***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND To examine the impact of a frequent her2 gene polymorphism ( Ile655Val ) on tumor growth and on the pharmacodynamics of treatment by trastuzumab . PATIENTS AND METHODS Experimental study : The growth characteristics of cells expressing the Ile or Val isoform were examined in vitro and after injection into nude mice . The effect of trastuzumab was determined in both experimental models . Clinical study : 61 patients with advanced breast cancers and treated by trastuzumab  were genotyped for HER2 by PCR-RFLP . The influence of HER2 genotype on the trastuzumab treatment was examined . RESULTS Experimental study : HER2-expressing cells acquired the characteristics of tumor cells . The Val isoform-expressing cells showed the highest growth capacity and developed aggressive tumors sensitive to trastuzumab . Clinical study : There was no link between tumor response or survival and HER2 genotype . All cases of treatment-related cardiotoxicity were found in the Ile/Val group and there was no cardiac toxicity in the Val/Val and Ile/Ile patients . CONCLUSIONS This study establishes a clear-cut difference between the two HER2 isoforms regarding their tumorogenic potential with an advantage for the Val/HER2 isoform . In breast cancer patients treated with trastuzumab  , the presence of a Val allele may constitute a risk factor for cardiac toxicity Abstract The aim of this prospect i ve clinical study is to evaluate the relationship between changes in functional cardiac parameters following anthracycline therapy and carbonyl reductase 3 ( CBR3p . V244 M ) and glutathione S transferase Pi ( GSTP1p . I105V ) polymorphisms . Seventy patients with normal cardiac function and no history of cardiac disease scheduled to undergo anthracycline chemotherapy were included in the study . The patients ’ cardiac function was evaluated by gated blood pool scintigraphy and echocardiography before and after chemotherapy , as well as 1 year following therapy . Gene polymorphisms were genotyped in 70 patients using TaqMan probes , vali date d by DNA sequencing . A deteriorating trend was observed in both systolic and diastolic parameters from GG to AA in CBR3p . V244 M polymorphism . Patients with G-allele carriers of GSTP1p . I105V polymorphism were common ( 60 % ) , with significantly decreased PFR compared to patiens with AA genotype . Variants of CBR3 and GSTP1 enzymes may be associated with changes in short-term functional cardiac parameters BACKGROUND The involvement of iron in anthracycline cardiotoxicity is supported by extensive experimental data , and by the preventive efficacy of dexrazoxane , an iron chelator . However , no clinical evidence of anthracycline-induced cardiac iron accumulation is available and the influence of previous iron overload or of genetic factors in human-induced heart disease is largely unknown . Our aim was to test the hypothesis that anthracyclines increase iron heart concentration and that HFE genotype modulates this iron deposit . METHODS We retrospectively evaluated cardiac events , cardiac iron and HFE genotype in 97 consecutive necropsies from patients with solid and hematological neoplasms .  Heart and liver iron concentration was determined by atomic absorption spectroscopy . HFE gene mutations ( C282Y and H63D ) linked to hereditary hemochromatosis were analyzed by Fluorescence Resonance Energy Transfer ( FRET ) genotyping . RESULTS Heart iron concentration was increased in cases treated with a cumulative doxorubicin dose greater than 200mg/m(2 ) ( 490 vs 240 μg/g ; p=0.01 ) , independently of liver iron load or transfusion history . HFE mutated haplotypes 282C/63D ( p=0.049 ) and 282Y/63H ( p=0.027 ) were associated to higher cardiac iron deposits . The haplotype C282Y-Y/H63D-H interacted with anthracyclines for increasing cardiac iron load . In a multivariate linear regression analysis both HFE genotypes and anthracyclines contributed to heart iron concentration ( R(2)=0.284 ) . CONCLUSIONS Our data support the occurrence of an HFE-modulated heart iron accumulation in individuals treated with anthracyclines , independently of systemic iron load . If prospect ively confirmed , iron-related parameters might be useful as predictive factors for anthracycline cardiotoxicity BACKGROUND The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity . Multiple genetic variants predictive of anthracycline-induced cardiotoxicity ( ACT ) in children were recently identified . The current study was aim ed to assess replication of these findings in an independent cohort of children . PROCEDURE . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients . Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort . RESULTS . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort ( P = 0.0062 , odds ratio ( OR ) 7.98 ) . Additional evidence for association of rs7853758 ( P = 0.058 , OR 0.46 ) and rs885004 ( P = 0.058 , OR 0.42 ) in SLC28A3 was found ( combined P = 1.6 × 10(-5 ) and P = 3.0 × 10(-5 ) , respectively ) . A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone . However , an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original ( AUC 0.77 vs. 0.68 , P = 0.0031 ) and replication cohort ( AUC 0.77 vs. 0.69 , P = 0.060 ) . CONCLUSIONS . We vali date d genetic variants in two genes predictive of ACT in an independent cohort . A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options Background Anthracyclines are important chemotherapeutic agents , but their use is limited by cardiotoxicity . C and i date gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure , but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular ( LV ) function . The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy . Methods We conducted a genome-wide association study ( GWAS ) of change in LV function after anthracycline exposure in 385 patients identified from BioVU , a re source linking DNA sample s to de-identified electronic medical record data . Variants with P values less than 1 × 10−5 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospect i ve clinical trial . Pathway analysis was performed to assess combined effects of multiple genetic variants . Results Both cohorts were middle-aged adults of predominantly European descent . Among 11 c and i date loci identified in discovery GWAS , one single nucleotide polymorphism near PR domain containing 2 , with ZNF domain ( PRDM2 ) , rs7542939 , had a combined P value of 6.5 × 10−7 in meta- analysis . Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome . Identified pathways related to DNA repair , cellular metabolism , and cardiac remodeling . Conclusion Using genome-wide association we identified a novel c and i date susceptibility locus near PRDM2 . Variation in genes belonging to pathways related to DNA repair , metabolism , and cardiac remodeling may influence changes in LV function after anthracycline exposure PURPOSE This study sought to estimate cardiac dysfunction ( CD ) risk for patients receiving trastuzumab ;  to characterize observed CD by severity , treatment , and clinical outcome ; to assess effects of baseline clinical risk factors on CD ; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD . PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed . Predefined criteria were used for the diagnosis , and the New York Heart Association functional classification system was used to document CD severity . Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset . RESULTS Patients treated with trastuzumab  were found to be at an increased risk for CD . The incidence was greatest in patients receiving concomitant  trastuzumab and anthracycline plus cyclophosphamide ( 27 % ) . The risk was substantially lower in patients receiving paclitaxel and trastuzumab ( 13 % ) or trastuzumab alone ( 3 % to 7 % ) ; however , most of these patients had received prior anthracycline therapy . CD was noted in 8 % of patients receiving anthracycline plus cyclophosphamide and 1 % receiving paclitaxel alone . Most trastuzumab-treated patients developing CD were symptomatic ( 75 % ) , and most improved with st and ard treatment for congestive heart failure ( 79 % ) . CONCLUSION Trastuzumab is associated with an increased risk of CD , which is greatest in patients receiving concurrent anthracyclines . In most patients with metastatic breast cancer , the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab The purpose of this study was to investigate , in the context of a prospect i ve node-positive-breast cancer trial HER2 containing-regimen ( UNICANCER-PACS 04 trial ) , the predictive value of HER2 , FCGRIIA , and FCGRIIIA gene polymorphisms for cardiac toxicity and efficacy of trastuzumab . We analyzed HER2–I655V , FCGR2A – H131R , and FCGR3A – V158F single nucleotide polymorphisms in patients in adjuvant setting treated by six courses of either  fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 , or epirubicin 75 mg/m2 and docetaxel 75 mg/m2 every 3 weeks then r and omly assigned , in case of HER2 overexpressing tumor , to either trastuzumab for 1 year or nothing . Left ventricular ejection fraction and clinical examination were monitored in each patient , seven times throughout the study to detect congestive heart failure or asymptomatic sub clinical cardiac toxicity . All genotypes were analyzed in relation to cardiac toxicity , EFS , and OS .  One hundred and thirty-two HER2-positive breast cancer patients were analyzed . The HER2–I655V genotype was significantly associated with cardiac toxicity ( p = 0.025 ) . The FCGR2A-131 H/H genotype was significantly correlated with a shorter EFS ( p = 0.027 ) . The FCGR3A-158 V/V genotype was not correlated with EFS nor OS . These results might be useful in making a treatment choice of HER2 blockers in adjuvant setting by with an increase in efficacy and decrease in toxicity IMPORTANCE This is the first r and omized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects . OBJECTIVE To determine as the primary end point whether angiotensin II antagonist treatment with c and esartan can prevent or ameliorate trastuzumab-related cardiotoxic effects , defined as a decline in left ventricular ejection fraction ( LVEF ) of more than 15 % or a decrease below the absolute value 45 % . DESIGN This r and omized , placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherl and s , enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 ( HER2 ) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab . INTERVENTIONS A total of 78 weeks of c and esartan ( 32 mg/d ) or placebo treatment ; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment . MAIN OUTCOMES AND MEASURES The primary outcome was LVEF . Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide ( NT-proBNP ) and high-sensitivity troponin T ( hs-TnT ) can be used as surrogate markers and whether genetic variability in germline ERBB2 ( formerly HER2 or HER2/neu ) correlates with trastuzumab-related cardiotoxic effects . RESULTS A total of 206 participants were evaluable ( mean age , 49 years ; age range , 25 - 69 years ) 103 in the c and esartan group ( mean age , 50 years ; age range , 25 - 69 years ) and 103 in the placebo group ( mean age , 50 years ; age range , 30 - 67 years ) . Of these , 36 manifested 
    Output:
    
Existing evidence supports the hypothesis that genetic variation contributes to chemotherapy-related cardiac dysfunction .