***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 Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and , to our knowledge , no trial has directly compared the three aromatase inhibitors anastrozole , exemestane , and letrozole . We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer . METHODS FATA-GIM3 is a multicentre , open-label , r and omised , phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer . Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery , any pathological tumour size , and axillary nodal status . Key exclusion criteria were hormone replacement therapy , recurrent or metastatic disease , previous treatment with tamoxifen , and another malignancy in the previous 10 years . Patients were r and omly assigned in an equal ratio to one of six treatment groups : oral anastrozole ( 1 mg per day ) , exemestane ( 25 mg per day ) , or letrozole ( 2·5 mg per day ) tablets upfront for 5 years ( upfront strategy ) or oral tamoxifen ( 20 mg per day ) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years ( switch strategy ) . R and omisation was done by a computerised minimisation procedure stratified for oestrogen receptor , progesterone receptor , and HER2 status ; previous chemotherapy ; and pathological nodal status . Neither the patients nor the physicians were masked to treatment allocation . The primary endpoint was disease-free survival . The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2 % difference in disease-free survival at 5 years . Primary efficacy analyses were done by intention to treat ; safety analyses included all patients for whom at least one safety case report form had been completed . Follow-up is ongoing . This trial is registered with the European Clinical Trials Data base , number 2006 - 004018 - 42 , and Clinical Trials.gov , number NCT00541086 . FINDINGS Between March 9 , 2007 , and July 31 , 2012 , 3697 patients were enrolled into the study . After a median follow-up of 60 months ( IQR 46 - 72 ) , 401 disease-free survival events were reported , including 211 ( 11 % ) of 1850 patients allocated to the switch strategy and 190 ( 10 % ) of 1847 patients allocated to upfront treatment . 5-year disease-free survival was 88·5 % ( 95 % CI 86·7 - 90·0 ) with the switch strategy and 89·8 % ( 88·2 - 91·2 ) with upfront treatment ( hazard ratio 0·89 , 95 % CI 0·73 - 1·08 ; p=0·23 ) . 5-year disease-free survival was 90·0 % ( 95 % CI 87·9 - 91·7 ) with anastrozole ( 124 events ) , 88·0 % ( 85·8 - 89·9 ) with exemestane ( 148 events ) , and 89·4 % ( 87·3 to 91·1 ) with letrozole ( 129 events ; p=0·24 ) . No unexpected serious adverse reactions or treatment-related deaths occurred . Musculoskeletal side-effects were the most frequent grade 3 - 4 events , reported in 130 ( 7 % ) of 1761 patients who received the switch strategy and 128 ( 7 % ) of 1766 patients who received upfront treatment  . Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule ( 924 [ 52 % ] of 1766 patients vs 745 [ 42 % ] of 1761 patients ) . All other grade 3 - 4 adverse events occurred in less than 2 % of patients in either group . INTERPRETATION 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors . None of the three aromatase inhibitors was superior to the others in terms of efficacy . Therefore , patient preference , tolerability , and financial constraints should be considered when deciding the optimal treatment approach in this setting . FUNDING Italian Drug Agency Background : The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity result ing from genetic variation and /or CYP2D6 inhibitor use . Additionally , baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied . Methods : Patients , treated with tamoxifen 20 mg once daily ( QD ) for at least 4 weeks , were classified as phenotypic extensive ( EM ) , intermediate ( IM ) , or poor ( PM ) metabolizer based on their genotype and comedication . In patients with an IM or PM phenotype , the tamoxifen dose was increased to 40 mg QD for 4 weeks . Tamoxifen , 4-OH-tamoxifen , N-desmethyltamoxifen , and endoxifen serum concentrations  were measured at baseline and 4 weeks after the dose increment . Side effects of tamoxifen  were assessed using the vali date d Functional Assessment of Cancer Therapy – Endocrine Symptom subscale ( FACT-ESS-19 ) . Results : The median baseline endoxifen concentration differed between EMs ( 11.4 mcg/L : n = 19 ) , IMs ( 8.3 mcg/L : n = 16 ) , and PMs ( 4.0 mcg/L : n = 7 ) , P = 0.040 .  Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L ( P < 0.001 ) and in 4 PMs from 3.8 to 7.8 mcg/L ( P = 0.001 ) , without influencing median FACT-ESS-19 scores . Conclusions : Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects . The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs . Future studies will clarify the direct effect of endoxifen exposure on  tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficacy PURPOSE Tamoxifen is an effective treatment for metastatic and primary breast cancer and is now being evaluated as a chemoprevention agent in healthy women . Any long-term effects on estrogen-sensitive tissues such as bone may have important therapeutic implication s. METHODS We measured bone mineral density ( BMD ) in the lumbar spine and hip using dual-energy x-ray