human
***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 PAM50 is a 50-gene test that is design ed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence ( ROR ) score . It has been developed to be carried out in qualified routine hospital pathology laboratories . PATIENTS AND METHODS One thous and four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer ( EBC ) treated with tamoxifen or tamoxifen followed by anastrozole from the prospect i ve r and omized ABCSG-8 trial were entered into this study . Patients did not receive adjuvant chemotherapy . RNA was extracted from paraffin blocks and analyzed using the PAM50 test . Both intrinsic subtype ( luminal A/B , HER2-enriched , basal-like ) and ROR score were calculated . The primary analysis was design ed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence ( DR ) over and above st and ard clinical variables . RESULTS In all tested subgroups , ROR score significantly adds prognostic information to the clinical predictor ( P<0.0001 ) . PAM50 assigns an intrinsic subtype to all cases , and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B ( P<0.0001 ) . Significant and clinical ly relevant discrimination between low- and high-risk groups occurred also within all tested subgroups . CONCLUSION ( S ) The results of the primary analysis , in combination with recently published results from the ATAC trial , constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC . A 10-year metastasis risk of < 3.5 % in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome -this finding could help to avoid unwarranted overtreatment . CLINICAL TRIAL NUMBER ABCSG 8 : NCT00291759 HER2 amplification , TOP2A aberrations , and absence of tissue inhibitor of metalloproteinase ( TIMP-1 ) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy , and this study was undertaken to vali date these findings in a similar , but independent , r and omized clinical trial . TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were r and omized to cyclophosphamide , epirubicin , and fluorouracil ( CEF ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in the MA.5 trial . Ninety-eight ( 24 % ) patients had no TIMP-1 staining of tumor cells , 27 % were HER2 amplified , and 18 % were TOP2A aberrant . Forty-four percentage was classified as HT responsive ( HER2 amplified and /or TIMP-1 negative ) and 37 % as 2 T responsive ( TOP2A aberrant and /or TIMP-1 negative ) . There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1 . In HT-responsive patients , CEF was superior to CMF with an improved RFS ( adjusted HR , 0.64 ; 95 % CI , 0.42–0.97 ) , but this was not significant for OS ( adjusted HR , 0.66 ; 95 % CI , 0.42–1.04 ) . A significant HT profile versus treatment interaction was detected for OS ( P = 0.03 ) . In 2T-responsive patients , CEF seemed to improve RFS compared to CMF ( adjusted HR , 0.67 ; 95 % CI , 0.43–1.03 ) and improved OS ( adjusted HR , 0.58 ; 95 % CI , 0.36–0.93 ) . A significant 2 T profile versus treatment interaction was detected for OS ( P = 0.01 ) . With this study , we vali date a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile ; however , we could not show a similarly significant reduction in RFS events , where a benefit of CEF over CMF was found irrespective of TIMP-1 status . Further studies are necessary before the HT and 2 T profiles may be used to direct the use of anthracyclines PURPOSE We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project ( NSABP ) -B 28 clinical trial . Expression levels were correlated with disease-free survival ( DFS ) and overall survival ( OS ) . Interaction between this marker and paclitaxel efficacy was also examined . METHODS Tissue microarrays were available for 1,942 patients ( 63 % of all trial participants ) who were r and omly assigned to receive either four courses of doxorubicin and cyclophosphamide ( AC ) or AC followed by four courses of adjuvant paclitaxel chemotherapy . All patients who were hormone receptor positive received adjuvant  endocrine therapy . Immunohistochemistry was used to measure Tau expression at M. D. And erson Cancer Center blinded to clinical outcome . Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center . RESULTS Forty-three percent of patients were Tau positive . Tau positivity correlated with estrogen receptor ( ER ) -positive status ( P < .0001 ) , lower histologic grade ( P < .001 ) , and lack of human epidermal growth factor receptor 2 ( HER2 ) expression ( P < .0001 ) . In univariate analyses , Tau- and ER-positive status were both associated with better DFS and OS ( P < .0001 ) whereas greater tumor size , high grade , lymph node- and HER2-positive status were each associated with worse DFS and OS ( P < .0001 ) . In multivariate analysis , the same variables except HER2 remained significant . There was no significant interaction between Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients . CONCLUSION High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy  , but there was no significant interaction between Tau expression and paclitaxel benefit Overexpression of topoisomerase II protein ( topo 2α ) is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than human epidermal growth factor receptor type 2 ( HER2 ) gene amplification or alterations in the topoisomerase II alpha gene ( TOP2A ) . The authors used tissue microarrays from 477 of 710 premenopausal women with node-positive breast cancer r and omized to CEF or CMF adjuvant chemotherapy in the NCIC Clinical Trials Group Mammary 5 ( MA.5 ) trial . No significant interaction was found between treatment and continuous topo 2α level in either relapse-free ( RFS ) or overall survival ( OS ) . In 136 patients ( 28.5 % ) whose tumors showed topo 2α overexpression by immunohistochemistry based on a cut-off of 13 % , CEF was superior to CMF for RFS ( adjusted HR 0.45 ; 95 % CI 0.25–0.82 ; P = 0.009 ) and OS ( adjusted HR 0.50 ; 95 % CI 0.26–0.96 ; P = 0.04 ) . When tumors lacked topo 2α overexpression , CEF was not superior for RFS ( adjusted HR 0.88 ; 95 % CI 0.64–1.22 ; P = 0.46 ) or OS ( adjusted HR 0.95 ; 95 % CI 0.66–1.38 ; P = 0.80 ) . Interaction between topo 2α and treatment was borderline significant for RFS ( P = 0.04 ) and OS ( P = 0.05 ) and not substantially more significant than between TOP2A gene alteration ( Pinteraction = 0.09 for RFS and 0.02 for OS ) or HER2 overexpression ( Pinteraction = 0.002 for RFS and 0.009 for OS ) . Topo 2α protein overexpression based on the cut-off identified in this study , TOP2A gene alterations and HER2 protein overexpression were each associated with responsiveness to anthracycline-containing chemotherapy . The topo 2α protein analysis was exploratory and will require further validation Introduction EndoPredict ( EP ) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive ( ER+ ) , human epidermal growth factor receptor 2–negative ( HER2− ) breast cancer ( BC ) who are being treated with adjuvant endocrine therapy .  Herein we report the prospect ive-retrospective clinical validation of EP in the node-positive , chemotherapy-treated , ER+/HER2− BC patients in the GEICAM 9906 trial . Methods The patients ( N = 1,246 ) were treated either with six cycles of fluorouracil , epirubicin and cyclophosphamide ( FEC ) or with four cycles of FEC followed by eight weekly courses of paclitaxel ( FEC-P ) , as well as with endocrine therapy if they had hormone receptor – positive disease . The patients were assigned to EP risk categories ( low or high ) according to prespecified cutoff levels . The primary endpoint in the clinical validation of EP was distant metastasis-free survival ( MFS ) . Metastasis rates were estimated using the Kaplan-Meier method , and multivariate analysis was performed using Cox regression . Results The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available sample s in the GEICAM 9906 trial . On the basis of the EP , 25 % of patients ( n = 141 ) were classified as low risk . MFS was 93 % in the low-risk group and 70 % in the high-risk group ( absolute risk reduction = 23 % , hazard ratio ( HR ) = 4.8 , 95 % confidence interval ( CI ) = 2.5 to 9.5 ; P < 0.0001 ) . Multivariate analysis showed that , in this ER+/HER2− cohort , EP results are an independent prognostic parameter after adjustment for age , grade , lymph node status , tumor size , treatment arm , ER and progesterone receptor ( PR ) status and proliferation index ( Ki67 ) . Using the predefined EPclin score , 13 % of patients ( n = 74 ) were assigned to the low-risk group , who had excellent outcomes and no distant recurrence events ( absolute risk reduction vs high-risk group = 28 % ; P < 0.0001 ) . Furthermore , EP was prognostic in premenopausal patients ( HR = 6.7 , 95 % CI = 2.4 to 18.3 ; P = 0.0002 ) and postmenopausal patients ( HR = 3.3 , 95 % CI = 1.3 to 8.5 ; P = 0.0109 ) . There were no statist 
    Output:
    
agent
RECOMMENDATIONS In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2 , the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX , EndoPredict , PAM50 , Breast Cancer Index , and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer .
