***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 
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    Input: BACKGROUND Three clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results . The overall evidence supports a reduction in the risk of breast cancer , but whether this benefit outweighs the risks and side-effects associated with tamoxifen is unclear . METHODS We undertook a double-blind placebo-controlled r and omised trial of tamoxifen , 20 mg/day for 5 years , in 7152 women aged 35 - 70 years , who were at increased risk of breast cancer . The primary outcome measure was the frequency of breast cancer ( including ductal carcinoma in situ ) . Analyses were by intention to treat after exclusion of 13 women found to have breast cancer at baseline mammography . FINDINGS After median follow-up of 50 months ( IQR 32 - 67 ) , 69 breast cancers had been diagnosed in 3578 women in the tamoxifen group and 101 in 3566 in the placebo group ( risk reduction 32 % [ 95 % CI 8 - 50 ] ; p=0.013 ) . Age , degree of risk , and use of hormone-replacement therapy did not affect the reduction . Endometrial cancer was non-significantly increased ( 11 vs 5 ; p=0.2 ) and thromboembolic events were significantly increased with tamoxifen ( 43 vs 17 ; odds ratio 2.5 [ 1.5 - 4.4 ] , p=0.001 ) , particularly after surgery . There was a significant excess of deaths from all causes in the tamoxifen group ( 25 vs 11 , p=0.028 ) . INTERPRETATION Prophylactic tamoxifen reduces the risk of breast cancer by about a third . Temporary cessation of tamoxifen should be considered and the use of appropriate antithrombotic measures is recommended during and after major surgery or periods of immobilisation . Prophylactic use of tamoxifen is contraindicated in women at high risk of thromboembolic disease . The combined evidence indicates that mortality from non-breast-cancer causes is not increased by tamoxifen . The overall risk to benefit ratio for the use of tamoxifen in prevention is still unclear , and continued follow-up of the current trials is essential BACKGROUND Ipsilateral breast tumor recurrence ( IBTR ) is the most common failure event after lumpectomy for ductal carcinoma in situ ( DCIS ) . We evaluated invasive IBTR ( I-IBTR ) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project ( NSABP ) r and omized trials for DCIS . METHODS In the NSABP B-17 trial ( accrual period : October 1 , 1985 , to December 31 , 1990 ) , patients with localized DCIS were r and omly assigned to the lumpectomy only ( LO , n = 403 ) group or to the  lumpectomy followed by radiotherapy ( LRT , n = 410 ) group . In the NSABP B-24 double-blinded , placebo-controlled trial ( accrual period : May 9 , 1991 , to April 13 , 1994 ) , all accrued patients were r and omly assigned to LRT+ placebo , ( n=900 ) or LRT + tamoxifen ( LRT + TAM , n = 899 ) . Endpoints included I-IBTR , DCIS-IBTR , contralateral breast cancers ( CBC ) , overall and breast cancer-specific survival , and survival after I-IBTR . Median follow-up was 207 months for the B-17 trial ( N = 813 patients ) and 163 months for the B-24 trial ( N = 1799 patients ) . RESULTS Of 490 IBTR events , 263 ( 53.7 % ) were invasive . Radiation reduced I-IBTR by 52 % in the LRT group compared with LO ( B-17 , hazard ratio [ HR ] of risk of I-IBTR = 0.48 , 95 % confidence interval [ CI ] = 0.33 to 0.69 , P < .001 ) . LRT + TAM reduced I-IBTR by 32 % compared with LRT + placebo ( B-24 , HR of risk of I-IBTR = 0.68 , 95 % CI = 0.49 to 0.95 , P = .025 ) . The 15-year cumulative incidence of I-IBTR was 19.4 % for LO , 8.9 % for LRT ( B-17 ) , 10.0 % for LRT + placebo ( B-24 ) , and 8.5 % for LRT + TAM . The 15-year cumulative incidence of all contralateral breast cancers was 10.3 % for LO , 10.2 % for LRT ( B-17 ) , 10.8 % for LRT + placebo ( B-24 ) , and 7.3 % for LRT + TAM . I-IBTR was associated with increased mortality risk ( HR of death = 1.75 , 95 % CI = 1.45 to 2.96 , P < .001 ) , whereas recurrence of DCIS was not . Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer . Among all patients ( with or without I-IBTR ) , the 15-year cumulative incidence of breast cancer death was 3.1 % for LO , 4.7 % for LRT ( B-17 ) , 2.7 % for LRT + placebo ( B-24 ) , and 2.3 % for LRT + TAM . CONCLUSIONS Although I-IBTR increased the risk for breast cancer-related death , radiation therapy and tamoxifen reduced I-IBTR , and long-term prognosis remained excellent after breast-conserving surgery for DCIS BACKGROUND Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates . To reduce this risk positive margins are , therefore , usually excised . Systemic treatment with tamoxifen or chemotherapy reduces local recurrence , along with radiotherapy . However , no studies to date have examined the correlation between chemoendocrine treatment , together with radiotherapy , and local relapse in patients with unexcised involved resection margins , having had breast conservation treatment . PATIENTS AND METHODS The histopathology reports were review ed of 184 patients who were treated from June 1991 to August 1995 within our r and omised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate ( 2 M ) + /- mitomycin-C ( 3 M ) and tamoxifen , used concurrently with radiation following conservation surgical treatment . Histological resection margin was considered positive if ductal carcinoma in situ ( DCIS ) or invasive carcinoma was present microscopically less than 1 mm from the excision margin . RESULTS Although 38 % of patients had unexcised microscopically involved margins , local relapse rate as first site of relapse was only 1.9 % after a median follow up of 57 months . There was no difference