***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 Prior studies with the use of a prospect ive-retrospective design including archival tumor sample s have shown that gene-expression assays provide clinical ly useful prognostic information . However , a prospect ively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker . METHODS We performed a prospect i ve trial involving women with hormone-receptor-positive , human epidermal growth factor receptor type 2 (HER2)-negative , axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension ( or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade ) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features . A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue , and the results were used to calculate a score indicating the risk of breast-cancer recurrence ; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10 , indicating a very low risk of recurrence ( on a scale of 0 to 100 , with higher scores indicating a greater risk of recurrence ) . RESULTS Of the 10,253 eligible women enrolled , 1626 women ( 15.9 % ) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy . At 5 years , in this patient population , the rate of invasive disease-free survival was 93.8 % ( 95 % confidence interval [ CI ] , 92.4 to 94.9 ) , the rate of freedom from recurrence of breast cancer at a distant site was 99.3 % ( 95 % CI , 98.7 to 99.6 ) , the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7 % ( 95 % CI , 97.9 to 99.2 ) , and the rate of overall survival was 98.0 % ( 95 % CI , 97.1 to 98.6 ) . CONCLUSIONS Among patients with hormone-receptor-positive , HER2-negative , axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features , those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00310180 . ) 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 We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit . DESIGN Independent evaluation of six genomic tests [ Oncotype Dx ™ , MammaPrint ( ® ) , Genomic Grade Index , PAM50 ( ROR-S ) , Breast Cancer Index , and EndoPredict ] was carried out by a panel of experts in three parameters : analytical validity , clinical validity , and clinical utility based on the principles of the EGAPP criteria . PANEL STATEMENTS : The majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx ™ and MammaPrint ( ® ) to be convincing . None of the genomic tests demonstrated robust evidence of clinical utility : it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome . CONCLUSIONS The IMPAKT 2012 Working Group proposed the following recommendations : ( i ) a need to develop models that integrate clinicopathologic factors along with genomic tests ; ( ii ) demonstration of clinical utility should be made in the context of a prospect i ve r and omized trial ; and ( iii ) the creation of registries for patients who are subjected to genomic testing in the daily practice PURPOSE The 21-gene Recurrence Score ( RS ) assay has been vali date d to quantify the risk of distant recurrence in tamoxifen-treated patients with lymph node-negative , estrogen receptor-positive breast cancer and predict magnitude of chemotherapy benefit . This multicenter study was design ed to prospect ively examine whether RS affects physician and patient adjuvant treatment selection and satisfaction . PATIENTS AND METHODS Before and after obtaining the 21-gene RS assay , medical oncologists stated their adjuvant treatment recommendation and confidence in it . Patients also indicated their treatment choice pre- and post-RS assay . Patients completed measures for decisional conflict , anxiety , and quality of life . RESULTS Seventeen medical oncologists at one community and three academic practice s consecutively enrolled 89 assessable patients . The medical oncologist treatment recommendation changed for 28 patients ( 31.% ) . Twenty-four patients ( 27 % ) changed their treatment decision . The largest change after the RS results was conversion from the medical oncologist 's pretest recommendation for chemotherapy plus hormonal therapy ( CHT ) to post-test recommendation for hormone therapy ( HT ) in 20 cases ( 22.5 % ) . Nine patients ( 10.1 % ) changed their treatment decision from CHT to HT . RS results increased medical oncologist confidence in their treatment recommendation in 68 cases ( 76 % ) . Patient anxiety and decisional conflict were significantly lower after RS results . CONCLUSION The results of this study indicate that the RS assay impacts medical oncologist adjuvant treatment recommendations , patient treatment choice , and patient anxiety 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 Summary Background For women with oestrogen receptor (ER)-positive early breast cancer , treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis . We aim ed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years . Methods In the worldwide Adjuvant Tamoxifen : Longer Against Shorter ( ATLAS ) trial , 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen  were r and omly allocated