No biomarker except for estrogen receptor , progesterone receptor , and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens .
***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 PAM50 is a 50-gene test that is design ed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence ( ROR ) score . It has been developed to be carried out in qualified routine hospital pathology laboratories . PATIENTS AND METHODS One thous and four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer ( EBC ) treated with tamoxifen or tamoxifen followed by anastrozole from the prospect i ve r and omized ABCSG-8 trial were entered into this study . Patients did not receive adjuvant chemotherapy . RNA was extracted from paraffin blocks and analyzed using the PAM50 test . Both intrinsic subtype ( luminal A/B , HER2-enriched , basal-like ) and ROR score were calculated . The primary analysis was design ed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence ( DR ) over and above st and ard clinical variables . RESULTS In all tested subgroups , ROR score significantly adds prognostic information to the clinical predictor ( P<0.0001 ) . PAM50 assigns an intrinsic subtype to all cases , and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B ( P<0.0001 ) . Significant and clinical ly relevant discrimination between low- and high-risk groups occurred also within all tested subgroups . CONCLUSION ( S ) The results of the primary analysis , in combination with recently published results from the ATAC trial , constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC . A 10-year metastasis risk of < 3.5 % in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome -this finding could help to avoid unwarranted overtreatment . CLINICAL TRIAL NUMBER ABCSG 8 : NCT00291759 HER2 amplification , TOP2A aberrations , and absence of tissue inhibitor of metalloproteinase ( TIMP-1 ) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy , and this study was undertaken to vali date these findings in a similar , but independent , r and omized clinical trial . TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were r and omized to cyclophosphamide , epirubicin , and fluorouracil ( CEF ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in the MA.5 trial . Ninety-eight ( 24 % ) patients had no TIMP-1 staining of tumor cells , 27 % were HER2 amplified , and 18 % were TOP2A aberrant . Forty-four percentage was classified as HT responsive ( HER2 amplified and /or TIMP-1 negative ) and 37 % as 2 T responsive ( TOP2A aberrant and /or TIMP-1 negative ) . There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1 . In HT-responsive patients , CEF was superior to CMF with an improved RFS ( adjusted HR , 0.64 ; 95 % CI , 0.42–0.97 ) , but this was not significant for OS ( adjusted HR , 0.66 ; 95 % CI , 0.42–1.04 ) . A significant HT profile versus treatment interaction was detected for OS ( P = 0.03 ) . In 2T-responsive patients , CEF seemed to improve RFS compared to CMF ( adjusted HR , 0.67 ; 95 % CI , 0.43–1.03 ) and improved OS ( adjusted HR , 0.58 ; 95 % CI , 0.36–0.93 ) . A significant 2 T profile versus treatment interaction was detected for OS ( P = 0.01 ) . With this study , we vali date a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile ; however , we could not show a similarly significant reduction in RFS events , where a benefit of CEF over CMF was found irrespective of TIMP-1 status . Further studies are necessary before the HT and 2 T profiles may be used to direct the use of anthracyclines PURPOSE We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project ( NSABP ) -B 28 clinical trial . Expression levels were correlated with disease-free survival ( DFS ) and overall survival ( OS ) . Interaction between this marker and paclitaxel efficacy was also examined . METHODS Tissue microarrays were available for 1,942 patients ( 63 % of all trial participants ) who were r and omly assigned to receive either four courses of doxorubicin and cyclophosphamide ( AC ) or AC followed by four courses of adjuvant paclitaxel chemotherapy . All patients who were hormone receptor positive received adjuvant  endocrine therapy . Immunohistochemistry was used to measure Tau expression at M. D. And erson Cancer Center blinded to clinical outcome . Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center . RESULTS Forty-three percent of patients were Tau positive . Tau positivity correlated with estrogen receptor ( ER ) -positive status ( P < .0001 ) , lower histologic grade ( P < .001 ) , and lack of human epidermal growth factor receptor 2 ( HER2 ) expression ( P < .0001 ) . In univariate analyses , Tau- and ER-positive status were both associated with better DFS and OS ( P < .0001 ) whereas greater tumor size , high grade , lymph node- and HER2-positive status were each associated with worse DFS and OS ( P < .0001 ) . In multivariate analysis , the same variables except HER2 remained significant . There was no significant interaction between Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients . CONCLUSION High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy  , but there was no significant interaction between Tau expression and paclitaxel benefit Overexpression of topoisomerase II protein ( topo 2α ) is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than human epidermal growth factor receptor type 2 ( HER2 ) gene amplification or alterations in the topoisomerase II alpha gene ( TOP2A ) . The authors used tissue microarrays from 477 of 710 premenopausal women with node-positive breast cancer r and omized to CEF or CMF adjuvant chemotherapy in the NCIC Clinical Trials Group Mammary 5 ( MA.5 ) trial . No significant interaction was found between treatment and continuous topo 2α level in either relapse-free ( RFS ) or overall survival ( OS ) . In 136 patients ( 28.5 % ) whose tumors showed topo 2α overexpression by immunohistochemistry based on a cut-off of 13 % , CEF was superior to CMF for RFS ( adjusted HR 0.45 ; 95 % CI 0.25–0.82 ; P = 0.009 ) and OS ( adjusted HR 0.50 ; 95 % CI 0.26–0.96 ; P = 0.04 ) . When tumors lacked topo 2α overexpression , CEF was not superior for RFS ( adjusted HR 0.88 ; 95 % CI 0.64–1.22 ; P = 0.46 ) or OS ( adjusted HR 0.95 ; 95 % CI 0.66–1.38 ; P = 0.80 ) . Interaction between topo 2α and treatment was borderline significant for RFS ( P = 0.04 ) and OS ( P = 0.05 ) and not substantially more significant than between TOP2A gene alteration ( Pinteraction = 0.09 for RFS and 0.02 for OS ) or HER2 overexpression ( Pinteraction = 0.002 for RFS and 0.009 for OS ) . Topo 2α protein overexpression based on the cut-off identified in this study , TOP2A gene alterations and HER2 protein overexpression were each associated with responsiveness to anthracycline-containing chemotherapy . The topo 2α protein analysis was exploratory and will require further validation Introduction EndoPredict ( EP ) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive ( ER+ ) , human epidermal growth factor receptor 2–negative ( HER2− ) breast cancer ( BC ) who are being treated with adjuvant endocrine therapy .  Herein we report the prospect ive-retrospective clinical validation of EP in the node-positive , chemotherapy-treated , ER+/HER2− BC patients in the GEICAM 9906 trial . Methods The patients ( N = 1,246 ) were treated either with six cycles of fluorouracil , epirubicin and cyclophosphamide ( FEC ) or with four cycles of FEC followed by eight weekly courses of paclitaxel ( FEC-P ) , as well as with endocrine therapy if they had hormone receptor – positive disease . The patients were assigned to EP risk categories ( low or high ) according to prespecified cutoff levels . The primary endpoint in the clinical validation of EP was distant metastasis-free survival ( MFS ) . Metastasis rates were estimated using the Kaplan-Meier method , and multivariate analysis was performed using Cox regression . Results The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available sample s in the GEICAM 9906 trial . On the basis of the EP , 25 % of patients ( n = 141 ) were classified as low risk . MFS was 93 % in the low-risk group and 70 % in the high-risk group ( absolute risk reduction = 23 % , hazard ratio ( HR ) = 4.8 , 95 % confidence interval ( CI ) = 2.5 to 9.5 ; P < 0.0001 ) . Multivariate analysis showed that , in this ER+/HER2− cohort , EP results are an independent prognostic parameter after adjustment for age , grade , lymph node status , tumor size , treatment arm , ER and progesterone receptor ( PR ) status and proliferation index ( Ki67 ) . Using the predefined EPclin score , 13 % of patients ( n = 74 ) were assigned to the low-risk group , who had excellent outcomes and no distant recurrence events ( absolute risk reduction vs high-risk group = 28 % ; P < 0.0001 ) . Furthermore , EP was prognostic in premenopausal patients ( HR = 6.7 , 95 % CI = 2.4 to 18.3 ; P = 0.0002 ) and postmenopausal patients ( HR = 3.3 , 95 % CI = 1.3 to 8.5 ; P = 0.0109 ) . There were no statist 
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