***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 
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    ***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 Introduction Patients with early-stage breast cancer , treated with endocrine therapy  , have approximately 90 % 5-year disease-free survival . However , for patients at higher risk of relapse despite endocrine therapy , additional adjuvant therapy , such as chemotherapy , may be indicated . The challenge is to prospect ively identify such patients . The Mammostrat ® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions . We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up . Methods Tissue microarrays from a consecutive series ( 1981 to 1998 ) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review . Of 1,390 cases stained , 197 received no adjuvant hormonal or chemotherapy , 1,044 received tamoxifen only , and 149 received a combination of hormonal therapy and chemotherapy . Median age at diagnosis was 57 , 71 % were postmenopausal , 23.9 % were node-positive and median tumor size was 1.5 cm . Sample s were stained using triplicate 0.6 mm2 tissue microarray cores , and positivity for p53 , HTF9C , CEACAM5 , NDRG1 and SLC7A5 was assessed . Each case was assigned a Mammostrat ® risk score , and distant recurrence-free survival ( DRFS ) , relapse-free survival ( RFS ) and overall survival ( OS ) were analyzed by marker positivity and risk score . Results Increased Mammostrat ® scores were significantly associated with reduced DRFS , RFS and OS in estrogen receptor (ER)-positive breast cancer ( P < 0.00001 ) . In multivariate analyses the risk score was independent of conventional risk factors for DRFS , RFS and OS ( P < 0.05 ) . In node-negative , tamoxifen-treated patients , 10-year recurrence rates were 7.6 ± 1.5 % in the low-risk group versus 20.0 ± 4.4 % in the high-risk group . Further , exploratory analyses revealed associations with outcome in both ER-negative and untreated patients . Conclusions This is the fifth independent study providing evidence that Mammostrat ® can act as an independent prognostic tool for ER-positive , tamoxifen-treated breast cancer . In addition , this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors . When viewed in the context of previous results , these data provide further support for this antibody panel as an aid to patient  management  in early-stage breast cancer The development of tumor biomarkers ready for clinical use is complex . We propose a refined system for biomarker study design , conduct , analysis , and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies , including those using archived specimens . Although fully prospect i ve r and omized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are the gold st and ard , such trials are costly , so we discuss more efficient indirect " prospect ive-retrospective " design s using archived specimens . In particular , we propose new guidelines that stipulate that 1 ) adequate amounts of archived tissue must be available from enough patients from a prospect i ve trial ( which for predictive factors should generally be a r and omized design ) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly representative of the patients in the trial ; 2 ) the test should be analytically and preanalytically vali date d for use with archived tissue ; 3 ) the plan for biomarker evaluation should be completely specified in writing before the performance of biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier ; and 4 ) the results from archived specimens should be vali date d using specimens from one or more similar , but separate , studies Purpose : To test the association between risk stratification and outcome in a prospect ively design ed , blinded retrospective study using tissue arrays of available paraffin blocks from the estrogen receptor – expressing , node-negative sample s from the National Surgical Adjuvant Breast and Bowel Project B14 and B20 tamoxifen and chemotherapy trials . Experimental Design : Tissue arrays were stained by immunohistochemistry targeting p53 , NDRG1 , SLC7A5 , CEACAM5 , and HTF9C . Risk stratification was done using predefined scoring rules , algorithm for combining scores , and cutoff points for low-risk , moderate-risk , and high-risk patient strata . Results : In a univariate Cox model , this test was significantly associated with recurrence-free interval [ HR , 1.3 ( 95 % confidence interval , 1.1 - 1.6 ) ; P = 0.006 ] . In a multivariate model it contributed information independent of age , tumor size , and menopausal status ( P = 0.007 ) . The Kaplan-Meier estimates of the proportion of recurrence-free after 10 years were 73 % , 86 % , and 85 % for the high-risk , moderate-risk , and low-risk groups ( P = 0.001 ) . The Kaplan-Meier estimates of the breast-cancer-specific-death rate were 23 % , 10 % , and 9 % ( P < 0.0001 ) . Exploratory analysis in patients ≥60 years old showed Kaplan-Meier estimates of the proportion of recurrence-free of 78 % , 89 % , and 92 % . Both high-risk and low-risk groups showed significant improvement on treatment with cytotoxic chemotherapy . Conclusions : Immunohistochemistry using five monoclonal antibodies assigns breast cancer patients to a risk index that was significantly associated with clinical outcome among the estrogen receptor – expressing , node-negative tamoxifen-treated patients . It seems that the test may be able to identify patients who have greater absolute benefit from adjuvant chemotherapy compared with unstratified patient population s. Exploratory analysis suggests that this test will be most useful in clinical decision making for postmenopausal patients Background We carried out a prospect i ve clinical study to evaluate the impact of the Recurrence  Score  ( RS ) on treatment decisions in early breast cancer ( EBC ) . Patients and methods A total of 379 eligible women with estrogen receptor positive ( ER+ ) , HER2-negative EBC and 0–3 positive lymph nodes were enrolled .  Treatment recommendations , patients ' decisional conflict , physicians ' confidence before and after knowledge of the RS and actual treatment data were recorded . Results Of the 366 assessable patients 244 were node negative ( N0 ) and 122 node positive ( N+ ) . Treatment recommendations changed in 33 % of all patients ( N0 30 % , N+ 39 % ) . In 38 % of all patients ( N0 39 % , N+ 37 % ) with an initial recommendation for chemoendocrine therapy , the post-RS recommendation changed to endocrine therapy , in 25 % ( N0 22 % , N+ 39 % ) with an initial recommendation for endocrine therapy only to combined chemoendocrine therapy , respectively . A patients ' decisional conflict score improved by 6 % ( P = 0.028 ) and physicians ' confidence increased in 45 % ( P < 0.001 ) of all cases . Overall , 33 % ( N0 29 % , N+ 38 % ) of fewer patients actually received chemotherapy  as compared with patients recommended chemotherapy pre-test . Using the test was cost-saving versus current clinical practice . Conclusion RS-guided chemotherapy decision-making result ed in a substantial modification of adjuvant chemotherapy usage in node-negative and node-positive ER+ EBC PURPOSE Patients with breast cancer experience progression and respond to treatment in diverse ways , but prognostic and predictive tools for the oncologist are limited . We have used gene expression data to guide the production of hundreds of novel antibody reagents to discover novel diagnostic tools for stratifying carcinoma patients . PATIENTS AND METHODS One hundred forty novel and 23 commercial antisera  , selected on their ability to differentially stain tumor sample s , were used to stain paraffin blocks from a retrospective breast cancer cohort . Cox proportional hazards and regression tree analysis identified minimal panels of reagents able to predict risk of recurrence . We tested the prognostic association of these prospect ively defined algorithms in two independent cohorts . RESULTS In both validation cohorts , the Kaplan-Meier estimates of recurrence confirmed that both the Cox model using five reagents ( p53 , NDRG1 , CEACAM5 , SLC7A5 , and HTF9C ) and the regression tree model using six reagents ( p53 , PR , Ki67 , NAT1 , SLC7A5 , and HTF9C ) distinguished estrogen receptor (ER)-positive patients with poor outcomes . The Cox model was superior and distinguished patients with poor outcomes from patients with good or moderate outcomes with a hazard ratio of 2.21 ( P = .0008 ) in validation cohort 1 and 1.88 ( P = .004 ) in cohort 2 . In multivariable analysis , the calculated risk of recurrence was independent of stage , grade , and lymph node status . A model proposed for ER-negative patients failed validation in the independent cohorts . CONCLUSION A panel of five antibodies can significantly improve on traditional prognosticators in predicting outcome for ER-positive breast cancer patients The prognostic accuracy for distant recurrence‐free survival using a 21‐gene reverse 
    Output:
    
The Recurrence Score has been shown to be an independent predictor of disease-free survival , overall survival , and distant recurrence-free interval in patients with ER+ , N+ EBC .
Outcomes from decision impact and health economics studies further indicate that the Recurrence Score affects physician treatment recommendations equally in patients with N+ or N0 disease .
It also indicates that a reduction in Recurrence Score-directed chemotherapy is cost-effective .
There is a large body of evidence to support the use of the  21-gene assay Recurrence Score in patients with N+ EBC .
Use of this assay could help guide treatment decisions for patients who are most likely to receive benefit from chemotherapy