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Published Ahead of Print on March 8, 2010 as 10.1200/JCO.2009.24.4798
JOURNAL OF CLINICAL ONCOLOGY Prediction of Risk of Distant Recurrence Using the 21-GeneRecurrence Score in Node-Negative and Node-PositivePostmenopausal Patients With Breast Cancer Treated WithAnastrozole or Tamoxifen: A TransATAC StudyMitch Dowsett, Jack Cuzick, Christopher Wale, John Forbes, Elizabeth A. Mallon, Janine Salter, Emma Quinn,Anita Dunbier, Michael Baum, Aman Buzdar, Anthony Howell, Roberto Bugarini, Frederick L. Baehner,and Steven Shak From the Royal Marsden Hospital; Wolfson Institute for Preventive Medi- cine, Queen Mary University of London; University College London, London; Purpose
To determine whether the Recurrence Score (RS) provided independent information on risk of
Royal Infirmary Glasgow; Christie Hospital, Manchester, United Kingdom; distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, Tamoxifen, Alone Newcastle Mater Hospital, Newcastle, or in Combination (ATAC) Trial.
New South Wales, Australia; The University of Texas M. D. Anderson Patients and Methods
RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor–
Cancer Center, Houston, TX; and Genomic Health, Redwood City, CA.
positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessedby quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox Submitted June 9, 2009; accepted December 3, 2009; published online proportional hazards models assessed the value of adding RS to a model with clinical variables (age, ahead of print at www.jco.org on tumor size, grade, and treatment) in node-negative (N0) and node-positive (N⫹) women.
March 8, 2010.
Written on behalf of the Arimidex, Reportable scores were available from 1,231 evaluable patients (N0, n ⫽ 872; N⫹, n ⫽ 306; and Tamoxifen, Alone or in Combination node status unknown, n ⫽ 53); 72, 74, and six DRs occurred in N0, N⫹, and node status unknown (ATAC) Trialists' Group.
patients, respectively. For both N0 and N⫹ patients, RS was significantly associated with time to Supported by Breakthrough Breast DR in multivariate analyses (P ⬍ .001 for N0 and P ⫽ .002 for N⫹). RS also showed significant Cancer and AstraZeneca. M.D.
prognostic value beyond that provided by Adjuvant! Online (P ⬍ .001). Nine-year DR rates in low acknowledges National Health Services (RS ⬍ 18), intermediate (RS ⫽ 18 to 30), and high RS (RS ⱖ 31) groups were 4%, 12%, and 25%, financial support to the Royal Marsden respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N⫹ patients. The prognostic National Institute for Health Research Biomedical Research Centre.
value of RS was similar in anastrozole- and tamoxifen-treated patients.
Authors' disclosures of potential con- flicts of interest and author contribu- This study confirmed the performance of RS in postmenopausal HR⫹ patients treated with tions are found at the end of this tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N⫹ hormone receptor–positive patients treated with anastrozole, adding Corresponding author: Mitch Dowsett, value to estimates with standard clinicopathologic features.
PhD, Royal Marsden Hospital, 237 Fulham Rd, London, SW3 6JJ, United J Clin Oncol 28. 2010 by American Society of Clinical Oncology Kingdom; e-mail: mitch.dowsett@ 2010 by American Society of Clinical Many individual molecular prognostic factors have been identified in patients with primary breast Primary breast cancer has highly heterogeneous cancer, but few have played any role in disease man- clinical behavior that is underpinned by similarly agement, whereas multigene prognostic tools have heterogeneous molecular pathology. The latter can begun to guide treatment decision making. Of be used for the prediction of prognosis and response these, the Recurrence Score (RS) that is derived to therapies. A recent international survey rated de- from the Oncotype DX assay (Genomic Health, velopment of a molecular signature to identify pa- Redwood City, CA) provides a validated estimate tients who could be spared chemotherapy as the of prognosis for patients with node-negative highest translational research priority for breast can- (N0), estrogen receptor (ER)–positive disease if cer.1 Prognostic indices may identify patients at such treated with tamoxifen alone. It has also been fou- low risk of recurrence that they could gain insuffi- nd that tamoxifen-treated patients with high RS cient benefit from chemotherapy to warrant the in- showed the greatest benefit from additional chemo- herent toxicity.
therapy, whereas patients with low RS had minimal, 2010 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by Genomic Health Inc on March 10, 2010 from 75.26.142.230.