to continue tamoxifen to 10 years or stop at 5 years ( open control ) . Allocation ( 1:1 ) was by central computer , using minimisation . After entry ( between 1996 and 2005 ) , yearly follow-up forms recorded any recurrence , second cancer , hospital admission , or death . We report effects on breast cancer outcomes among the 6846 women with ER-positive disease , and side-effects among all women ( with positive , negative , or unknown ER status ) . Long-term follow-up still continues . This study is registered , number IS RCT N19652633 . Findings Among women with ER-positive disease , allocation to continue tamoxifen  reduced the risk of breast cancer recurrence ( 617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls , p=0·002 ) , reduced breast cancer mortality ( 331 deaths vs 397 deaths , p=0·01 ) , and reduced overall mortality ( 639 deaths vs 722 deaths , p=0·01 ) . The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 ( recurrence rate ratio [ RR ] 0·90 [ 95 % CI 0·79–1·02 ] during years 5–9 and 0·75 [ 0·62–0·90 ] in later years ; breast cancer mortality RR 0·97 [ 0·79–1·18 ] during years 5–9 and 0·71 [ 0·58–0·88 ] in later years ) . The cumulative risk of recurrence during years 5–14 was 21·4 % for women allocated to continue versus 25·1 % for controls ; breast cancer mortality during years 5–14 was 12·2 % for women allocated to continue versus 15·0 % for controls ( absolute mortality reduction 2·8 % ) . Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease , and an intermediate effect among 4800 women with unknown ER status . Among all 12 894 women , mortality without recurrence from causes other than breast cancer was little affected ( 691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls ; RR 0·99 [ 0·89–1·10 ] ; p=0·84 ) . For the incidence ( hospitalisation or death ) rates of specific diseases , RRs were as follows : pulmonary embolus 1·87 ( 95 % CI 1·13–3·07 , p=0·01 [ including 0·2 % mortality in both treatment groups ] ) , stroke 1·06 ( 0·83–1·36 ) , ischaemic heart disease 0·76 ( 0·60–0·95 , p=0·02 ) , and endometrial cancer 1·74 ( 1·30–2·34 , p=0·0002 ) . The cumulative risk of endometrial cancer during years 5–14 was 3·1 % ( mortality 0·4 % ) for women allocated to continue versus 1·6 % ( mortality 0·2 % ) for controls ( absolute mortality increase 0·2 % ) . Interpretation For women with ER-positive disease , continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality , particularly after year 10 . These results , taken together with results from previous trials of 5 years of tamoxifen treatment versus none , suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis . Funding Cancer Research UK , UK Medical Research Council , AstraZeneca UK , US Army , EU-Biomed 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 36 
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Evidence of clinical validity for Oncotype DX was confirmed as adequate .
With regard to clinical utility , although there was evidence from prospect i ve retrospective studies that the Oncotype DX test predicts benefit from chemotherapy , and there was adequate evidence that the use of Oncotype DX gene expression profiling in clinical practice changes treatment decisions regarding chemotherapy , no direct evidence was found that the use of Oncotype DX testing leads to improved clinical outcomes .
In a previous recommendation statement , the EGAPP Working Group ( EWG ) found adequate evidence for clinical validity of some gene expression profiling tests in predicting distant disease recurrence in women with early-stage , hormone receptor – positive , lymph-node-negative breast cancer who are treated with tamoxifen , but insufficient evidence that use of these tests for decisions about chemotherapy treatment has clinical utility .
The current recommendation statement up date s these findings for Oncotype DX and extends them to the population of women with lymph node – positive disease , using evidence from recent systematic review s and other sources .Analytic validity : The previous recommendation statement found that evidence was inadequate to enable quantitative determination of the analytic validity of Oncotype DX .
Clinical validity : The EWG found that new evidence published since the original evidence review supports the clinical validity of Oncotype DX in predicting risk of distant metastases in women with hormone receptor – positive , early-stage breast cancer that is either node-negative or node-positive .
Clinical utility : No direct evidence was found that use of  Oncotype DX tumor gene expression profiling  to guide treatment decisions improves clinical outcomes in women with early breast cancer .
There is indirect evidence , from prospect i ve retrospective studies on archived tissue sample s from r and omized controlled trials , that the Oncotype DX test can predict benefit from chemotherapy .
Large , prospect i ve , r and omized , controlled trials currently in progress may provide evidence of clinical utility .