapeutiques, et ce en complement des donnees provenant des essais cliniques controles. La methodologie de constitution de la plateforme de RWD ESME repose sur une approche multi sources pour centraliser et standardiser les donnees nationales relatives a la prise en charge (PEC) des patients dans les 18 centres de lutte contre le cancer. Methodes La plateforme ESME, geree par R&D Unicancer, integre des variables issues de bases de donnees structurees (donnees relatives aux sejours hospitaliers et donnees sur les medicaments dispenses dans les centres), ainsi que des donnees non structurees issues du dossier patient informatise (DPI). L’integration des donnees du DPI implique une relecture systematique par des techniciens d’etudes cliniques specifiquement formes, tenant compte si disponibles des donnees des bases locales (donnees des bases RCP, donnees issues de l’enquete permanente cancer si poursuivie…). La plateforme pour laquelle la gestion de l’anonymat est geree centre par centre, regroupe l’ensemble des donnees anonymisees consolidees des differentes sources. Cette methodologie fait l’objet de controles qualite, d’audit interne sur le recueil et de constitution de listes de preselection, ainsi que de controles de data-management systematiques. Les donnees collectees sont mises a jour annuellement et la plateforme integre les donnees des patients nouvellement diagnostiques. Resultats et discussion Le premier volet de ce programme concerne la plateforme ESME « Cancer du sein metastatique » (CSM) pour laquelle les dossiers de 16 736 patients ont ete selectionnes et valides. L’objectif final est de 25 000 dossiers completes valides attendus d’ici 2019. Il etait important de pouvoir capter les patients PEC pour un CSM non hospitalises et ne recevant pas de traitement dans le centre. Environ 12 % ont ainsi ete identifies comme etant exclusivement pris en charge par des therapies orales ou hormonotherapie avec un suivi en consultation dans les centres. Le controle qualite (CQ) sur site du processus de selection a ete realise chez environ 20 % des dossiers non selectionnes, et 13 % des dossiers selectionnes ont ete controles manuellement pour certains criteres majeurs. Ces criteres seront detailles avec les taux d’erreurs par critere et leurs implications pour l’exploitation des donnees. La plateforme ESME constitue une source unique en Europe de donnees en vie reelle pour la PEC du CSM. Elle est accessible a l’interrogation par des equipes de recherche ou des partenaires industriels, apres validation des questions de recherche par le comite scientifique ESME (CSE), sous le controle d’un comite de deontologie et d’un comite consultatif international (dix projets de recherche sont actuellement en cours). Conclusion La plateforme ESME constituera a terme une source unique et independante d’analyse de donnees dans une grande variete de pathologies d’organes ou de domaines therapeutiques en oncologie. Elle pourra contribuer a une meilleure comprehension de l’utilisation des strategies therapeutiques en vraie vie ainsi que leurs determinants. Ces donnees peuvent guider la communaute scientifique vers une prise de decision adaptee au contexte et ameliorer la PEC du patient en oncologie.

Objective Telomeres are protected by tightly regulated factors and elongated by telomerase. Short and/or deprotected chromosomes are recombinogenic and thereby cancer prone. Materials and Methods Together with the quantification of telomerase activity (TA), measuring telomere length (TL) and expression of the genes that govern telomere protection and elongation are useful for assessing telomere homeostasis. Results By these means we demonstrate that TL, hTERT , and TA are in the order acute myelogenous leukemia (AML) > T-cell acute lymphoblastic leukemia (T-ALL) > B-cell acute lymphoblastic leukemia (B-ALL) > T-ALL > AML, and B-ALL > AML > T-ALL. AML0 and AML3 display the lowest amounts of hTERT transcripts, and ALL and AML cells with cytogenetic abnormalities possess the shortest telomeres. hTERT expression includes phenotype-specific RNA maturation and correlates with TA but not with TL. A wide ratio of TA to hTERT expression between leukemia subtypes suggests phenotype-specific hTERT post-transcriptional deregulations. B- and T-ALL overexpress Ku70 and Pinx1, T-ALL PTOP and RAP1 , and B-ALL TRF2 , the expression of which is significantly higher in cases with abnormal karyotype. hTERT transcription and TL correlate with response to intensive chemotherapy, and hTERT and RAD50 are independent prognostic factors for survival. Conclusions Each leukemia subtype possesses specific telomere dysregulations that rely on phenotype, karyotype, response to treatment, and survival.

The decision-making bodies of the University Claude Bernard Lyon 1 (UCBL) established a Health Observatory - OSPEL (Observatory of Health Personnel, University of Lyon 1) whose mission is to report epidemiological results on the health of university staff. An initial study had the following objectives: 1 / identify and collect the health issues and themes that staff wanted to see addressed by OSPEL and 2 / test the survey methodology through self-administered questionnaire via Internet from a representative sample of UCBL staff. In December 2008, a sample of 15% of the professional population of the university (n = 694) was invited by e-mail to answer a self-administered questionnaire available on the Internet. A sample of 607 people received this e-mail and 242 staff responded (39.9% rate of participation). A weight was factored in and applied to responses to redress the sample base of respondents and render it representative of the professional population at UCBL. Respondents chose three priority themes, "Quality of Life - Overall Health ? Well-being, "Mental Health-Stress" and "Occupational Risks" as the primary topics to be addressed by OSPEL. Respondents were predominantly women (63.5%), administrative and technical staff (56.8%), as well as professors (77.3%). The interest of this study is centered on the reactivity and the ubiquity of the Internet / Intranet methodology which facilitated the targeted collection of the health expectations of university staff. This survey is a first step in the development of more focused epidemiological investigations in line with the expectations of UCBL staff. Future surveys should consider the physical and temporal constraints suggested in this study.

