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Background: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known., Methods: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger., Results: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%)., Conclusions: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score., Methods: We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death)., Results: Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25., Conclusions: Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

Background: Identification of clinically relevant oncogenic drivers in advanced cancer is critical in selecting appropriate targeted therapy. Using next-generation sequencing (NGS)-based clinical cancer gene assay, we performed comprehensive genomic profiling (CGP) of advanced cases of lung adenocarcinoma., Methods: Formalin-fixed paraffin-embedded tumors from 51 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods were collected, and CGP was performed via hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer., Results: Genomic profiles of all 51 cases were obtained, with a median coverage of 564x and a total of 190 individual genomic alterations (GAs). GAs per specimen was a mean of 3.7 (range 0-10).Cancer genomes are characterized by 50% (80/190) non-synonymous base substitutions, 15% (29/190) insertions or deletion, and 3% (5/190) splice site mutation. TP53 mutation was the most common GAs (15%, n=29/190), followed by CDKN2A homozygous loss (5%, n=10/190), KRAS mutation (4%, n=8/190), EGFR mutation (4%, n=8/190) and MDM2 amplification (2%, n=5/190). As per NCCN guidelines, targetable GAs were identified in 16 patients (31%) (BRAF mutation [n=1], EGFR mutation [n=8], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], CD74-ROS1 rearrangement [n=1], EZR-ROS1 rearrangement [n=5], and SLC34A2-ROS1 rearrangement [n=1])., Conclusion: Fifty eight percent of patients wild type by standard testing for EGFR/KRAS/ALK have GAs identifiable by CGP that suggest benefit from target therapy. CGP used when standard molecular testing for NSCLC is negative can reveal additional avenues of benefit from targeted therapy., Competing Interests: SMA and JRG are employees of and have equity interest in Foundation Medicine, Inc.

Background: There are five multi-gene expression based prognostic tests for breast cancer offered as reference lab tests - Mammaprint, MapQuant Dx, OncotypeDx, PAM50 Breast Cancer Intrinsic Subtype Classifier, and Theros Breast Cancer Index. Each claims to provide additional prognostic information beyond conventional prognostic markers and to aid in determining who should receive systemic therapy. Evidence for their clinical utility was reviewed to determine whether any of them should be considered as routine clinical test., Methods: Peer reviewed publications, meeting abstracts, and information provided by company web sites have been reviewed to compile information regarding their clinical utility according to the following criteria; (1) Analytical validity and regulatory approval of the reference lab test. (2) Level of evidence for clinical utility. (3) Whether published evidences support prognostic and/or predictive claim., Results: While published evidences for clinical claims for OncotypeDx and Mammaprint used reference lab tests, and the supporting evidences for other tests come from academic assays before being converted to reference lab tests, results from two large randomized clinical trials testing the clinical utility of OncotypeDx and Mammaprint are still several years away and until that time none of the markers would reach level I evidence by Marker Utility Grading System. However Oncotype Dx has reached a level IB evidence according to Simon modification to Marker Utility Grading System. Therefore OncotypeDx may be considered for routine clinical use as an adjunct to clinical and pathological information and has been incorporated into clinical guidelines in USA. While Mammaprint, MapQuantDx, and PAM50 have been repeatedly demonstrated to provide robust prognostic information, evidence for its worth as a predictive marker for chemotherapy benefit is yet to come from randomize clinical trials and therefore its utility is limited to prognostication. Meta-analysis of publicly available microarray based gene expression studies demonstrated that gene expression assays provide similar information and the most important information they provide is the proliferation activity. In untreated population, the prognostic impact of proliferation genes is limited to ER+HER2- subset since HER2+ or ER-HER2- subsets are associated with high proliferation activity. Therefore the clinical utility of these gene expression based tests is mainly for ER+HER2- subset. Since they are usually treated with adjuvant anti-estrogen therapies, for their clinical utility, demonstration of the interaction between the gene expression markers and chemotherapy in anti-estrogen treated cohort in a randomized clinical trial would be required. While OncoytpeDx is the only test supported by studies in a randomized clinical trial for adjuvant chemotherapy, other gene expression based tests are expected to provide similar information. Gene expression profiling assays as more reproducible and precise surrogates for tumor grade (MapQauntDx and Theros Breast Cancer Index) are very promising assays. However, absence of definitive predefined cut-off for defining the subset that benefit from chemotherapy validated in cohorts from randomized trials limit their clinical application., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients., Patients and Methods: We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06., Results: A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV., Conclusion: RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.

