***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: Summary Human breast carcinoma is biologically heterogeneous , and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread . It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy . Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer . In the present study , we investigated  apoptosis , expression of p27Kip1 and p53 retrospectively in 181 human breast cancer specimens . In addition , their relevance to the biological behaviour of breast cancer was examined . Our studies found a significant association among high histological grade , high p53 , low apoptosis and low p27 . Our results also demonstrated that , in human breast cancer , low levels of p27 and apoptotic index ( AI ) strongly correlated with the presence of lymph node metastasis and decreased patient survival . In node-negative patients , however , p27 also had prognostic value for relapse-free and overall survival in multivariate analysis . Furthermore p27 and AI had predictive value for the benefits of chemotherapy . These latter observations should prompt prospect i ve r and omized studies design ed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients It is generally thought that future advances in the treatment and cure of breast cancer patients will be made possible through a deeper underst and ing of tumor biology and an improved capability to define the prognosis of each single patient . This will lead to the formulation of new , more selective , and patient-tailored therapies . It is therefore important , when study ing potential prognostic factors , to follow method ologic requirements and guidelines which involve the carrying out of prospect i ve studies as confirmatory steps . Repeatedly or recently investigated prognostic markers ( tumor size , menopausal status , ER , PgR , 3H thymidine labeling index , c-erbB-2 and p27 expression ) were evaluated on a series of 286 prospect ively recruited node negative breast cancer patients who underwent loco-regional treatment alone and were closely followed . The individual and relative prognostic contribution of each variable with respect to other factors , as well as their ability to identify node negative patients at risk , were assessed by univariate and multivariate analysis . At a five-year follow-up , only tumor size ( p = 0.021 ) and TLI ( p = 0.016 ) individually proved to be significant prognostic indicators of relapse-free survival . Conversely , p27 expression was not related to RFS and c-erbB-2 expression appeared to have only a short-term effect on patient prognosis . TLI and tumor size , tested in multivariate analysis along with ER and menopausal status , maintained their independent prognostic relevance . The study , performed on a large series of node-negative patients given loco-regional treatment alone  , for the first time prospect ively recruited , showed the prognostic relevance of TLI and its independence from other clinico-pathologic and biologic factors over a five-year period BACKGROUND Abnormal expression of the cell cycle regulatory proteins p27(Kip1 ) ( p27 ) and cyclin E may be associated with breast cancer survival and relapse . We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome . METHODS We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 ( 68 % ) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313 , in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently ( n = 1595 ) or sequentially ( n = 1527 ) . Disease-free and overall survival were equivalent in the two arms . Expression of the proteins was rated on a scale of 1 - 7 , and the median value was used as the cut point . Log-rank tests and Cox regression analyses were used to assess associations with survival . Overall survival was defined as time to death from all causes ; disease-free survival was defined as time to recurrence or death . All P values were from two-sided statistical tests . RESULTS Lower p27 expression was associated with worse overall survival ( unadjusted hazard ratio [ HR ] = 1.50 , 95 % confidence interval [ CI ] = 1.21 to 1.86 ) and disease-free survival ( unadjusted HR = 1.31 , 95 % CI = 1.10 to 1.57 ) than higher p27 expression . Among hormone receptor-positive patients , lower p27 expression was associated with worse overall survival ( HR = 1.42 , 95 % CI = 1.05 to 1.94 ) and worse disease-free survival ( HR = 1.27 , 95 % CI = 0.99 to 1.63 ) than higher p27 expression after adjustment for treatment , menopausal status , tumor size , and number of positive lymph nodes . Among these patients , 5-year overall survival associated with higher p27 expression ( 0.91 , 95 % CI = 0.89 to 0.93 ) was similar to that associated with lower p27 expression ( 0.85 , 95 % CI = 0.82 to 0.87 ) . No association between p27 expression and survival was found in hormone receptor-negative patients .  Cyclin E expression was not statistically significantly associated with overall survival ( HR = 1.12 , 95 % CI = 0.91 to 1.38 ) or disease-free survival ( HR = 1.09 , 95 % CI = 0.92 to 1.29 ) . CONCLUSIONS Low p27 expression appears to be associated with poor prognosis , especially among patients with steroid receptor-positive tumors PURPOSE To determine the predictive value of p27Kip1 in premenopausal women with early-stage hormone receptor-positive breast cancer . PATIENTS AND METHODS We retrospectively examined tumor specimens from 512 patients with breast cancer who were enrolled onto Austrian Breast and Colorectal Cancer Study Group ( ABCSG ) Trial 5 . In this trial , premenopausal , hormone receptor-positive breast cancer patients with stage I and II disease were r and omly assigned to receive either 5 years of tamoxifen plus 3 years of goserelin or six cycles of cyclophosphamide , methotrexate , and fluorouracil . p27Kip1 expression was assessed by immunohistochemistry , and its association with clinical outcome was determined . Statistical analyses were performed to test for interaction between p27Kip1 status and treatment . RESULTS High p27Kip1 expression ( nuclear p27Kip1 staining in > /= 50 % of tumor cells ) independently predicted superior relapse-free survival ( RFS ) and overall survival ( OS ) in both the total study population ( RFS : relative risk [ RR ] , 0.53 ; 95 % CI , 0.34 to 0.82 ; P = .004 ; OS : RR , 0.29 ; 95 % CI , 0.15 to 0.58 ; P < .001 ) and patients treated with combination endocrine therapy ( RFS : RR , 0.32 ; 95 % CI , 0.16 to 0.63 ; P = .001 ; OS : RR , 0.16 ; 95 % CI , 0.05 to 0.53 ; P = .003 ) . The interaction between p27Kip1 expression and treatment was statistically significant for RFS ( P = .04 ) but not for OS ( P = .27 ) . CONCLUSION High p27Kip1 expression was an independent predictor of responsiveness to hormonal therapy and thus may be useful for the selection of premenopausal women with early-stage hormone receptor-positive breast cancer for adjuvant combination endocrine therapy 
    Output:
    
This meta- analysis indicates that reduced p27 is an independent prognostic factor for poor overall and disease-free cancer survival