A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer
Soonmyung Paik, M.D., Steven Shak, M.D., Gong Tang, Ph.D., Chungyeul Kim, M.D., Joffre Baker, Ph.D., Maureen Cronin, Ph.D., Frederick L. Baehner, M.D., Michael G. Walker, Ph.D., Drew Watson, Ph.D., Taesung Park, Ph.D., William Hiller, H.T., Edwin R. Fisher, M.D., D. Lawrence Wickerham, M.D., John Bryant, Ph.D., and Norman Wolmark, M.D.
Background The likelihood of distant recurrence in patientswith breast cancer who have no involved lymph nodes and estrogen-receptor–positivetumors 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 prospectively selected genes in paraffin-embeddedtumor tissue would correlate with the likelihood of distantrecurrence in patients with node-negative, tamoxifen-treatedbreast cancer who were enrolled in the National Surgical AdjuvantBreast and Bowel Project clinical trial B-14. The levels ofexpression of 16 cancer-related genes and 5 reference geneswere used in a prospectively defined algorithm to calculatea 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 675tumor blocks. The proportions of patients categorized as havinga low, intermediate, or high risk by the RT-PCR assay were 51,22, and 27 percent, respectively. The Kaplan–Meier estimatesof the rates of distant recurrence at 10 years in the low-risk,intermediate-risk, and high-risk groups were 6.8 percent (95percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percentconfidence interval, 8.3 to 20.3), and 30.5 percent (95 percentconfidence interval, 23.6 to 37.4). The rate in the low-riskgroup was significantly lower than that in the high-risk group(P<0.001). In a multivariate Cox model, the recurrence scoreprovided significant predictive power that was independent ofage and tumor size (P<0.001). The recurrence score was alsopredictive of overall survival (P<0.001) and could be usedas a continuous function to predict distant recurrence in individualpatients.
Conclusions The recurrence score has been validated as quantifyingthe likelihood of distant recurrence in tamoxifen-treated patientswith node-negative, estrogen-receptor–positive breastcancer.
Over the past two decades, the molecular dissection of cancerhas increased our understanding of the pathways that are alteredin neoplastic cells.1,2 Nevertheless, the diagnosis of cancerand decisions about its treatment still rely largely on classichistopathological and immunohistochemical techniques. A morequantitative approach to diagnosis and rational individualizationof treatment are needed.
Large clinical trials, such as National Surgical Adjuvant Breastand Bowel Project (NSABP) trials B-14 and B-20, have demonstratedthe benefit of tamoxifen and chemotherapy in women who havenode-negative, estrogen-receptor–positive breast cancer.3,4,5However, since the likelihood of distant recurrence in patientstreated with tamoxifen alone after surgery is about 15 percentat 10 years, at least 85 percent of patients would be overtreatedwith chemotherapy if it were offered to everyone. Numerous attemptshave been made to identify biomarkers of residual risk,6,7,8,9but none of them have been recommended for guiding treatment.10,11,12,13,14,15Molecular signatures of gene expression in tumor tissue thatcorrelate with recurrence of breast cancer have been identifiedby methods based on the use of DNA arrays.16,17,18,19,20,21However, the requirement for fresh or snap-frozen tissue anduncertainties about the reproducibility of such methods havelimited their clinical application.
We used a multistep approach to develop an assay of the expressionof tumor-related genes for use with routinely prepared tumorblocks and to validate the assay clinically. First, a high-throughput,real-time, reverse-transcriptase–polymerase-chain-reaction(RT-PCR) method was developed to quantify gene expression withthe use of sections of fixed, paraffin-embedded tumor tissue.22Second, we selected 250 candidate genes from the published literature,genomic databases, and experiments based on DNA arrays performedon fresh-frozen tissue.17,18,19,23 Third, we analyzed data fromthree independent clinical studies of breast cancer involvinga total of 447 patients, including the tamoxifen-only groupof NSABP trial B-20, to test the relation between expressionof the 250 candidate genes and the recurrence of breast cancer.24,25,26Fourth, we used the results of the three studies to select apanel of 16 cancer-related genes and 5 reference genes and designedan algorithm, based on the levels of expression of these genes,to compute a recurrence score for each tumor sample. The studyreported here was performed to validate the ability of the prospectivelydefined, 21-gene RT-PCR assay and recurrence-score algorithmto quantify the likelihood of distant recurrence in patientswith node-negative, estrogen-receptor–positive breastcancer who had been treated with tamoxifen in the large, multicenterNSABP trial B-14.
