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Claudia De Lorenzo,1,2,* Rolando Paciello,1,2,* Gennaro Riccio,3 Domenica Rea,4 Antonio Barbieri,4 Carmela Coppola,4 Nicola Maurea4 1Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Naples, Italy; 2Ceinge, Biotecnologie Avanzate s.c.a.r.l., Naples, Italy; 3Department of Pharmacy, Federico II University, Naples, Italy; 4Division of Cardiology, Istituto Nazionale Tumori – Irccs Fondazione G. Pascale, Naples, Italy *These authors contributed equally to this work Purpose: Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody–drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity.Methods: The cardiotoxic effects were tested in vitro on rat cardiomyoblasts, human fetal cardiomyocytes, adult-like cardiomyocytes, and in vivo on a mouse model.Results: All the treated cardiac cell lines were significantly affected by treatment with the tested drugs. Surprisingly, TDM1 showed stronger inhibitory effects on cardiac cells with respect to trastuzumab and pertuzumab by more significantly reducing the cell viability and by changing the morphology of these cells. TDM1 also affected the beating phenotype of adult-like cardiomyocytes in vitro and reduced fractional shortening and ejection fraction in vivo in a mouse model. We also found that ranolazine attenuated not only the cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments both in vitro and in vivo, as demonstrated by the recovery of fractional shortening and ejection fraction values in mice pretreated with TDM1.Conclusion: We demonstrated that it is possible to predict the eventual cardiotoxic effects of novel approved anticancer drugs early by using in vitro and in vivo approaches, which can also be useful to screen in advance the cardioprotective agents, so as to avoid the onset of unwanted cardiotoxic side effects. Keywords: breast cancer, immunotherapy, pertuzumab, trastuzumab-DM1, ranolazine

Sabrina Bimonte,1,* Antonio Barbieri,2,* Marco Cascella,1,* Domenica Rea,2,* Giuseppe Palma,2 Vitale Del Vecchio,2 Cira Antonietta Forte,1 Francesco Del Prato,1 Claudio Arra,1 Arturo Cuomo2 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale”, 2Animal Facility Unit, Department of Research, National Cancer Institute “G. Pascale”, Naples, Italy *These authors contributed equally tothis work Background: Naloxone is viewed as a specific competitive opioid antagonist acting at the level of opioid receptors (µ, δ, and κ) with blended agonist-adversary or agonist action. The role of naloxone in tumor cell growth has been poorly studied in human cancer cell lines.Materials and methods: In the present study, we report findings from in vitro and in vivo experiments performed to evaluate the effects of naloxone on human breast cancer cell growth and progression. In vitro assays were conducted on estrogen receptor-negative human breast carcinoma cells, MDA.MB231, treated with naloxone at different concentrations (10–100 µM). In vivo experiments were performed on a mouse model of human triple-negative breast cancer generated by using MDA.MB231 injected subcutaneously in mice. Naloxone was daily intraperitoneally injected in mice at 0.357 mg/kg for 2 weeks and at 0.714 mg/kg for the next 2 weeks. Microvessels formation was detected by fluorescein isothiocyanate-dextran (100 µL) injected into the tail vein of mice and confirmed by immunohistochemistry with CD31 on mice tumor sections.Results: In vitro tests showed that the cell proliferation of MDA.MB231 was inhibited by naloxone in a dose-dependent manner, whereas the cell death was increased. In vivo studies demonstrated that tumors of mice treated with naloxone were significantly smaller than those observed in the control groups, as long as naloxone was administered. Finally, naloxone was not able to impair the microvessel formation in tumors of treated mice.Conclusion: Our data showed, for the first time, that naloxone reduced breast cancer progression without affecting angiogenesis. Keywords: naloxone, breast cancer, proliferation, microvessel formation, angiogenesis

Atypical chronic myeloid leukemia (aCML) is a clonal disorder belonging to the myelodysplastic/myeloproliferative syndromes. About 13% of aCML cases carry somatic mutations in ETNK1 gene, encoding for H243Y, N244S, and G245V substitutions. We previously showed that ETNK1 mutations cause a decreased catalytic activity of the enzyme. Despite this evidence however, their oncogenic role remained largely unexplained. Since ETNK1 activity is essential for the synthesis of phosphatidylethanolamine (PE) and given that PE is one of the most abundant phospholipids in the inner membrane of mitochondria, we focused our attention on mitochondrial activity. In order to characterize the oncogenic effect of ETNK1 variants we generated CRISPR/Cas9 clones carrying heterozygous N244S mutation and homozygous ETNK1 deletion (KO cells) on the 293 Flp-In™ cell-line. Both N244S and KO cells showed a significant increase in mitochondrial activity (1.78 and 2.13 fold increase, respectively; p= 0.0096 and p=0.0050) compared to WT, as assessed by MitoTracker™ Red. In line with this finding, electron microscopy revealed a significant modification in mitochondria morphology for N244S and KO cells, changing from an elongated, tubular shape to a round, swollen one. ATP (1.67 and 1.68 fold; p