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Copyright 2010 by the American Society of Clinical Oncology. All rights reserved. Dowsett et al
if any, chemotherapy benefit.2-4 Recently, it has been reported that Oncotype DX is prognostic for hormone receptor–positive, post- The Adjuvant! Online Web site (http://www.adjuvantonline.com) was menopausal, tamoxifen-treated patients with positive nodes and that used to estimate 10-year risk of recurrence and death for each N0 patient byentering the values of the following clinical variables: tumor grade (1, 2, or 3), chemotherapy provides little, if any, benefit for patients with low RS, ER status (negative or positive), tumor size (0.1 to 1, 1.1 to 2, 2.1 to 3, 3.1 to 5, despite the presence of positive nodes.5 or ⬎ 5 cm), and age in years.10 The Adjuvant! Online risk of recurrence was Large randomized trials have established the safety and effi- adjusted for the respective effects of tamoxifen and anastrozole as specified in cacy of aromatase inhibitors (AIs) in patients with hormone the online documentation. To compare the prognostic ability of Adjuvant! receptor–positive breast cancer, and AIs are widely used in clinical Online (version 8.0) and RS in N0 patients, the 10-year predicted risk of any practice.6 The performance of the RS has not been evaluated in pa- recurrence or mortality was calculated from Adjuvant! Online and evaluated tients treated with an AI. The Arimidex, Tamoxifen, Alone or in in conjunction with the predicted risk of DR by RS.
Combination (ATAC) trial compared adjuvant treatment with anas- trozole (Arimidex; AstraZeneca, London, United Kingdom) versus Analyses were performed according to a prespecified statistical analysis tamoxifen versus a combination of both for 5 years in postmenopausal plan approved by the ATAC Steering Committee. Cox proportional hazards women with early-stage, operable breast cancer.7 Our objective was to (PH) regression models were fitted to TTDR, TTR, and OS, and hazard ratios evaluate the prognostic value of the Oncotype DX assay for distant (HRs) and associated 95% CIs were estimated. Likelihood ratio tests were used recurrence (DR) in postmenopausal women with localized N0 and for hypothesis testing. The hypothesis that there was a significant difference node-positive (N⫹) breast cancer treated with either tamoxifen or between the (reduced) PH model for DR based on patient age, pathologictumor size, local tumor grade, and treatment versus a full PH model, in which anastrozole alone in the ATAC trial.
the RS was also included, was tested in the prospectively defined primaryanalysis of N0, hormone receptor–positive patients treated either with tamox-ifen or anastrozole. The adequacy of the PH assumption was verified for all PATIENTS AND METHODS
variables by testing for a nonzero slope in a linear regression of the scaledSchoenfeld residual versus time. Improvements in prediction value were as-sessed by changes in the likelihood ratio ␹2 value, which provides a quantitative measure of the relative amount of information in this score compared with The ATAC trial evaluated the efficacy and safety of 5 years of anastrozole, other variables. Centrally assessed tumor grade was used instead of local grade tamoxifen, or the combination of both treatments in postmenopausal women in all subsequent analyses because of the expectation of greater reliability. The with localized breast cancer.7 Under the TransATAC protocol, formalin-fixed, number of positive nodes (one to three v ⱖ four positive nodes) was also paraffin-embedded blocks of the primary tumor were collected from as many included as a covariate for analyses in N⫹ patients.
hormone receptor–positive patients as possible from the monotherapy arms.8 To determine whether RS had a prognostic effect independent of Adju- Collection ceased on September 30, 2006. The current study examined vant! Online in N0 patients, the reduced PH model for DR, based on Adjuvant! samples collected from the United Kingdom, which constituted 79% of Online–predicted 10-year recurrence rate (based on tumor grade, ER status, the collection.