Methods
Patients
NSABP trial B-14 (entitled "A Clinical Trial to Assess Tamoxifenin Patients with Primary Breast Cancer and Negative AxillaryNodes Whose Tumors Are Positive for Estrogen Receptors") enrolled2892 patients who were randomly assigned to receive placeboor tamoxifen between January 4, 1982, and January 25, 1988,and enrolled 1235 additional patients, all treated with tamoxifen,between January 26, 1988, and October 17, 1988. The currentstudy of the recurrence score was approved by the Essex InstitutionalReview Board (Lebanon, N.J.) and by the institutional reviewboards of Allegheny General Hospital and the University of Pittsburgh(both in Pittsburgh). The need for additional informed consentwas waived by the institutional review boards.
Sample Preparation
Paraffin blocks with cancer cells occupying less than 5 percentof the section area were excluded from the study. Macrodissectionwas performed with the use of a safety blade for cases involvingnontumor elements that were amenable to macrodissection andthat constituted more than 50 percent of the overall area ofthe tissue section. RNA was extracted from three 10-µmsections when macrodissection had not been performed or fromsix 10-µm sections when macrodissection had been performed.
Assay Methods, Gene Selection, and Recurrence-Score Algorithm
Gene expression in fixed, paraffin-embedded tumor tissue wasmeasured as described by Cronin et al.22 The Oncotype DX assay(Genomic Health) was used. In brief, after RNA extraction andDNase I treatment, total RNA content was measured and the absenceof DNA contamination was verified (as described in the Supplementary Appendix,available with the full text of this article at www.nejm.org).Reverse transcription was performed and was followed by quantitativeTaqMan RT-PCR reactions in 384-well plates, performed with theuse of Prism 7900HT instruments (Applied Biosystems). The expressionof each gene was measured in triplicate and then normalizedrelative to a set of five reference genes (ACTB [the gene encoding-actin], GAPDH, GUS, RPLPO, and TFRC). Reference-normalizedexpression measurements ranged from 0 to 15, where a 1-unitincrease reflected an approximate doubling of RNA.
The list of 21 genes and the recurrence-score algorithm (Figure 1)were designed by analyzing the results of the three independentpreliminary studies involving 447 patients and 250 candidategenes24,25,26 (as described in the Supplementary Appendix).The selection of the final 16 cancer-related genes was basedprimarily on the strength of their performance in all threestudies and the consistency of primer or probe performance inthe assay. The range of possible recurrence scores was 0 to100 (where higher scores indicated a greater likelihood of recurrence)and was derived from the reference-normalized expression measurementsfor the 16 cancer-related genes.
Figure 1. Panel of 21 Genes and the Recurrence-Score Algorithm.
The recurrence score on a scale from 0 to 100 is derived from the reference-normalized expression measurements in four steps. First, expression for each gene is normalized relative to the expression of the five reference genes (ACTB [the gene encoding -actin], GAPDH, GUS, RPLPO, and TFRC). Reference-normalized expression measurements range from 0 to 15, with a 1-unit increase reflecting approximately a doubling of RNA. Genes are grouped on the basis of function, correlated expression, or both. Second, the GRB7, ER, proliferation, and invasion group scores are calculated from individual gene-expression measurements, as follows: GRB7 group score = 0.9 x GRB7 + 0.1 x HER2 (if the result is less than 8, then the GRB7 group score is considered 8); ER group score = (0.8 x ER + 1.2 x PGR + BCL2 + SCUBE2) ÷ 4; proliferation group score = (Survivin + KI67 + MYBL2 + CCNB1 [the gene encoding cyclin B1] + STK15) ÷ 5 (if the result is less than 6.5, then the proliferation group score is considered 6.5); and invasion group score = (CTSL2 [the gene encoding cathepsin L2] + MMP11 [the gene encoding stromolysin 3]) ÷ 2. The unscaled recurrence score (RSU) is calculated with the use of coefficients that are predefined on the basis of regression analysis of gene expression and recurrence in the three training studies24,25,26: RSU = + 0.47 x GRB7 group score – 0.34 x ER group score + 1.04 x proliferation group score + 0.10 x invasion group score + 0.05 x CD68 – 0.08 x GSTM1 – 0.07 x BAG1. A plus sign indicates that increased expression is associated with an increased risk of recurrence, and a minus sign indicates that increased expression is associated with a decreased risk of recurrence. Fourth, the recurrence score (RS) is rescaled from the unscaled recurrence score, as follows: RS=0 if RSU<0; RS=20x(RSU–6.7) if 0RSU100; and RS=100 if RSU>100.
