***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: Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women . This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer . Non-diabetic women with operable invasive breast cancer received pre-operative metformin . A pilot cohort of eight patients had core biopsy of the cancer at presentation , a week later ( without treatment ; internal control ) , then following metformin 500-mg o.d . for 1 week increased to 1-g b.d . for a further week continued to surgery . A further 47 patients had core biopsy at diagnosis were r and omized to metformin ( the same dose regimen ) or no drug , and 2 weeks later had core biopsy at surgery . Ki67 immunohistochemistry , transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment . Seven patients ( 7/32 , 21.9 % ) receiving metformin withdrew because of gastrointestinal upset . The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort ( P = 0.041 , paired t-test ) and in the metformin arm ( P = 0.027 , Wilcoxon rank test ) but was unchanged in the internal control or metformin control arms . Messenger RNA expression was significantly downregulated by metformin for PDE3B ( phosphodiesterase 3B , cGMP-inhibited ; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase , AMPK ) , confirmed by immunohistochemistry , SSR3 , TP53 and CCDC14 . By ingenuity pathway analysis , the tumour necrosis factor receptor 1 ( TNFR1 ) signaling pathway was most affected by metformin : TGFB and MEKK were upregulated and cdc42 downregulated ; mTOR and AMPK pathways were also affected . Gene set analysis additionally revealed that p53 , BRCA1 and cell cycle pathways also had reduced expression following metformin .  Mean serum insulin remained stable in patients receiving metformin but rose in control patients . This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin Introduction : We conducted a presurgical trial to assess the tissue-related effects of metformin in overweight/obese breast cancer ( BC ) patients . Methods : Metformin 1,500 mg daily was administered to 35 nondiabetics with stage 0–III BC , body mass index ( BMI ) ≥ 25 kg/m2 . The primary endpoint was tumor proliferation change ( i.e. , ki-67 ) . Tumor proliferation change was compared to untreated historical controls , matched by age , BMI , and stage . Results : There was no reduction in ln(ki-67 )  after metformin ( p = .98 ) or compared to controls ( p = .47 ) . There was a significant reduction in BMI , cholesterol , and leptin . Conclusion : Despite no proliferation changes , we observed reductions in other relevant biomarkers Previous observational studies have suggested that metformin  in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications . This r and omized , double-blind , placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients . Female breast cancer patients ( N = 105 ) , at least 6 months post-mastectomy , with obesity ( ≥25 kg/m2 ) and /or pre-diabetes ( fasting blood sugar levels ≥100 mg/dL ) , were r and omly assigned to three groups ( placebo , metformin 500 mg , and metformin 1000 mg ) stratified by tamoxifen use . A linear mixed model for repeated measurements among three groups and ANOVA for profile differences during 6 months of treatment were used for the intention-to-treat analysis . The metformin 1000 mg group had a significantly greater decline in glucose and HbA1c levels between treatment weeks 0 and 6 month ( p = 0.008 and 0.009 , respectively ) , and the declines increased with an increase in body mass index ( BMI ) level ( p interaction with BMI = 0.007 and 0.067 , respectively ) . A marginally significant different effect from the metformin 1000 mg treatment was detected for glucose and HbA1c levels ( p interaction = 0.084 and 0.063 , respectively ) in the intention-to-treat analysis . Metformin 1000 mg treatment had a favorable effect on controlling glucose and HbA1C levels in obese non-diabetic breast cancer patients , indicating prognostic importance . Further trials are needed to eluci date the risk – benefit ratio of long-term use of metformin PURPOSE Metformin is associated with reduced breast cancer risk in observational studies in patients with diabetes , but clinical evidence for antitumor activity is unclear . The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer . PATIENTS AND METHODS After tumor biopsy , we r and omly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day ( n = 100 ) or placebo ( n = 100 ) . The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values . RESULTS Overall , the metformin effect on Ki-67 change relative to placebo was not statistically significant , with a mean proportional increase of 4.0 % ( 95 % CI , -5.6 % to 14.4 % ) 4 weeks apart . However , there was a different drug effect depending on insulin resistance ( homeostasis model assessment [ HOMA ] index > 2.8 , fasting glucose [ mmol/L ] × insulin [mU/L]/22.5 ; P(interaction ) = .045 ) , with a nonsignificant mean proportional decrease in Ki-67 of 10.5 % ( 95 % CI , -26.1 % to 8.4 % ) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1 % ( 95 % CI , -0.6 % to 24.2 % ) with HOMA less than or equal to 2.8 . A different effect of metformin according to HOMA index was noted also in luminal B tumors ( P(interaction ) = .05 ) . Similar trends to drug effect modifications were observed according to body mass index ( P = .143 ) , waist/hip girth-ratio ( P = .058 ) , moderate alcohol consumption ( P = .005 ) , and C-reactive protein ( P = .080 ) . CONCLUSION Metformin before surgery did not significantly affect Ki-67 overall , but showed significantly different effects according to insulin resistance , particularly in luminal B tumors . Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population Background This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis . Methods Overweight/obese postmenopausal breast cancer survivors ( n = 333 ) were r and omly assigned to metformin vs placebo and to a weight loss intervention vs control ( ie , usual care ) . The 2 × 2 factorial design allows a single r and omized trial to investigate the effect of two factors and interactions between them . Outcomes were changes in fasting insulin , glucose , C-reactive protein ( CRP ) , estradiol , testosterone , and sex-hormone binding globulin ( SHBG ) . The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control . All tests of statistical significance were two-sided . Results A total of 313 women ( 94.0 % ) completed the six-month trial .  High prescription adherence ( ie , ≥80 % of pills taken ) ranged from 65.9 % of participants in the metformin group to 81.3 % of those in the placebo group ( P < .002 ) . Mean percent weight loss was statistically significantly higher in the weight loss group ( -5.5 % , 95 % confidence interval [ CI ] = -6.3 % to -4.8 % ) compared with the control group ( -2.7 % , 95 % CI = -3.5 % to -1.9 % ) . Statistically significant group differences ( ie , percent change in metformin group minus placebo group ) were -7.9 % ( 95 % CI = -15.0 % to -0.8 % ) for insulin , -10.0 % ( 95 % CI = -18.5 % to -1.5 % ) for estradiol , -9.5 % ( 95 % CI = -15.2 % to -3.8 % ) for testosterone , and 7.5 % ( 95 % CI = 2.4 % to 12.6 % ) for SHBG . Statistically significant group differences ( ie , percent change in weight loss group minus placebo group ) were -12.5 % ( 95 % CI = -19.6 % to -5.3 % ) for insulin and 5.3 % ( 95 % CI = 0.2 % to 10.4 % ) for SHBG . Conclusions As adjuvant therapy , weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality 
    Output:
    
We did not observe non-linear changes in the dose – response relationship between metformin and biomarkers as outcomes .
Conclusions Breast cancer patients receiving metformin as treatment for diabetes showed significant reduction in levels of insulin , fasting glucose , CRP , HOMA , leptin , BMI , and Ki-67