BACKGROUND The objective of this report was to estimate long-term outcome and prognostic factors in children and adolescents who presented with metastatic osteosarcoma at diagnosis. Patients were treated in six French pediatric oncology centers with surgery and multiagent chemotherapy, mainly with high-dose methotrexate. Their medical records were reviewed retrospectively. METHODS The medical records of patients who were treated for metastatic osteosarcoma from 1987 to 2000 were reviewed. Patients were treated with the chemotherapy regimens recommended for nonmetastatic disease in children (the French Society of Pediatric Oncology OS 87 and OS 94 protocols) or, in a few patients, with other chemotherapy regimens. Surgical excision of the primary tumor and, when possible, of all metastatic sites was performed based on a personalized assessment of each patient's situation. RESULTS Seventy-eight patients age < 20 years were treated. Forty-six patients (59%) had only 1 metastatic site (35 to the lungs and 11 to bone). Twenty-eight patients (36%) achieved a complete remission after combination chemotherapy and surgery. The event-free survival and overall survival rates at 5 years were 14% and 19%, respectively. To date, 14 patients (18%) have remained alive with a median follow-up of 112 months. Pretreatment features associated with a shorter event-free survival in the multivariate analysis were metastasis to at least two organs and high alkaline phosphatase level. Patients with at least 1 of these poor prognostic factors had a 2.6% event-free survival rate at 5 years despite treatment. CONCLUSIONS The survival of patients with metastatic osteosarcoma were treated with conventional chemotherapy and surgery remained very poor. Patients should be classified into different prognostic groups and treated accordingly. New therapeutic approaches are warranted to improve the prognosis for patients with the most severe disease. Cancer 2005. © 2005 American Cancer Society.

The preferences of advanced cancer patients and the impact of cancer management on relatives remain partly unknown. We present the preliminary results of a prospective study evaluating quality of care (QC), quality of life (QoL) and family impact (FI) in advanced cancer patients treated at home or in hospital, depending on their own choice. QC is evaluated using STAS questionnaire, and QoL and symptom control using EORTC QLQ-C30, Spielberger questionnaire and VAS for pain evaluation. FI is evaluated using GHQ28 and semi-structured interviews conducted at days 0, 15, 30, then monthly until death. Intermediate analysis of 52 patients (100 expected) of whom 63 % had chosen home care, 26 % in-hospital care. Actual assignment is home care: 56 %, in-hospital care: 44 %. Place of death is home: 15 %, hospital: 85 %. In the QC study, the two symptoms most frequently rated by nurses are anxiety and pain, in either group. Patient information and communication are also similar in both groups. The QoL and symptom study shows that patients also rate pain as frequent (84 %) but moderate (mean VAS score 2.5/10). However, the most frequent symptom is fatigue (100 %). Anxiety is rated higher at hospital, as well as FI (anxiety, insomnia, social dysfunction and global score). Palliative care research is sometimes difficult but feasible. In this study, most patients prefer home care. Anxiety and FI seem lower at home. However, re-hospitalisations just before death are frequent and death generally occurs in hospital.

Purpose Few clinical prognostic factors have been identified for patients with metastatic renal cell carcinoma (MRCC), and no biomarker is known in this disease. Several endogenous cytokines have demonstrated interesting and significant correlations with survival in these patients. Our objective was to analyze the prognostic value of circulating vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and interleukin-6 (IL-6). Patients and Methods Serum levels of IL-6, IL-10, and VEGF were measured in patients with MRCC. Their prognostic value for response to treatment and progression-free and overall survival was evaluated. Pretreatment samples were obtained from 138 patients of a large randomized multicentric trial. Endogenous cytokine levels were determined using immunoassays. Univariate and multivariate analyses were performed to evaluate the prognostic value of each factor further controlled by an internal validation test. Threshold values for serum IL-6 and VEGF were determined using the quartile method. Results Serum IL-6 was detectable in 70% of the patients. IL-10 and VEGF were elevated in 8% and 71% of the patients, respectively. None of these circulating factors was correlated with response to treatment. IL-10 was not significantly correlated with progression-free or overall survival. Despite significant correlation with survival, VEGF was not an independent prognostic factor in the multivariate analysis. Finally, IL-6 was significantly correlated with progression-free survival and overall survival, and has prognostic value for overall survival. Conclusion Circulating IL-6 level appears to be an important independent prognostic factor in patients with MRCC; if confirmed in further studies, it could be considered for treatment decisions in these patients.