tumor size and age) and treatment group, was compared with the (full) PHmodel, which also included the RS predicted risk.2 The Adjuvant! Online– predicted 10-year risk of recurrence with surgery alone was adjusted (ie, The Oncotype DX RS was determined from fixed paraffin-embedded reduced) for the effects of tamoxifen or anastrozole as specified in the online tissue as previously described.2 After review of hematoxylin and eosin–stained documentation. Kaplan-Meier curves were calculated for RS groups and slides to determine whether sufficient invasive breast cancer was present and tested for equality using the log-rank test.
whether manual microdissection was indicated, RNA was extracted from three To define the continuous relation between RS, as a linear covariate, and 10-␮m unstained sections. Total RNA content was measured, and the absence 9-year risk of DR, the logarithm of the baseline cumulative hazard function of DNA contamination was verified. Gene expression profiling by standard- was fitted by constrained cubic splines with three df. These models11 tend to be ized quantitative reverse transcriptase polymerase chain reaction for the On- more robust for prediction of survival probabilities and corresponding confi- cotype DX assay was performed using the prespecified 21 Oncotype DX genes.
dence limits at late follow-up times as a result of the modeling of the baseline Reference-normalized expression measurements for each of the 16 cancer- cumulative hazard function by natural cubic splines (in contrast to using the related genes ranged from 2 to 16, where each one-unit increase reflects crude hazard function itself). Prediction of risks was then obtained by PH approximately a two-fold increase in RNA. The RS, on a scale from 0 to 100, model after having verified the appropriateness of the proportional assump- was derived from the reference-normalized expression measurements for the tion and the linear functional form for RS. There were minimal data after 9 16 cancer-related genes.
years, and the decision to calculate estimates of DR at 9 years was made beforethe data analyses, in keeping with previous ATAC analyses.7 Analyses were also conducted with TTR and OS as end points. All hypothesis tests were con- Local reading of tumor grade was derived from the case record forms.
ducted at the two-sided P ⫽ .05 level.
Central tumor grade was assessed by E.A.M. using the Elston and Ellis system.9ER status was derived centrally by immunohistochemistry.8 Study End Points
The association between RS and time to DR (TTDR, also known as Characteristics of Study Population and
DR-free interval), time to recurrence (TTR, also known as recurrence-free interval), and overall survival (OS) was evaluated. TTDR, the time from Four thousand one hundred sixty hormone receptor–positive random assignment to first DR, was the prospectively defined primary end patients were randomly assigned to the monotherapy arms of the point. For TTDR, contralateral disease, local/regional recurrence, and other ATAC trial. A total of 2,006 blocks were obtained; 1,372 blocks from second primary cancers were not considered as events; death before DR wasconsidered a censoring event. TTR was defined as time from random assign- patients from the United Kingdom contained sufficient invasive tu- ment to first locoregional recurrence, DR, or contralateral disease. OS was mor for analysis; reverse transcriptase polymerase chain reaction was defined as time from random assignment to death from any cause.
successful in 1,308 samples (95%). After merging the genomic and 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by Genomic Health Inc on March 10, 2010 from 75.26.142.230.
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patients were treated with tamoxifen, and 622 were treated with Table 1. Summary of Demographics and Clinical Characteristics of
anastrozole. The clinical characteristics of the 1,231 patients in this Patients in the Present Study Versus the Broader Population of Hormone Receptor–Positive Patients in the Anastrozole and Tamoxifen study are listed in Table 1, along with the characteristics of the 2,929 Single-Agent Arms of the Original ATAC Trial randomly assigned, hormone receptor–positive patients in the ATAC % of Patients in Single- trial who were not included in this study. Although there were several Agent Arms of ATAC statistically significant differences, the magnitude of the differences Trial Not Included in In the N0 and N⫹ subgroups, 72 patients (8%) and 74 patients (24%), respectively, experienced DR. Six DR events (11%) occurred in patients with unknown nodal status. In N0 patients, 59% had an RS of less than 18, 26% had an RS of 18 to 30, and 15% had an RS of ⱖ 31; in ⫹ patients, the distribution was 52%, 31%, and 17%, respectively.