Cutoff points were prespecified to classify patients into thefollowing categories: low risk (recurrence score, less than18), intermediate risk (recurrence score, 18 or higher but lessthan 31), and high risk (recurrence score, 31 or higher). Thecutoff points were chosen on the basis of the results of NSABPtrial B-20.
Reproducibility within and between blocks was assessed by performingthe 21-gene assay in five serial sections from six blocks intwo patients. The within-block standard deviation for the recurrencescore was 0.72 recurrence-score unit (95 percent confidenceinterval, 0.55 to 1.04). The total within-patient standard deviation(including between-block and within-block standard deviations)was 2.2 recurrence-score units.
Study Design and End Points
Patients were eligible if they had been randomly assigned toreceive tamoxifen or had received tamoxifen as a member of theregistration group of NSABP trial B-14 and if a tumor blockwas available in the NSABP Tissue Bank. Exclusion criteria wereinsufficient tumor tissue (less than 5 percent of the overalltissue sample) as assessed by histopathological analysis, insufficientRNA (less than 0.5 µg), or a weak RT-PCR signal (averagecycle threshold for the reference genes, greater than 35).
The first prespecified primary objective was to determine whetherthe proportion of patients who were free of a distant recurrencefor more than 10 years after surgery was significantly greaterin the low-risk group than in the high-risk group. The secondprespecified primary objective was to determine whether therewas a statistically significant relation between the recurrencescore and the risk of distant recurrence — one that wentbeyond the relation between recurrence and the standard measuresof the patient's age and the size of the tumor. Contralateraldisease, other second primary cancers, and death before distantrecurrence were considered censoring events. Recurrence in theipsilateral breast, local recurrence, and regional recurrencewere not considered events or censoring events.
Prespecified secondary objectives included determination ofthe relapse-free interval (the time from surgery to any recurrence)over a 10-year period and the 10-year overall mortality fromany cause in the low-risk and high-risk groups; the degree ofagreement in the assignment of tumor grade among three pathologists;and the performance of the recurrence score in the context ofthe interobserver variability in tumor grading.
No samples from trial B-14 were used for prior testing or training.The prospectively defined assay methods and end points werefinalized in a protocol signed on August 27, 2003. RT-PCR analysiswas initiated on September 5, 2003, and RT-PCR data were transferredto the NSABP for analysis on September 29, 2003.
Estrogen- and progesterone-receptor proteins were measured byligand-binding assays. HER2 DNA was measured by a fluorescencein situ hybridization assay (PathVysion, Vysis). Tumor gradewas determined independently by three pathologists from theNSABP, Stanford University Medical Center, and the Universityof California, San Francisco, School of Medicine with use ofa modification of the Bloom–Richardson grading criteria.27
Statistical Analysis
We tested the hypothesis that the proportion of patients whoare free of a distant recurrence at 10 years would be significantlyhigher in the low-risk group (recurrence score, less than 18)than in the high-risk group (recurrence score, 31 or higher).The test statistic was derived by adjusting the difference betweenthe Kaplan–Meier estimates of the 10-year rate of distantrecurrence in the two groups by the corresponding Greenwoodvariance estimates. A P value of less than 0.05 (two-sided)was considered to indicate a significant result. We also testedthe hypothesis that there would be a significant differencebetween a (reduced) Cox proportional-hazards model for distantrecurrence based only on age and clinical tumor size and a (full)proportional-hazards model based on age, clinical tumor size,and recurrence score. A P value of less than 0.05 (two-sided)in the likelihood-ratio test was considered to indicate a significantresult. To define the continuous relation between the recurrencescore and the 10-year risk of distant recurrence, the data werefitted by a time-varying, piecewise, log-hazard ratio modelwith the recurrence score and its quadratic term included ascovariates.28 The 10-year rate of distant recurrence was thenestimated by a Breslow-type function.29 The NSABP designed thestudy, collected the clinical data, and analyzed the results.The assay was carried out by Genomic Health. The NSABP heldthe combined clinical and laboratory data (after the removalof identifying information) and performed the data analyses.The manuscript was written by the NSABP, with input from GenomicHealth.