in distant relapse ( P = 0.2 ) and survival ( P = 0.5 ) between the positive and negative margins groups . CONCLUSIONS The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with  radiotherapy . Further clinical trials are required We have investigated primary ductal carcinomas in situ ( DCIS ) of the breast and their local recurrences after breast-conserving therapy ( BCT )  for histological characteristics and marker expression . Patients who were r and omized in the EORTC trial 10853 ( wide local excision versus excision plus radiotherapy ) and who developed a local recurrence were identified . Histology was review ed for 116 cases ; oestrogen and progesterone receptor status , and HER2/neu and p53 overexpression were assessed for 71 cases . Comparing the primary DCIS and the invasive or non-invasive recurrence , concordant histology was found in 62 % , and identical marker expression in 63 % . Although 11 % of the recurrences developed at a distance from the primary DCIS , nearly all these showed the same histological and immunohistochemical profile . 5 patients developed well-differentiated DCIS or grade I invasive carcinoma after poorly differentiated DCIS . Although these recurrences occurred in the same quadrant as the primary DCIS , they may be considered as second primary tumours . Only 4 patients developed poorly differentiated DCIS or grade III invasive carcinoma after well differentiated DCIS . We conclude that in most cases the primary DCIS and its local recurrence are related histologically or by marker expression , suggesting that local recurrence usually reflects outgrowth of residual DCIS ; progression of well differentiated DCIS towards poorly differentiated DCIS or grade III invasive carcinoma is a non-frequent event . © 2001 Cancer Research PURPOSE N-(4-hydroxyphenyl ) retinamide ( ¿ 4-HPR , Fenretinide ; R.W. Johnson Pharmaceutical Research Institute , Springhouse , PA ) and tamoxifen ( TAM ) have synergistic antitumor and chemopreventive activity against mammary cancer in pre clinical studies . We performed a pilot study of this combination in women at high risk for developing breast cancer . PATIENTS AND METHODS Thirty-two women were treated with four cycles of 4-HPR , 200 mg orally ( PO ) for 25 days of each 28-day cycle , and TAM , 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone .  Tolerability , dark adaptometry , tissue biopsies , and retinoid plasma concentrations ( Cp ) were evaluated . RESULTS Symptomatic reversible nyctalopia developed in two patients ( 6 % ) on 4-HPR , but 16 ( 73 % ) of 22 patients had reversible changes in dark adaptation , which correlated with relative decrease in Cp retinol ( P < /=.01 ) . Four patients stopped treatment for side effects , and 84 % of patients had hot flashes . Other commonly reported ( grade < /= 2 ) reversible toxicities included skin and ocular dryness , fatigue , and mood changes . Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4 . Baseline mean + /- SD Cp retinol was 708 + /- 280 ng/mL. Mean + /- SD Cp of 4-HPR , N-(4-methoxyphenyl ) retinamide ( 4-MPR ) , and retinol after 1 month of 4-HPR were 0.34 + /- 0.21 micromol/L , 0.28 + /- 0.21 micromol/L , and 282 + /- 127 ng/mL , respectively . Mean retinoid Cps did not change after 3 months of 4-HPR + TAM . CONCLUSIONS TAM administration did not affect Cp 4-HPR or 4-MPR . Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients . TAM + 4-HPR has acceptable tolerability for this high-risk cohort BACKGROUND Initial results from the first International Breast Cancer Intervention Study ( IBIS-I ) found that tamoxifen reduced the risk of invasive estrogen receptor (ER)-positive tumors by 31 % in women at increased risk for breast cancer , but most of the follow-up at this time was during the active treatment phase . We report an up date d analysis of IBIS-I that focuses on the period after active treatment was completed , a time for which little evidence from other trials is available . METHODS A total of 7145 women who were aged 35 - 70 years and at increased risk of breast cancer were r and omly assigned to receive either tamoxifen ( 20 mg/day ) or placebo for 5 years . The primary outcome measure was the incidence of breast cancer ( including ductal carcinoma in situ ) , but side effects were also investigated . Relative risks were computed as the ratio of incidence rates . All statistical tests were two-sided . RESULTS After a median follow-up of 96 months after r and omization , 142 breast cancers were diagnosed in the 3579 women in the tamoxifen group and 195 in the 3575 women in the placebo group ( 4.97 versus 6.82 per 1000 woman-years , respectively ; risk ratio [ RR ] = 0.73 , 95 % confidence interval [ CI ] = 0.58 to 0.91 , P = .004 ) . The prophylactic effect of tamoxifen was fairly constant for the entire follow-up period , and no diminution of benefit was observed for up to 10 years after r and omization . However , side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment . For example , deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment ( 52 versus 23 cases , RR = 2.26 , 95 % CI = 1.36 to 3.87 ) but not after tamoxifen was stopped ( 16 versus 14 cases , RR = 1.14 , 95 % CI = 0.52 to 2.53 ) . The two arms did not differ in the risk of ER-negative invasive tumors ( 35 in each arm , RR = 1.00 , 95 % CI = 0.61 to 1.65 ) across the entire follow-up period , but the risk of ER-positive invasive breast cancer 
    Output:
    
While tamoxifen after local excision for DCIS ( with or without adjuvant radiotherapy ) reduced the risk of recurrent DCIS ( in the ipsi- and contralateral breast ) , it did not reduce the risk of overall mortality