RS and Risk of DR
In the prespecified primary analysis in all N0 patients, RS for a 50-point change (eg, RS ⫽ 55 v RS ⫽ 5) was significantly associated with risk of DR (HR ⫽ 3.92; 95% CI, 2.08 to 7.39; ⌬␹2 ⫽ 15.5; P ⬍ .001) when adjusted for the effects of tumor size, local grade, age, and treatment. When local grade was replaced with central grade in the multivariate analysis, RS adjusted for the same features was also significantly associated with the risk of DR (HR ⫽ 5.25; 95% CI, 2.84 Tamoxifen before surgery to 9.73; ⌬␹2 ⫽ 22.7; P ⬍ .001; Table 2), and the difference between the two was not statistically significant. Tumor size and RS were each separately statistically significant in predicting TTDR in N0 patients (⌬␹2 ⫽ 16.5, P ⬍ .001 and ⌬␹2 ⫽ 22.7, P ⬍ .001, respectively). The RS was also predictive of TTDR in N⫹ patients, with an HR of 3.47 (95% Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination; HRT, CI, 1.64 to 7.38; ⌬␹2 ⫽ 9.4; P ⫽ .002) in multivariate analyses; number hormone replacement therapy; BMI, body mass index.
ⴱThe unknown category was not used for comparisons.
of positive nodes (⌬␹2 ⫽ 22.7, P ⬍ .001) and tumor size (⌬␹2 ⫽ 7.7,P ⫽ .006) were also statistically significant variables in multivari-ate analyses.
Kaplan-Meier curves (Figs 1A and 1B) show clear differences in clinical databases, 77 patients were excluded as a result of clinical absolute DR rates for N0 and N⫹ patients according to RS. The rates characteristics (65 patients received adjuvant chemotherapy, four of DR at 9 years in the RS less than 18, RS 18 to 30, and RS ⱖ 31 groups patients were hormone receptor negative, and eight patients did were 4% (95% CI, 3% to 7%), 12% (95% CI, 8% to 18%), and 25% not start endocrine therapy). In the 1,231 evaluable patients, median (95% CI, 17% to 34%), respectively, in N0 patients and 17% (95% CI, follow-up time was 8.5 years. Eight hundred seventy-two patients 12% to 24%), 28% (95% CI, 20% to 39%), and 49% (95% CI, 35% to (71%) were N0, 306 patients (25%) were N⫹ (243 [79%] with one to 64%), respectively, in N⫹ patients. When adjusted for clinical vari- three positive nodes and 63 [21%] with ⱖ four positive nodes), and ables, in N0 patients, the HR between high and low RS groups was 53 patients (4%) had unknown nodal status. Six hundred nine 5.2 (95% CI, 2.7 to 10.1) and the HR between intermediate and low Table 2. Multivariate Cox Proportional Hazard Models for Estimating the Added Effect of Recurrence Score in N0 and N⫹ Patients
N0 Patients (n ⫽ 872) N⫹ Patients (n ⫽ 306) Recurrence score† Tumor size: ⬎ 2 v ⱕ 2 cm Moderate v well Poor v well Age: ⬍ 65 v ⱖ 65 years Positive nodes: ⱖ 4 v 1-3 nodes Abbreviation: HR, hazard ratio.
ⴱLikelihood ratio test was used; analyses have also been adjusted for treatment. ⌬␹2 P values are based on the value of adding the specified variable to a model including all other variables.
†Recurrence Score was a continuous variable, with the HR for distant recurrence calculated relative to an increment of 50 units (eg, the HR for Recurrence Score ⫽ 55 v Recurrence Score ⫽ 5), chosen to be consistent with prior clinical validation studies.
‡2 df.
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Log-rank P < .001 High v Low 5.2 (2.7 to 10.1) Proportion Distant Int v Low Distant Recurrence Log-rank P < .001 1–3 Positive Nodes 4+ Positive Nodes Fig 2. Predicted risk of distant recurrence and 95% CI as a continuous function
of the recurrence score (RS), by number of positive nodes. Vertical lines High v Low Proportion Distant delineate the borders between the prespecified RS groups. Rug plot shows Int v Low the similarity of the distributions of RS in patients with 0, 1 to 3, and 4⫹positive nodes.
Fig 1. (A) Kaplan-Meier plots of distant recurrence by recurrence score group in
cally significant when Adjuvant! Online was calculated using central node negative patients, both treatment arms (N ⫽ 872). Hazard ratios (HR) for RS grade (Spearman rank correlation group adjusted for tumor size, grade, age, and treatment. (B) Kaplan-Meier plots ⫽ 0.23; P ⬍ .001; Fig 4) or local of distant recurrence by recurrence score group in node positive patients, both grade (Spearman rank correlation ⫽ 0.22; P ⬍ .001); only approxi- treatment arms (N ⫽ 306). HRs for RS group adjusted for tumor size, grade, age, mately 5% of the variability in the estimates of recurrence using either treatment, and number of positive nodes.
of these scores was explained by the other. Thus, the prognostic infor-mation from RS was independent of the prognostic effect of Adjuvant! RS groups was 2.5 (95% CI, 1.3 to 4.5); in N⫹ patients, the HRs Online and vice versa. In a model adjusted for treatment, RS and were 2.7 (95% CI, 1.5 to 5.1) and 1.8 (95% CI, 1.0 to 3.2), respec- Adjuvant! Online each provided a comparable degree of mutually tively. Similar results were observed considering OS as an end point independent predictive information (⌬␹2 ⫽ 21.9, P ⬍ .001 for both).
(Appendix Figs A1 and A2, online only); the OS rates at 9 years in Similar results were observed for local grade and for Adjuvant! Online the RS less than 18, RS 18 to 30, and RS ⱖ 31 groups were 88%, estimates of OS (data not shown).
84%, and 73%, respectively, in N0 patients and 74%, 69%, and54%, respectively, in N⫹ patients.
The risk of DR increased linearly with increasing RS (Fig 2). For any RS, the risk of DR was higher for N⫹ than N0 patients and forpatients with ⱖ four positive nodes than patients with one to threepositive nodes. Similar results were obtained with fractional polyno- mial regression12 (data not shown).
Node negative, both arms (n = 872) RS and Risk of DR by Treatment
Tamoxifen (n = 432) The prognostic value of RS was assessed by treatment group Anastrozole (n = 440) using a multivariate Cox PH model adjusted for tumor size, centraltumor grade, nodal status, and age. The HRs for DR for a 50-pointchange in RS in the separate treatment groups, adjusted for tumor size, Node positive, both arms (n = 306) Tamoxifen (n = 152) central tumor grade, number of nodes, and age, are shown in Figure 3.
Anastrozole (n = 154) Additional analyses indicated that there was no significant RS ⫻ treat-ment interaction in any subgroup (ie, P ⱖ .34 in all patients, P ⱖ .33 in N0 patients, and P ⱖ .40 in N⫹ patients), with tumor grade assessedeither centrally or locally.
Fig 3. Hazard ratios and 95% CIs for a 50-point difference in recurrence score
RS, Adjuvant! Online, and Recurrence
(RS), by nodal status and treatment, adjusted for tumor size, central tumor grade,number of nodes, and age. Area of the square is proportional to the number of The correlation between predicted risk of DR by RS and of distant recurrence events. Hazard ratios are on a logarithmic scale and per recurrence by Adjuvant! Online for N0 patients was low but statisti- 50-point difference in RS.
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pected, but this was not significantly different from the estimate using Spearman rank correlation = 0.23 local grade. In addition, the primary end point examined, TTDR (ie, P < .001 DR-free interval), is clinically highly relevant, being a strongly predic-tive surrogate marker for breast cancer–specific mortality.15 More- over, the clinical follow-up in this study (median, 8.5 years) wasrelatively long.
The results from the RS were highly consistent with all the previ- ous observations. A low RS (⬍ 18) was associated with a low (3% to 7%) likelihood of DR at 9 years in N0 patients in this study and wasassociated with excellent OS.
The results of the overall ATAC study indicate that there is a 16% relative reduction in the rate of DR for patients treated withanastrozole compared with patients treated with tamoxifen.7 Inthis study, the HR for RS was similar in both treatment arms, andthere was no significant interaction of RS with treatment arm.
Thus, the relative risk reduction for anastrozole compared withtamoxifen is similar across different values of the RS, and accord- Adjuvant! Risk Using Central Grade (%)† ingly, the absolute benefit for anastrozole compared with tamox- Fig 4. Predicted risk of recurrence by recurrence score (RS) and Adjuvant! N0
ifen would be predicted to be larger in patients with a high RS and patients (n ⫽ 872). (*) Predicted risk of distant recurrence at 10 years from RS.
smaller in patients with a low RS. However, the number of patients (†) Predicted risk of recurrence at 10 years from Adjuvant! available for analysis does not allow accurate quantification of thisdifference, and the possibility of some interaction between RS andtreatment cannot be fully excluded.
We have confirmed the previous observations from the National Surgical Adjuvant Breast and Bowel Project B-142 and Eastern Coop- Over recent years, increasing proportions of patients with breast erative Oncology Group 219716 studies that there is a poor correlation cancer have been diagnosed with small hormone receptor–positive between the RS and Adjuvant! Online, but we also confirmed that tumors and negative axillary nodes. Overall, these patients have rela- both measures provide substantial independent prognostic informa- tively good prognosis, which is improved further by adjuvant endo- tion. The independent prognostic nature of standard clinical param- crine therapy that virtually all hormone receptor–positive women are eters, such as tumor size, tumor grade, and patient age, which are used scheduled to receive. However, some of these patients are destined to in Adjuvant! Online, and the molecular predictors used in the RS experience relapse even with endocrine therapy and would appropri- indicates that there is an opportunity to combine the two types of ately be considered for adjuvant cytotoxic chemotherapy.
measures to provide a single integrated prognostic tool for the oncol- Clinical parameters can help characterize risk and, in some cases, ogist. A proper comparison between the RS and Adjuvant! Online in have been integrated as convenient Web-based algorithms as with N⫹ patients could not be performed because of variable nodal status, Adjuvant! Online.10 However, parameters such as tumor size and which is included in Adjuvant! Online but not in the RS.
nodal status do not reveal the wide molecular heterogeneity seen Although our study did not directly evaluate the value of RS in between breast tumors even within the hormone receptor–positive predicting the benefit of chemotherapy, other studies, such as the subgroup.13-14 The Oncotype DX test uses molecular features of tu- National Surgical Adjuvant Breast and Bowel Project B-204 study, the mors to stratify the residual risk of DR in patients with hormone Southwest Oncology Group5 study, the study by Gianni et al,17 and receptor–positive N0 primary breast cancer treated with tamoxifen.
the study by Chang et al,18 suggest that there is little, if any, benefit of This test had not been assessed for its prediction of residual risk in chemotherapy for patients with low RS tumors for a variety of chem- AI-treated patients. The current analysis within the ATAC trial popu- otherapy regimens. Thus, the absolute risk reduction associated with lation, in addition to providing a set of patients treated with the AI the addition of chemotherapy to hormonal therapy in patients with anastrozole, has provided a more contemporary population oftamoxifen-treated patients than those reported previously and has low RS and one to three positive nodes is likely to be modest, at least in also validated the test for patients from outside of North America.
the first 10 years.
Although there were several statistically significant differences in base- In summary, this study has confirmed the performance of RS in line characteristics between the hormone receptor–positive ATAC postmenopausal hormone receptor–positive patients treated with ta- patients included and not included in this study, the magnitude of the moxifen in a large contemporary population. It demonstrates for the differences was small and not clinically meaningful.
first time that RS is an independent predictor of DR in N0 and N⫹ Strengths of the study are its use of a standardized quantitative hormone receptor–positive patients treated with anastrozole. The in- assay where all the methods and the analysis plan were prospectively formation from the RS adds to that provided by standard measures defined and all of the laboratory data were obtained blinded to study such as nodal status, patient age, tumor size, and tumor grade. The outcome or other clinical factors. The robustness of the RS was con- established relationship between RS and DR for tamoxifen may now firmed by its prognostic value in the presence of both local and central be applied for anastrozole with an approximately 16% adjustment for grade. The higher HR for DR when using central grade was unex- the lower risk of DR with the AI.
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AstraZeneca; Jack Cuzick, AstraZeneca; Aman Buzdar, AstraZeneca AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS
Expert Testimony: None Other Remuneration: None
OF INTEREST
Although all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subject Conception and design: Mitch Dowsett, Jack Cuzick, John Forbes,
matter under consideration in this article. Certain relationships marked Michael Baum, Aman Buzdar, Anthony Howell, Steven Shak with a "U" are those for which no compensation was received; those Administrative support: Frederick L. Baehner
relationships marked with a "C" were compensated. For a detailed Provision of study materials or patients: Mitch Dowsett, John Forbes,
description of the disclosure categories, or for more information about Anita Dunbier, Michael Baum, Aman Buzdar, Anthony Howell ASCO's conflict of interest policy, please refer to the Author Disclosure Collection and assembly of data: Mitch Dowsett, Jack Cuzick,
Declaration and the Disclosures of Potential Conflicts of Interest section in Christopher Wale, Elizabeth A. Mallon, Janine Salter, Emma Quinn, Information for Contributors. Anita Dunbier, Roberto Bugarini, Frederick L. Baehner, Steven Shak Employment or Leadership Position: Roberto Bugarini, Genomic
Data analysis and interpretation: Mitch Dowsett, Jack Cuzick,
Health (C); Frederick L. Baehner, Genomic Health (C); Steven Christopher Wale, John Forbes, Elizabeth A. Mallon, Janine Salter, Shak, Genomic Health (C) Consultant or Advisory Role: Mitch
Emma Quinn, Anita Dunbier, Roberto Bugarini, Frederick L. Baehner, Dowsett, AstraZeneca (C); Jack Cuzick, AstraZeneca (C); John Forbes, AstraZeneca (U); Michael Baum, AstraZeneca (C); Aman Manuscript writing: Mitch Dowsett, Jack Cuzick, Christopher Wale,
Buzdar, AstraZeneca (C) Stock Ownership: Roberto Bugarini,
Janine Salter, Roberto Bugarini, Steven Shak Genomic Health; Frederick L. Baehner, Genomic Health; Steven Shak, Final approval of manuscript: Mitch Dowsett, Jack Cuzick, Christopher
Genomic Health Honoraria: Mitch Dowsett, AstraZeneca; Jack Cuzick,
Wale, John Forbes, Elizabeth A. Mallon, Janine Salter, Emma Quinn, AstraZeneca; John Forbes, AstraZeneca; Michael Baum, AstraZeneca; Anita Dunbier, Michael Baum, Aman Buzdar, Anthony Howell, Roberto Aman Buzdar, AstraZeneca Research Funding: Mitch Dowsett,
Bugarini, Frederick L. Baehner, Steven Shak 7. Arimidex, Tamoxifen, Alone or in Combination
tional form for continuous predictors in multivariable (ATAC) Trialists' Group, Forbes JF, Cuzick J, et al: model building. Stat Med 26:5512-5528, 2007 Effect of anastrozole and tamoxifen as adjuvant 13. Sotiriou C, Pusztai L: Gene-expression signa-
1. Dowsett M, Goldhirsch A, Hayes DF, et al:
treatment for early-stage breast cancer: 100-month tures in breast cancer. N Engl J Med 360:790-800, International Web-based consultation on priorities analysis of the ATAC trial. Lancet Oncol 9:45-53, for translational breast cancer research. Breast Can- 14. Mackay A, Urruticoechea A, Dixon JM, et al:
cer Res 9:R81, 2007 8. Dowsett M, Allred C, Knox J, et al: Relation-
Molecular response to aromatase inhibitor treat- 2. Paik S, Shak S, Tang G, et al: A multigene
ship between quantitative estrogen and progester- ment in primary breast cancer. Breast Cancer Res assay to predict recurrence of tamoxifen-treated, one receptor expression and human epidermal node-negative breast cancer. N Engl J Med 351: growth factor receptor 2 (HER-2) status with recur- 15. Cuzick J: Primary endpoints for randomised
rence in the Arimidex, Tamoxifen, Alone or in Com- trials of cancer therapy. Lancet 371:2156-2158, bination trial. J Clin Oncol 26:1059-1065, 2008 3. Habel LA, Shak S, Jacobs MK, et al. A
9. Elston CW, Ellis IO: Pathological prognostic
population-based study of tumor gene expression 16. Goldstein LJ, Gray R, Badve S, et al: Prognos-
factors in breast cancer: I. The value of histological and risk of breast cancer death among lymph node- tic utility of the 21-gene assay in hormone receptor- grade in breast cancer: Experience from a large negative patients. Breast Cancer Res 8:R25, 2006 positive operable breast cancer compared with study with long-term follow-up. Histopathology 19: 4. Paik S, Tang G, Shak S, et al: Gene expression
classical clinicopathologic features. J Clin Oncol and benefit of chemotherapy in women with node- 26:4063-4071, 2008 10. Ravdin PM, Siminoff LA, Davis GJ: Computer
negative, estrogen receptor-positive breast cancer.
program to assist in making decisions about adju- 17. Gianni, Zambetti M, Clark K, et al: Gene
J Clin Oncol 24:3726-3734, 2006 vant therapy for women with early breast cancer.
expression profiles in paraffin-embedded core bi- 5. Albain K, Barlow W, Shak S, et al: Prognostic
J Clin Oncol 19:980-991, 2001 opsy tissue predict response to chemotherapy in and predictive value of the 21-gene recurrence 11. Royston P, Parmar MK: Flexible parametric
women with locally advanced breast cancer. J Clin score assay in postmenopausal women with node- proportional-hazards and proportional-odds models Oncol 23:7265-7277, 2005 positive, estrogen receptor positive breast cancer for censored survival data, with application to prog- 18. Chang J, Makris A, Gutierrez MC, et al: Gene
on chemotherapy: A retrospective analysis of a nostic modeling and estimation of treatment ef- randomized trial. Lancet Oncol 11:55-65, 2010 fects. Stat Med 21:2175-2197, 2002 embedded core biopsies predict docetaxel chemo- 6. Smith IE, Dowsett M: Aromatase inhibitors in
12. Sauerbrei W, Royston P, Binder H: Selection
sensitivity in breast cancer patients. Breast Cancer breast cancer. N Engl J Med 348:2431-2442, 2003 of important variables and determination of func- Res Treat 108:233-240, 2008 We thank collaborating investigators and pathologists and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Steering and Pathology Committees for guidance; and many at GHI, including Audrey Goddard, Angela Chen, Carl Yoshizawa, Drew Watson, Chithra Sanghi, Clare Alexander, Meike Labusch, Jackie Brooks, and Lauren Intagliata for their efforts.
2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by Genomic Health Inc on March 10, 2010 from 75.26.142.230.
Copyright 2010 by the American Society of Clinical Oncology. All rights reserved. Recurrence Score in TransATAC
Log-rank P < .001 RS Risk Group
High v Low Int v Low Fig A1. Overall survival by recurrence score (RS) group in node-negative patients. Hazard ratio (HR) adjusted for tumor size, grade, age, and treatment.
Log-rank P = .002 RS Risk Group
High v Low Int v Low Fig A2. Overall survival by recurrence score (RS) group in node-positive patients. Hazard ratio (HR) adjusted for tumor size, grade, age, treatment, and number of
positive nodes.
2010 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by Genomic Health Inc on March 10, 2010 from 75.26.142.230.
Copyright 2010 by the American Society of Clinical Oncology. All rights reserved.

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