Purpose: The 21-gene OncotypeDX recurrence score (RS) assay quantifies the risk of distant recurrence in tamoxifen-treated patients with node-negative, estrogen receptor (ER)-positive breast cancer. We investigated the association between RS and risk for locoregional recurrence (LRR) in patients with node-negative, ER-positive breast cancer from two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials (NSABP B-14 and B-20)., Patients and Methods: RS was available for 895 tamoxifen-treated patients (from both trials), 355 placebo-treated patients (from B-14), and 424 chemotherapy plus tamoxifen-treated patients (from B-20). The primary end point was time to first LRR. Distant metastases, second primary cancers, and deaths before LRR were censored., Results: In tamoxifen-treated patients, LRR was significantly associated with RS risk groups (P < .001). The 10-year Kaplan-Meier estimate of LRR was 4.% (95% CI, 2.3% to 6.3%) for patients with a low RS (< 18), 7.2% (95% CI, 3.4% to 11.0%) for those with intermediate RS (18-30), and 15.8% (95% CI, 10.4% to 21.2%) for those with a high RS (> 30). There were also significant associations between RS and LRR in placebo-treated patients from B-14 (P = .022) and in chemotherapy plus tamoxifen-treated patients from B-20 (P = .028). In multivariate analysis, RS was an independent significant predictor of LRR along with age and type of initial treatment., Conclusion: Similar to the association between RS and risk for distant recurrence, a significant association exists between RS and risk for LRR. This information has biologic consequences and potential clinical implications relative to locoregional therapy decisions for patients with node-negative and ER-positive breast cancer.

Background: Multigene assays performed on the primary tumors from women with non-metastatic breast cancer provide useful prognostic information and discriminate excellent versus poor outcome potential in diverse clinical scenarios. Recently, analyses were conducted to determine if these assays predict who benefits from adjuvant chemotherapy added to endocrine therapy and conversely, who might avoid chemotherapy because of lack of substantial benefit. This literature-based review summarizes these data and provides a perspective on the limitations and clinical utility of these assays., Methods: The literature regarding multigene assays and signatures in early breast cancer was surveyed. Only two assays-- the 21-gene recurrence score (RS) assay (Oncotype DX) and the 70-gene signature (MammaPrint)--were analyzed in randomized or non-randomized clinical populations in order to determine the predictive utility of the test in the adjuvant chemotherapy setting in patients whose tumors were estrogen-receptor positive. These data are summarized by type of clinical analysis, with information on clinical utility and comparative studies with standard clinical-pathologic factors., Results: From 2 independent analyses in phase III clinical trial settings with tamoxifen-alone control arms, the 21-gene RS assay defines a group of patients with low scores who do not appear to benefit from chemotherapy, and a second group with very high scores who derive major benefit from CMF or CAF chemotherapy. One study was conducted in node-negative disease, and the second in a node-positive population. Interaction terms were significant in both studies, and the effect of the assay remained upon adjustment for other standard factors. Utilizing a non-randomized clinical setting, the 70-gene signature could also predict chemotherapy benefit in the high risk group, versus no apparent benefit in the low risk group, an effect that remained after adjustment for standard factors. For both assays, the discordance rate between the assay prediction and clinical-pathologic risk category was approximately 30%. Clinical utility studies showed use of the assay results in a change in treatment decision in 25-30% of cases, most commonly from chemoendocrine therapy to endocrine therapy alone., Summary: The prediction of adjuvant chemotherapy benefit over and above endocrine therapy using multigene assay-determined risk category differs greatly across risk level and challenges the previous adjuvant therapy paradigm that degree of benefit is the same regardless of risk. These data justify current clinical use of these assays, while ongoing prospective studies will refine their role in practice settings.