Policy decisions regarding breast cancer screening and treatment programmes may be misplaced unless the decision process includes the appropriate utilities and disutilities of mammography screening and its sequelae. The objectives of this study were to critically review how economic evaluations have valued the health states associated with breast cancer screening, and appraise the primary evidence informing health state utility values (cardinal measures of quality of life). A systematic review was conducted up to September 2018 of studies that elicited or used utilities relevant to mammography screening. The methods used to elicit utilities and the quality of the reported values were tabulated and analysed narratively. 40 economic evaluations of breast cancer screening programmes and 10 primary studies measuring utilities for health states associated with mammography were reviewed in full. The economic evaluations made different assumptions about the measures used, duration applied and the sequalae included in each health state. 22 evaluations referenced utilities based on assumptions or used measures that were not methodologically appropriate. There was significant heterogeneity in the utilities generated by the 10 primary studies, including the methods and population used to derive them. No study asked women to explicitly consider the risk of overdiagnosis when valuing the health states described. Utilities informing breast screening policy are restricted in their ability to reflect the full benefits and harms. Evaluating the true cost-effectiveness of breast cancer screening will remain problematic, unless the methodological challenges associated with valuing the disutilities of screening are adequately addressed.

Background The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).Findings In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.64, 95% CI 0.52-0.78) and 2-4 (RR 0.80, 0.68-0.93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12.1% vs 14.2%; RR 0.85, 0.75-0.96; 2p=0.009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.74, 0.62-0.89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0.90, 0.81-0.99; 2p=0.045), though the breast cancer mortality reduction was not significant (RR 0.89, 0.78-1.03; 2p=0.11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0.56, 0.46-0.67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8.7% vs 10.1%; 2p=0.015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0.70, 0.64-0.77), but not significantly thereafter (RR 0.93, 0.86-1.01; 2p=0.08). Breast cancer mortality was reduced both while treatments differed (RR 0.79, 0.67-0.92), and subsequently (RR 0.89, 0.81-0.99), and for all periods combined (RR 0.86, 0.80-0.94; 2p=0.0005). All-cause mortality was also reduced (RR 0.88, 0.82-0.94; 2p=0.0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0.4% vs 1.2%; RR 0.33, 0.21-0.51) but more bone fractures (5-year risk 8.2% vs 5.5%; RR 1.42, 1.28-1.57); non-breast-cancer mortality was similar.Interpretation Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments diff er, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Copyright (C) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Open Access article distributed under the terms of CC BY.

Carmela Coppola,1 Gennaro Riccio,1 Antonio Barbieri,2 Maria Gaia Monti,3 Giovanna Piscopo,1 Domenica Rea,2 Claudio Arra,2 Carlo Maurea,1 Claudia De Lorenzo,4,5 Nicola Maurea1 1Division of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 2Animal Facility Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 3Department of Translational Medical Sciences, University Federico II, Naples, Italy; 4Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy; 5CEINGE Biotecnologie Avanzate, Naples, Italy Objective: Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage.Methods: Groups of six mice were injected with trastuzumab or doxorubicin, used either as single agents or in combination. Cardiac function was evaluated by transthoracic echocardiography measurements before and after treatment for 2 or 7 days, by using a Vevo 2100 high-resolution imaging system. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations, such as cardiac fibrosis, apoptosis, capillary density, and inflammatory response.Results: Trastuzumab-related cardiotoxicity was detected early by 2D strain imaging. Radial strain was reduced after 2 days in mice treated with trastuzumab alone (21.2%±8.0% vs 40.5%±4.8% sham; P

Aim: Due to increasing life expectancy, patients with breast cancer remain at risk of dying due to breast cancer over a long time. This study aims to assess the impact of age on breast cancer mortality and other cause mortality 10 years after diagnosis. Methods: Postmenopausal patients with hormone-receptor positive breast cancer were included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. Age at diagnosis was categorised as

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21–34). Molecular relapse-free survival for these patients was 61% (95% CI 57–64) at 6 months and 50% (46–54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (