***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 The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor-positive tumors is poorly defined by clinical and histopathological measures . METHODS We tested whether the results of a reverse-transcriptase-polymerase-chain-reaction ( RT-PCR ) assay of 21 prospect ively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative , tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14 . The levels of expression of 16 cancer-related genes and 5 reference genes were used in a prospect ively defined algorithm to calculate a recurrence score and to determine a risk group ( low , intermediate , or high ) for each patient . RESULTS Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks . The proportions of patients categorized as having a low , intermediate , or high risk by the RT-PCR assay were 51 , 22 , and 27 percent , respectively . The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk , intermediate-risk , and high-risk groups were 6.8 percent ( 95 percent confidence interval , 4.0 to 9.6 ) , 14.3 percent ( 95 percent confidence interval , 8.3 to 20.3 ) , and 30.5 percent ( 95 percent confidence interval , 23.6 to 37.4 ) . The rate in the low-risk group was significantly lower than that in the high-risk group ( P<0.001 ) . In a multivariate Cox model , the recurrence score provided significant predictive power that was independent of age and tumor size ( P<0.001 ) . The recurrence score was also predictive of overall survival ( P<0.001 ) and could be used as a continuous function to predict distant recurrence in individual patients . CONCLUSIONS The recurrence score has been vali date d as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative , estrogen-receptor-positive breast cancer BACKGROUND Amplification of the human epidermal growth factor receptor type 2 ( HER2 , also called HER2/neu ) gene and overexpression of its product in breast-cancer cells may be associated with responsiveness to anthracycline-containing chemotherapy regimens . METHODS In the r and omized , controlled Mammary.5 trial , we studied 639 formalin-fixed paraffin-embedded specimens obtained from 710 premenopausal women with node-positive breast cancer who had received either cyclophosphamide , epirubicin , and fluorouracil ( CEF ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) as adjuvant chemotherapy .  HER2 amplification or overexpression was evaluated with the use of fluorescence in situ hybridization , immunohistochemical analysis , and polymerase-chain-reaction analysis . RESULTS Amplification of HER2 was associated with a poor prognosis regardless of the type of treatment . In patients whose tumors showed amplification of HER2 , CEF was superior to CMF when assessed on the basis of relapse-free survival ( hazard ratio , 0.52 ; 95 percent confidence interval , 0.34 to 0.80 ; P=0.003 ) and overall survival ( hazard ratio , 0.65 ; 95 percent confidence interval , 0.42 to 1.02 ; P=0.06 ) . For women whose tumors lacked amplification of HER2 , CEF did not improve relapse-free survival ( hazard ratio for relapse , 0.91 ; 95 percent confidence interval , 0.71 to 1.18 ; P=0.49 ) or overall survival ( hazard ratio for death , 1.06 ; 95 percent confidence interval , 0.83 to 1.44 ; P=0.68 ) . The adjusted hazard ratio for the interaction between treatment and HER2 amplification was 1.96 for relapse-free survival ( 95 percent confidence interval , 1.15 to 3.36 ; P=0.01 ) and 2.04 for overall survival ( 95 percent confidence interval , 1.14 to 3.65 ; P=0.02 ) . CONCLUSIONS Amplification of HER2 in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy . ( cancer.gov number , NCI-V90 - 0027 . ) PURPOSE Histologic grade , Nottingham Prognostic Index ( NPI ) , estrogen receptor ( ER ) and progesterone receptor ( PgR ) status , and tumor size have previously been shown to be important prognostic indicators for distant recurrence of breast cancer . The purpose of this study was to compare the prognostic value of these factors with flow cytometric S-phase fraction ( SPF ) , urokinase plasminogen activator ( uPA ) , and plasminogen activator inhibitor type 1 ( PAI-1 ) in premenopausal patients with lymph node-negative breast cancer . PATIENTS AND METHODS In 237 consecutive premenopausal patients with lymph node-negative breast cancer and freshly frozen tumor material available ,  SPF , ER and PgR status , uPA and its inhibitor PAI-1 , histologic grade , and NPI  were evaluated . RESULTS  SPF  was univariately the most powerful prognostic factor for distant recurrence , followed by uPA , histologic grade , PgR , age , ER , NPI , and PAI-1 , the latter being nonsignificant . Multivariate analysis