Context: Gene expression-based prognostic assays for breast cancer are now available as commercial reference laboratory tests covered by insurance., Objective: To provide practicing pathologists with information about the nature of these assays, differences among them, and their use by clinical oncologists in the management of patients diagnosed with breast cancer., Data Sources: Review of literature and unpublished data from the National Surgical Adjuvant Breast and Bowel Project. This review focused on a general conceptual description of the technology behind these assays and differences among them to aid understanding by pathologists in practice., Conclusions: While these assays are clinically useful, they are still evolving. The future development of gene expression-based markers will need to be more clinical-context-specific to be clinically useful.

Several multigene markers that predict relapse more accurately than classical clinicopathologic features have been developed. The 21-gene assay was developed specifically for patients with estrogen receptor (ER)-positive breast cancer, and has been shown to predict distant recurrence more accurately that classical clinicopathologic features in patients with ER-positive breast cancer and negative axillary nodes treated with adjuvant tamoxifen; validation studies in this population led to its approval as a diagnostic test. In a similar population, it also may be used to assess the benefit of adding chemotherapy to hormonal therapy. Other validation studies indicate that it also predicts the risk of distant and local recurrence in other populations with ER-positive disease, including node-negative patients receiving no adjuvant therapy and patients with positive axillary nodes treated with doxorubicin-containing chemotherapy. The Trial Assigning Individualized Options for Treatment (TAILORx) is multicenter trial that integrates the 21-gene assay into the clinical decision-making process and is designed to refine the utility of the assay in clinical practice and to provide a resource for evaluating additional molecular markers as they are developed in the future.

Gene expression in diseased tissues can indicate the contribution to a disease process and potentially guide therapeutic decision-making. Archival tissues with associated clinical outcome may be useful to discover or validate the role of a candidate gene in a disease process or the response to therapy. Such archival tissues are commonly formalin-fixed and paraffin-embedded, restricting the methods available for gene expression analysis. Obviously, the detection of proteins in tissues requires adaptation for each protein and the detection of secreted proteins can prove difficult or of reduced value since the protein detected may not reflect the total amount produced. Thus, we describe here a reliable method for the detection of mRNA in archival tissues. The method for mRNA in situ hybridization (ISH) was adapted by us for >15 different genes and applied to several hundred tissue microarrays (TMAs) and full sections generating >10,000 expression data points. We also discuss the utility of TMAs to simultaneously analyze several hundred tissue samples on one slide to minimize variability and preserve valuable tissue samples. Experimental protocols are provided that can be implemented without major hurdles in a typical molecular pathology laboratory and we discuss quantitative analysis as well as advantages and limitations of ISH with a special focus on secreted proteins. We conclude that ISH is a reliable and cost effective approach to gene expression analysis in archival tissues that is amenable to screening of series of tissues or of genes of interest.

Although endocrine therapy is highly effective in the treatment of endocrine receptor-positive breast cancer, chemotherapy has been shown to provide clinical benefit when added to tamoxifen. However, baseline risk after tamoxifen treatment is so low, especially in patients who are axillary node negative, that significant overtreatment will result if chemotherapy is given to every patient. Robust prognostic and predictive markers need to be developed to identify those at high risk of treatment failure. Although comprehensive gene expression profiling methods do offer promise, they require fresh or frozen tumor samples. To take advantage of existing archived tissue blocks with clinical follow-up collected from finished clinical trials, such as National Surgical Adjuvant Breast and Bowel Project trials B-20 and B-14, technologies that allow interrogation of archived blocks for gene expression profiling need to be realized. Recent developments in gene expression profiling technologies are discussed with their implications in clinical management of endocrine receptor-positive breast cancer.

Breast cancer is a heterogenous disease in terms of both clinical behavior and molecular characteristics. To develop prognostic and predictive markers for breast cancer, it would be useful to be able to analyze formalin-fixed paraffin-embedded tissue (FPET) collected and banked from completed clinical trials. RNAs extracted from FPETs are chemically modified and fragmented, and are therefore not ideal substrates for gene-expression profiling assays. However, methods are being developed to optimize the use of such RNAs for high-throughput gene expression profiling assays. For microarray analysis, existing methods may be adequate for fresh FPET, but they do not work well with older FPET. For older samples, real-time reverse transcription-polymerase chain reaction is the method of choice for gene-expression profiling.