absorptiometry ( DXA ) in premenopausal and postmenopausal healthy women who participated in our placebo-controlled tamoxifen chemoprevention of breast cancer trial . RESULTS BMD data are now available from 179 women for this analysis . In premenopausal women , BMD decreased progressively in the lumbar spine ( P < .001 ) and in the hip ( P < .05 ) for women on tamoxifen , but not those on placebo . The mean annual loss in lumbar BMD per year over the 3-year study period in tamoxifen-treated compliant women who remained premenopausal throughout the study period was 1.44 % ( 1.88 % calculated on an intent-to-treat basis ) compared with a small gain of 0.24 % per annum for women on placebo ( P < .001 ) . Tamoxifen had the opposite effect in postmenopausal women . The mean annual increase in BMD for women on tamoxifen was 1.17 % in the spine ( P < .005 ) and 1.71 % in the hip ( P < .001 ) compared with a noninsignificant loss for women on placebo . CONCLUSION These results indicate that tamoxifen treatment is associated with a significant loss of BMD in premenopausal women , whereas it prevents bone loss in postmenopausal women . These adverse and beneficial effects of tamoxifen should be considered in the assessment of the therapeutic benefits for both the adjuvant treatment and the chemoprevention of breast cancer BACKGROUND The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ . This report assesses the effect of these drugs on quality of life and symptoms . METHODS The study was done at 333 hospitals in North America . Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were r and omly assigned to receive either tamoxifen ( 20 mg/day ) or anastrazole ( 1 mg/day ) for 5 years , stratified by age ( < 60 years vs ≥60 years ) . Patients and investigators were masked to treatment allocation . Patients completed question naires at baseline and every 6 months thereafter for 6 years . The primary outcomes were SF-12 physical and mental health component scale scores , and vasomotor symptoms ( as per the BCPT symptom scale ) . Secondary outcomes were vaginal symptoms and sexual functioning . Exploratory outcomes were musculoskeletal pain , bladder symptoms , gynaecological symptoms , cognitive symptoms , weight problems , vitality , and depression . We did the analyses by intention to treat , including patients who completed question naires at baseline and at least once during follow-up . This study is registered with Clinical Trials.gov , NCT00053898 . FINDINGS Between Jan 6 , 2003 , and June 15 , 2006 , 3104 patients were enrolled in the study , of whom 1193 were included in the quality -of-life sub study : 601 assigned to tamoxifen and 592 assigned to anastrozole . We detected no significant difference between treatment groups for : physical health scores ( mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole ; p=0·20 ) , mental health scores ( 52·38 vs 51·48 ; p=0·38 ) , energy and fatigue ( 58·34 vs 57·54 ; p=0·86 ) , or symptoms of depression ( 6·19 vs 6·39 ; p=0·46 ) over 5 years . Vasomotor symptoms ( 1·33 vs 1·17 ; p=0·011 ) , difficulty with bladder control ( 0·96 vs 0·80 ; p=0·0002 ) , and gynaecological symptoms ( 0·29 vs 0·18 ; p<0·0001 ) were significantly more severe in the tamoxifen group than in the anastrozole group . Musculoskeletal pain ( 1·50 vs 1·72 ; p=0·0006 ) and vaginal symptoms ( 0·76 vs 0·86 ; p=0·035 ) were significantly worse in the anastrozole group than in the tamoxifen group . Sexual functioning did not differ significantly between the two treatments ( 43·65 vs 45·29 ; p=0·56 ) . Younger age was significantly associated with more severe vasomotor symptoms ( mean severity score 1·45 for age < 60 years vs 0·65 for age ≥60 years ; p=0·0006 ) , vaginal symptoms ( 0·98 vs 0·65 ; p<0·0001 ) , weight problems ( 1·32 vs 1·02 ; p<0·0001 ) , and gynaecological symptoms ( 0·26 vs 0·22 ; p=0·014 ) . INTERPRETATION Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years , decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug . For women younger than 60 years old , treatment decisions might be driven by efficacy ( favouring anastrozole ) ; however , if the side-effects of anastrozole are intolerable , then switching to tamoxifen is a good alternative . FUNDING US National Cancer Institute , AstraZeneca Pharmaceuticals Summary Because treatment for breast cancer may adversely affect skeletal metabolism , we investigated vertebral fracture risk in women with non-metastatic breast cancer . The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population . The incidence of vertebral fracture , however , was nearly five times greater than normal in women from the time of first diagnosis [ odds ratio ( OR ) , 4.7 ; 95 % confidence interval ( 95 % CI ) , 2.3–9.9 ] , and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases ( OR , 22.7 ; 95 % CI , 9.1–57.1 ) . We conclude that vertebral fracture risk is markedly increased in women with breast cancer BACKGROUND Adjuvant tamoxifen therapy is effective for postmenopausal women with endocr 
    Output:
    
Results Although conflicting literature exists , the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment .
Conclusions and recommendations Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER-positive breast cancer patients .