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: Prognostic markers help to stratify patients for treatment by identifying patients with different risks of outcome ( e.g. recurrence of disease ) , and are important tools in the management of cancer and many other diseases . Systematic review and meta-analytical approaches to identifying the most valuable prognostic markers are needed because ( sometimes conflicting ) evidence relating to markers is often published across a number of studies . To investigate the practicality of this approach , an empirical investigation of a systematic review of  tumour markers for neuroblastoma was performed ; 260 studies of prognostic markers were identified , which considered 130 different markers . The reporting of these studies was often inadequate , in terms of both statistical analysis and presentation , and there was considerable heterogeneity for many important clinical /statistical factors . These problems restricted both the extraction of data and the meta- analysis of results from the primary studies , limiting feasibility of the evidence -based approach . Guidelines for reporting the results of primary prognostic marker studies in cancer , and other diseases , are given in order to facilitate both the interpretation of individual studies and the undertaking of systematic review s , meta- analysis and , ultimately , evidence -based practice . General availability of full individual patient data is a necessary step forward and would overcome the majority of problems encountered , including poorly reported summary statistics and variability in cutoff level , outcome assessed and adjustment factors used . It would also limit the problem of reporting bias , although publication bias will remain a concern until studies are prospect ively registered . Such changes in practice would help important evidence -based review s to be conducted in order to establish the most appropriate prognostic markers for clinical use , which should ultimately improve patient care PURPOSE To develop a guideline to improve the accuracy of immunohistochemical ( IHC ) estrogen receptor ( ER ) and progesterone receptor ( PgR ) testing in breast cancer and the utility of these receptors as predictive markers . METHODS The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance . RESULTS Up to 20 % of current IHC determinations of ER and PgR testing worldwide may be inaccurate ( false negative or false positive ) . Most of the issues with testing have occurred because of variation in preanalytic variables , thresholds for positivity , and interpretation criteria . RECOMMENDATIONS The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences . A testing algorithm that relies on accurate , reproducible assay performance is proposed . Elements to reliably reduce assay variation are specified . It is recommended that ER and PgR assays be considered positive if there are at least 1 % positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal ( normal epithelial elements ) and external controls . The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of r and omized clinical trials BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . PURPOSE To examine the importance of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , human epidermal growth factor receptor 2 ( HER-2 ) , and constructed subtypes in a large study r and omly assigning patients to receive or not receive postmastectomy radiotherapy ( PMRT ) .  PATIENTS AND METHODS The present analysis included 1,000 of the 3,083 high-risk breast cancer patients r and omly assigned to PMRT in the Danish Breast Cancer Cooperative Group ( DBCG ) protocol 82 trials b and c. Tissue microarray sections were stained for ER , PgR , and HER-2 . Median follow-up time for patients alive was 17 years . End points were locoregional recurrence as isolated first event , distant metastases , and overall survival . For statistical analyses four subgroups were constructed from hormonal receptors ( Rec ) . Rec+ was defined as ER+ and /or PgR+ . Rec-as both ER- and PgR- . The four subgroups were Rec+/HER-2- , Rec+/HER-2 + , Rec-/HER-2-(triple negative ) , and Rec-/HER-2 + . RESULTS A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients ( including the two Rec+ subtypes ) . No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis , the hormonal receptor-negative and HER-2 + patients , and in particular the Rec-/HER-2 + subtype . Furthermore , comparing hazard ratios and 95 % CIs , significantly smaller improvements in locoregional recurrence control after PMRT were found for ER- and PgR-tumors compared with the ER+ and PgR+ tumors ( P = .003 and .04 , respectively ) , and for the triple-negative ( P = .02 ) , and the Rec-/HER-2 + subtypes ( P = .003 ) compared with the Rec+/HER-2-subtype . CONCLUSION Hormonal receptor status , HER-2 , and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome . A total of 85 cDNA microarray experiments representing 78 cancers , three fibroadenomas , and four normal breast tissues were analyzed by hierarchical clustering . As reported previously , the cancers could be classified into a basal epithelial-like group , an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression . A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups , each with a distinctive expression profile . These subtypes proved to be reasonably robust by clustering using two different gene sets : first , a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and , second , a gene set that highly correlated with patient outcome . Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospect i ve study showed significantly different outcomes for the patients belonging to the various groups , including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups PURPOSE To evaluate the risk of locoregional recurrence ( LRR ) associated with locoregional treatment of women with primary breast cancer tumors negative for estrogen receptor , progesterone receptor , and human epidermal growth factor receptor 2 ( triple-negative breast cancer [ TNBC ] ) . PATIENTS AND METHODS Patients diagnosed with TNBC were identified from a cancer registry in a single institution ( n=768 ) .  LRR-free survival was estimated using Kaplan-Meier analysis . The Cox proportional hazards regression model was used to determine risk of LRR on the basis of locoregional management : breast-conserving therapy ( BCT ; ie , lumpectomy and adjuvant radiation therapy [ RT ] ) and modified radical mastectomy ( MRM ) in the TNBC population and T1 - 2N0 subgroup . RESULTS At a median follow-up of 7.2 years , 77 patients ( 10 % ) with TNBC developed LRR . Five-year LRR-free survival was 94 % , 85 % , and 87 % in the BCT , MRM , and MRM + RT groups , respectively ( P < .001 ) . In multivariate analysis , MRM ( compared with BCT ) , lymphovascular invasion and lymph node positivity were associated with increased LRR . Conversely , adjuvant chemotherapy was associated with decreased risk of LRR . For patients with T1 - 2N0 tumors , 5-year LRR-free survival was 96 % and 90 % in the BCT and MRM groups , respectively ( P = .027 ) , and MRM was the only independent prognostic factor associated with increased LRR compared with BCT ( hazard ratio , 2.53 ; 95 % CI , 1.12 to 5.75 ; P = .0264 ) . CONCLUSION Women with T1 - 2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT . Prospect i ve studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC BACKGROUND In 1976 , we initiated a r and omized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer . METHODS A total of 1851 women for whom follow-up data were available and nodal status was known underwent r and omly assigned treatment consisting of total mastectomy , lumpectomy alone , or lumpectomy and breast irradiation . Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained . RESULTS The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation , as compared with 39.2 percent in the women who underwent lumpectomy without irradiation ( P<0.001 ) . No significant differences were observed among the three groups of women with respect to disease-free survival , distant-disease-free survival , or overall survival . The hazard ratio for death among the women who underwent lumpectomy alone , as compared with those who underwent total mastectomy , was 1.05 ( 95 percent confidence interval , 0.90 to 1.23 ; P=0.51 ) . The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation , as compared with those who underwent total mastectomy , was 0.97 ( 95 percent confidence interval , 0.83 to 1.14 ; P=0.74 ) . Among the lumpectomy-treated women whose surgical specimens had tumor-free margins , the hazard ratio for death among the women who underwent postoperative breast irradiation , as compared with those who did not , was 0.91 ( 95 percent confidence interval , 0.77 to 1.06 ; P=0.23 ) . Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer . This decrease was partially offset by an increase in deaths from other causes . CONCLUSIONS Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer , provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained Background Triple-negative ( TN ) breast cancers lack estrogen receptor ( ER ) , progesterone receptor ( PR ) , and HER2/neu amplification ( HER2 ) . Few studies have been dedicated to characterizing this subset of cancer . Material s and Methods Retrospective review of a prospect ively collected data base of patients treated for invasive breast cancer at a single institution . Three tumor marker groups were compared : TN [ ER−/PR−/HER2− ] , HER2 + [ ERx/PRx/HER2 + ] , and ER+ [ ER+/PRx/HER2− ] . Results Over 8 years , 123 TN , 210 HER2 + , and 728 ER+ patients were identified . On average , TN patients were younger ( mean age TN 59.7 , HER2 + 62.0 , ER+ 64.5 years 
    Output:
    
agent