Altered expression of genes in diseased tissues can prognosticate a distinct natural progression of the disease as well as predict sensitivity or resistance to particular therapies. Archival tissues from patients with a known medical history and treatments are an invaluable resource to validate the utility of candidate genes for prognosis and prediction of therapy outcomes. However, stored tissues with associated long-term follow-up information typically are formalin-fixed, paraffin-embedded specimen and this can severely restrict the methods applicable for gene expression analysis. We report here on the utility of tissue microarrays (TMAs) that use valuable tissues sparingly and provide a platform for simultaneous analysis of gene expression in several hundred samples. In particular, we describe a stable method applicable to mRNA expression screening in such archival tissues. TMAs are constructed from sections of small drill cores, taken from tissue blocks of archival tissues and multiple samples can thus be arranged on a single microscope slide. We used mRNA in situ hybridization (ISH) on >500 full sections and >100 TMAs for >10 different cDNAs that yielded >10,000 data points. We provide detailed experimental protocols that can be implemented without major hurdles in a molecular pathology laboratory and discuss quantitative analysis and the advantages and limitations of ISH. We conclude that gene expression analysis in archival tissues by ISH is reliable and particularly useful when no protein detection methods are available for a candidate gene.

It has been suggested that Id-1 has a critical role in the tumour progression and aggressiveness of several human cancers. However, the clinicopathological and biological significance of Id-1 overexpression remains unclear in human primary cancer. To investigate the association between Id-1 expression and cell proliferation or tumour angiogenesis, we examined the cell cycle kinetic indices (the proliferation and apoptotic indices, PI and AI) and intratumoral microvessel density (MVD) in 65 human pancreatic cancers. We also investigated the relationship between its expression and various clinicopathological factors to determine the clinical significance of Id-1 overexpression. Out of a total 65 cases, 32 (49.3%) showed overexpression of Id-1 vs normal tissues. Id-1 expression was found to be significantly associated with MVD (P=0.002). In further analysis of subgroups with higher and lower Id-1 expression, tumours with higher Id-1 expression (scores 4 and 5) showed significantly higher MVD than tumours with lower expression of Id-1 (scores 2 and 3) (111.18+/-57.14 vs 64.13+/-28.19, P<0.001). However, no significant association was found between Id-1 overexpression and patient survival rate. No significant association was also found between Id-1 expression and cell cycle kinetic indices (PI or AI) in pancreatic cancer. Moreover, the overexpression of Id-1 protein was not correlated with any significant clinicopathologic factors. These findings indicate that Id-1 overexpression is closely related with tumour angiogenesis and a higher density of intratumoral vessel, but that it is not associated with a poorer prognosis of survival or a higher cell proliferative potential in human pancreatic cancer.

Nitric oxide (NO) is produced by NO synthases (nNOS, iNOS, and eNOS) expressed in various human tissues and depending on the amount of NO produced in each tissue, the physiological function of NO is determined. However, due to the difficulty in obtaining normal human tissues, little is known about the basal levels of each of the three NOS mRNAsand proteins expressed constitutively in various human tissues. Results of the present study indicate that the basal levels of each of the three NOS mRNAs and proteins expressed in various regions of brain and peripheral tissues are different both in their sizes and in their contents. In Northern blot analysis, two different-sized mRNAs were found for each NOS isozymes: for the nNOS, approximately 12 and <12 kb mRNAs; for the iNOS, 4.2 and 4.5 kb mRNAs; for the eNOS, 4.2 and 4.4 kb mRNAs. In the Western blot, several different-sized NOS proteins were detected ( approximately 160, approximately 140, and approximately 130 kDa for nNOS; approximately 130 kDa for iNOS and eNOS) with tissue-specific expression patterns. These differential expression patterns of NOS mRNAs and proteins were caused by alternative splicing in the open-reading frame, and 5'- and/or 3'-untranslated regions of NOS mRNAs. These results suggest that regulation for differential expression of the three NOS genes in various human tissues may occur by alternative splicing of the NOS mRNAs in tissue-specific patterns., (Copyright 2000 Academic Press.)

Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. Results: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus-resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. Conclusions: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC. [ABSTRACT FROM AUTHOR]

Background: Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively 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 prospective 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; ClinicalTrials.gov number, NCT00310180.). [ABSTRACT FROM AUTHOR]