// Xiaojun Jiang 1 , Daniel Pissaloux 1 , Christelle De La Fouchardiere 2 , Francoise Desseigne 2 , Qing Wang 1 , Valery Attignon 1 , Marie-Eve Fondrevelle 5 , Arnaud De La Fouchardiere 5 , Maurice Perol 2 , Philippe Cassier 2 , Christelle Seigne 3 , David Perol 3 , Isabelle Ray-Coquard 2 , Pierre Meeus 4 , Jerome Fayette 2 , Aude Flechon 2 , Axel Le Cesne 7 , Nicolas Penel 6 , Olivier Tredan 2 , Jean-Yves Blay 1, 2 1 Department of Translational Research, Centre Leon Berard, 69008 Lyon France 2 Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France 3 Department of Clinical Research, Centre Leon Berard, 69008 Lyon France 4 Department of Surgery, Centre Leon Berard, 69008 Lyon France 5 Department of Pathobiology, Centre Leon Berard, 69008 Lyon France 6 Department of Medical Oncology, Centre Oscar Lambret, 59020 Lille France 7 Department of Medical Oncology, Gustave Roussy, 94805, Villejuif France Correspondence to: Xiaojun Jiang, e-mail: xiaojun.jiang@lyon.unicancer.fr Jean-Yves Blay, e-mail: jean-yves.blay@lyon.unicancer.fr Keywords: multi-kinase inhibitor, biomarker, regorafenib, chromosomal instability Received: May 06, 2015 Accepted: July 09, 2015 Published: July 21, 2015 ABSTRACT Validated predictive biomarkers for multi-tyrosine kinase inhibitors (MTKI) efficacy are lacking. We hypothesized that interindividual response variability is partially dependent on somatic DNA copy number alterations (SCNAs), particularly those of genes encoding the protein tyrosines targeted by MTKI (called target genes). Genomic alterations were investigated in MTKI responsive and non responsive patients with different histological subtypes included in the ProfiLER protocol (NCT 01774409). From March 2013 to August 2014, 58 patients with advanced cancer treated with one of 7 MTKIs were included in the ProfiLER trial and split into one discovery cohort ( n = 13), and 2 validation cohorts ( n = 12 and 33). An analysis of the copy number alterations of kinase-coding genes for each of 7 MTKIs was conducted. A prediction algorithm (SUMSCAN) based on the presence of specific gene gains (Tumor Target Charge, TTC) and losses (Tumor Target Losses, TTL) was conceived and validated in 2 independent validation cohorts. MTKI sensitive tumors present a characteristic SCNA profile including a global gain profile, and specific gains for target genes while MTKI resistant tumors present the opposite. SUMSCAN favorable patients achieved longer progression-free and overall survival. This work shows that the copy number sum of kinase-coding genes enables the prediction of response of cancer patients to MTKI, opening a novel paradigm for the treatment selection of these patients.

Introduction: We previously showed that T ( Methods: Lymphocytes, NK, monocytes and DC subpopulations quantification and functional competence after reactivation (PMA/ionomycin, TLR7/8-Ligand) were assessed by multiparametric flow-cytometry (surface markers/ intracytoplasmic cytokines) on fresh whole blood (D0, D21, D57, D78, EOS). Impact of CYT107 treatment before (D0-D21) or during (D57-D78) chemotherapy on immune parameters was assessed. Results: At inclusion, 20 patients presented strong quantitative alteration of all lymphocytes subsets compared to a healthy donor women cohort (n=30). Inflammatory monocytes (infl-Mo) and DC subsets were quantitatively reduced. CD4 CD45R0+ T (IFNγ/IL-2), Tγδ cells and NK (IFNγ) cytokine productions were altered independently of quantitative alterations highlighting the importance to assess both. Pre-chemotherapy, CYT107 significantly increased CD3 T cell absolute number (median relative evolution: CYT107+128.5%[39;606cells/µL] vs placebo +1.6%[-34;85cells/µL], p=0.002) involving both CD4 (p=0.002) or CD8 (p=0.006) T cells and naïve (CD4:p=0.005 and CD8:p Conclusion: CYT107 administered before chemotherapy, increases all T cell subsets absolute number but no other compartments without affecting their functional responses. Interestingly, during chemotherapy, CYT107 induces an increase of CD8 memory cells, known to play a role in long lasting defense against tumors. Citation Format: Christine Menetrier-Caux, Isabelle Ray-Coquard, Claire Cropet, Estelle Verronese, Thomas Bachelot, Olivier Tredan, Gwenaelle Garin, Pierre Heudel, Axelle N'Kodia, Ana Delgado, Christine Bardin-Dit-Courageot, Chantal Rigal, Gilles Clapisson, Sylvie Chabaud, David Perol, Paul Rebattu, Thérèse Croughs, Nicolas Pasqual, Manuarii Manuel, Michel Morre, Jean-Yves Blay, Christophe Caux. Interleukin-7 (CYT107) treatment in lymphopenic 1st line metastatic breast carcinoma patients treated with chemotherapy regimen (Capecitabine) favors the restoration of T-cell subsets number. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2574. doi:10.1158/1538-7445.AM2014-2574