***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: Prognostic markers help to stratify patients for treatment by identifying patients with different risks of outcome ( e.g. recurrence of disease ) , and are important tools in the management of cancer and many other diseases . Systematic review and meta-analytical approaches to identifying the most valuable prognostic markers are needed because ( sometimes conflicting ) evidence relating to markers is often published across a number of studies . To investigate the practicality of this approach , an empirical investigation of a systematic review of  tumour markers for neuroblastoma was performed ; 260 studies of prognostic markers were identified , which considered 130 different markers . The reporting of these studies was often inadequate , in terms of both statistical analysis and presentation , and there was considerable heterogeneity for many important clinical /statistical factors . These problems restricted both the extraction of data and the meta- analysis of results from the primary studies , limiting feasibility of the evidence -based approach . Guidelines for reporting the results of primary prognostic marker studies in cancer , and other diseases , are given in order to facilitate both the interpretation of individual studies and the undertaking of systematic review s , meta- analysis and , ultimately , evidence -based practice . General availability of full individual patient data is a necessary step forward and would overcome the majority of problems encountered , including poorly reported summary statistics and variability in cutoff level , outcome assessed and adjustment factors used . It would also limit the problem of reporting bias , although publication bias will remain a concern until studies are prospect ively registered . Such changes in practice would help important evidence -based review s to be conducted in order to establish the most appropriate prognostic markers for clinical use , which should ultimately improve patient care PURPOSE To develop a guideline to improve the accuracy of immunohistochemical ( IHC ) estrogen receptor ( ER ) and progesterone receptor ( PgR ) testing in breast cancer and the utility of these receptors as predictive markers . METHODS The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance . RESULTS Up to 20 % of current IHC determinations of ER and PgR testing worldwide may be inaccurate ( false negative or false positive ) . Most of the issues with testing have occurred because of variation in preanalytic variables , thresholds for positivity , and interpretation criteria . RECOMMENDATIONS The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences . A testing algorithm that relies on accurate , reproducible assay performance is proposed . Elements to reliably reduce assay variation are specified . It is recommended that ER and PgR assays be considered positive if there are at least 1 % positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal ( normal epithelial elements ) and external controls . The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of r and omized clinical trials BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . PURPOSE To examine the importance of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , human epidermal growth factor receptor 2 ( HER-2 ) , and constructed subtypes in a large study r and omly assigning patients to receive or not receive postmastectomy radiotherapy ( PMRT ) .  PATIENTS AND METHODS The present analysis included 1,000 of the 3,083 high-risk breast cancer patients r and omly assigned to PMRT in the Danish Breast Cancer Cooperative Group ( DBCG ) protocol 82 trials b and c. Tissue microarray sections were stained for ER , PgR , and HER-2 . Median follow-up time for patients alive was 17 years . End points were locoregional recurrence as isolated first event , distant metastases , and overall survival . For statistical analyses four subgroups were constructed from hormonal receptors ( Rec ) . Rec+ was defined as ER+ and /or PgR+ . Rec-as both ER- and PgR- . The four subgroups were Rec+/HER-2- , Rec+/HER-2 + , Rec-/HER-2-(triple negative ) , and Rec-/HER-2 + . RESULTS A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients ( including the two Rec+ subtypes ) . No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis , the hormonal receptor-negative and HER-2 + patients , and in particular the Rec-/HER-2 + subtype . Furthermore , comparing hazard ratios and 95 % CIs , significantly smaller improvements in locoregional recurrence control after PMRT were found for ER- and PgR-tumors compared with the ER+ and PgR+ tumors ( P = .003 and .04 , respectively ) , and for the triple-negative ( P = .02 ) , and the Rec-/HER-2 + subtypes ( P = .003 ) compared with the Rec+/HER-2-subtype . CONCLUSION Hormonal receptor status , HER-2 , and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome . A total of 85 cDNA microarray experiments representing 78 cancers , three fibroadenomas , and four normal breast tissues were analyzed by hierarchical clustering . As reported previously , the cancers could be classified into a basal epithelial-like group , an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression . A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups , each with a distinctive expression profile . These subtypes proved to be reasonably robust by clustering using two different gene sets : first , a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and , second , a gene set that highly correlated with patient outcome . Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospect i ve study showed significantly different outcomes for the patients belonging to the various groups , including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups PURPOSE To evaluate the risk of locoregional recurrence ( LRR ) associated with locoregional treatment of women with primary breast cancer tumors negative for estrogen receptor , progesterone receptor , and human epidermal growth factor receptor 2 ( triple-negative breast cancer [ TNBC ] ) . PATIENTS AND METHODS Patients diagnosed with TNBC were identified from a cancer registry in a single institution ( n=768 ) .  LRR-free survival was estimated using Kaplan-Meier analysis . The Cox proportional hazards regression model was used to determine risk of LRR on the basis of locoregional management : breast-conserving therapy ( BCT ; ie , lumpectomy and adjuvant radiation therapy [ RT ] ) and modified radical mastectomy ( MRM ) in the TNBC population and T1 - 2N0 subgroup . RESULTS At a median follow-up of 7.2 years , 77 patients ( 10 % ) with TNBC developed LRR . Five-year LRR-free survival was 94 % , 85 % , and 87 % in the BCT , MRM , and MRM + RT groups , respectively ( P < .001 ) . In multivariate analysis , MRM ( compared with BCT ) , lymphovascular invasion and lymph node positivity were associated with increased LRR . Conversely , adjuvant chemotherapy was associated with decreased risk of LRR . For patients with T1 - 2N0 tumors , 5-year LRR-free survival was 96 % and 90 % in the BCT and MRM groups , respectively ( P = .027 ) , and MRM was the only independent prognostic factor associated with increased LRR compared with BCT ( hazard ratio , 2.53 ; 95 % CI , 1.12 to 5.75 ; P = .0264 ) . CONCLUSION Women with T1 - 2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT . Prospect i ve studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC BACKGROUND In 1976 , we initiated a r and omized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer . METHODS A total of 1851 women for whom follow-up data were available and nodal status was known underwent r and omly assigned treatment consisting of total mastectomy , lumpectomy alone , or lumpectomy and breast irradiation . Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained . RESULTS The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation , as compared with 39.2 percent in the women who underwent lumpectomy without irradiation ( P<0.001 ) . No significant differences were observed among the three groups of women with respect to disease-free survival , distant-disease-free survival , or overall survival . The hazard ratio for death among the women who underwent lumpectomy alone , as compared with those who underwent total mastectomy , was 1.05 ( 95 percent confidence interval , 0.90 to 1.23 ; P=0.51 ) . The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation , as compared with those who underwent total mastectomy , was 0.97 ( 95 percent confidence interval , 0.83 to 1.14 ; P=0.74 ) . Among the lumpectomy-treated women whose surgical specimens had tumor-free margins , the hazard ratio for death among the women who underwent postoperative breast irradiation , as compared with those who did not , was 0.91 ( 95 percent confidence interval , 0.77 to 1.06 ; P=0.23 ) . Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer . This decrease was partially offset by an increase in deaths from other causes . CONCLUSIONS Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer , provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained Background Triple-negative ( TN ) breast cancers lack estrogen receptor ( ER ) , progesterone receptor ( PR ) , and HER2/neu amplification ( HER2 ) . Few studies have been dedicated to characterizing this subset of cancer . Material s and Methods Retrospective review of a prospect ively collected data base of patients treated for invasive breast cancer at a single institution . Three tumor marker groups were compared : TN [ ER−/PR−/HER2− ] , HER2 + [ ERx/PRx/HER2 + ] , and ER+ [ ER+/PRx/HER2− ] . Results Over 8 years , 123 TN , 210 HER2 + , and 728 ER+ patients were identified . On average , TN patients were younger ( mean age TN 59.7 , HER2 + 62.0 , ER+ 64.5 years 
    Output:
    