revealed that neither NPI nor histologic grade was significant after adjustment for SPF , a fact that may be explained by the strong association between these factors . uPA was , however , an independent prognostic factor in addition to SPF , NPI , or histologic grade . CONCLUSION In this prospect i ve study , SPF and uPA were found to be independent prognostic factors in premenopausal women with lymph node-negative breast cancer . We suggest that SPF , if performed under st and ardized conditions , can replace histologic grade as a selection instrument for adjuvant medical treatment . The value of the combination of SPF and uPA needs to be confirmed in an independent prospect i ve trial 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 Proteomic analysis of body fluids , including breast nipple aspirate fluid ( NAF ) , holds promise to aid in early cancer detection . We conducted a prospect i ve trial that collected NAF from women scheduled for diagnostic breast surgery to determine 1 ) the consistency of proteomic results , 2 ) protein masses associated with breast cancer , 3 ) subsets of women with a unique proteomic profile and 4 ) a breast cancer predictive model .  NAF was collected preoperatively in 114 women and analyzed by SELDI-TOF mass spectrometry  over a 3 - 50 kDa range using H4 , NP and SAX ProteinChips . For all 3 chips , the same protein peaks were detected over 90 % of the time in duplicate sample s. The overall coefficient of variation was < or = 0.17 % for each chip for the internal st and ard and < or = 0.29 % for the unknown proteins . Seven c and i date protein ion masses frequently expressed in NAF were identified . Three ( 5,200-H4 , p=.04 , 11,880-H4 , p=.07 and 13,880 Da-SAX , p=.03 ) were differentially expressed in women with/without breast cancer . Protein expression differed between women with/without pathologic nipple discharge ( PND ) , but the 5,200 , 11,880 and 13,880 proteins remained associated with breast cancer even if PND sample s were excluded . Subset analysis identified differences in expression between benign disease and DCIS and between DCIS and invasive cancer for the 5,200 and 33,400 Da proteins . The best cancer detection model included age , parity and the 11,880 Da protein , and excluded women with PND . 1 ) NAF proteomic analysis using SELDI-TOF is reproducible with the same sample set across different platforms , 2 ) differential proteomic expression exists between women/without breast cancer and 3 ) combining proteomic and clinical information that are available before surgery optimizes the prediction of which women have breast cancer BACKGROUND Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin . A retrospective study was design ed to test this hypothesis . METHODS In National Surgical Adjuvant Breast and Bowel Project protocol B-11 , patients with axillary lymph node-positive , hormone receptor-negative breast cancer were r and omly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil ( PF ) or a combination of L-phenylalanine mustard , 5-fluorouracil , and doxorubicin ( PAF ) . Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients . Statistical analyses were performed to test for interaction between treatment and erbB-2 status ( positive versus negative ) with respect to disease-free survival ( DFS ) , survival , recurrence-free survival ( RFS ) , and distant disease-free survival ( DDFS ) . Reported P values are two-sided . RESULTS Overexpression of erbB-2 ( i.e. , positive immunohistochemical staining ) was observed in 239 ( 37.5 % ) of the 638 tumors studied . Overexpression was associated with tumor size ( P=.02 ) , lack of estrogen receptors ( P=.008 ) , and the number of positive lymph nodes ( P=.0001 ) . After a mean time on study of 13.5 years , the clinical benefit from doxorubicin ( PAF versus PF ) was statistically significant for patients with erbB-2-positive tumors -- DFS : relative risk of failure (RR)=0.60 ( 95 % confidence interval [CI]=0.44 - 0.83 ) , P=.001 ; survival : RR=0.66 ( 95 % CI=0.47 - 0.92 ) , P = .01 ; RFS : RR=0.58 ( 95 % CI=0.42 - 0.82 ) , P=.002 ; DDFS : RR=0.61 ( 95 % CI=0.44 - 0.85 ) , P=.003 . However , it was not significant for patients with erbB-2-negative tumors-DFS : RR= 
    Output:
    
The following categories showed evidence of clinical utility and were recommended for use in practice : CA 15 - 3 , CA 27.29 , carcinoembryonic antigen , estrogen receptor , progesterone receptor , human epidermal growth factor receptor 2 , urokinase plasminogen activator , plasminogen activator inhibitor 1 , and certain multiparameter gene expression assays .
Not all applications for these markers were supported , however .