Results
Characteristics of the Patients
Paraffin blocks containing sufficient specimens of tissue involvedby invasive breast cancer were available from 675 of 2617 tamoxifen-treatedpatients in trial B-14. RT-PCR was successful in 668 of the675 blocks. The 668 patients who corresponded to these blockswere similar in terms of age distribution and the distributionof tumor size to the overall group of 2617 tamoxifen-treatedpatients (Table 1 of the Supplementary Appendix). For the groupof 668 patients whose tumor sample could be evaluated, the Kaplan–Meierestimate for the proportion who had no distant recurrence 10years after surgery was 85 percent.
Recurrence Rates in the Low-Risk and High-Risk Groups
The Kaplan–Meier estimate for the proportion of patientsin the low-risk group who were free of a distant recurrenceat 10 years (93.2 percent) was significantly greater than theproportion in the high-risk category (69.5 percent) (P<0.001)(Table 1 and Figure 2). The recurrence score was also significantlycorrelated with two secondary end points: the relapse-free intervaland overall survival (P<0.001 for both) (Fig. 2B and 2C ofthe Supplementary Appendix).
Figure 2. Likelihood of Distant Recurrence, According to Recurrence-Score Categories.
A low risk was defined as a recurrence score of less than 18, an intermediate risk as a score of 18 or higher but less than 31, and a high risk as a score of 31 or higher. There were 28 recurrences in the low-risk group, 25 in the intermediate-risk group, and 56 in the high-risk group. The difference among the groups is significant (P<0.001).
Recurrence Score, Age, Tumor Size, and Risk of Distant Recurrence
As expected, younger patients (those less than 50 years of age)had higher rates of distant recurrence at 10 years than olderpatients (21.1 percent [95 percent confidence interval, 15.1to 26.8 percent] vs. 12.3 percent [95 percent confidence interval,9.1 to 15.3 percent]), whereas patients with smaller tumors(diameter, 2 cm or less) had lower estimated rates of distantrecurrence at 10 years than those with larger tumors (13.3 percent[95 percent confidence interval, 9.9 to 16.8 percent] vs. 17.5percent [95 percent confidence interval, 12.6 to 22.3 percent]).In a multivariate Cox model in which distant recurrence wasevaluated in relation to both age and tumor size, age alonewas significantly correlated with distant recurrence (P=0.004,with younger patients more likely to have recurrence), whereastumor size trended toward significance (P=0.06, with largertumors more likely to recur) (Table 2). In a multivariate Coxmodel in which distant recurrence was evaluated in relationto the recurrence score, age, and tumor size, the recurrencescore provided significant predictive power that was independentof age and tumor size (P<0.001) (Table 2). When recurrencescore was added to the model, age and tumor size were no longerstatistically significant. Similar results were observed whenmore than two categories of age and tumor size were used inthe model (data not shown).
Table 2. Multivariate Cox Proportional Analysis of Age, Tumor Size, and Recurrence Score in Relation to the Likelihood of Distant Recurrence.
Estrogen- and Progesterone-Receptor Proteins and Amplification of HER2
No relation was observed between the levels of estrogen- orprogesterone-receptor proteins and the risk of distant recurrence(Fig. 1 of the Supplementary Appendix). HER2 was amplified in55 of the 668 tumors (8.2 percent) and not amplified in 605tumors (90.6 percent); the result was indeterminate in 8 (1.2percent). The Kaplan–Meier estimate of the proportionof patients free of distant recurrence at 10 years among thosewith tumors in which HER2 was amplified was 75.0 percent (95percent confidence interval, 63.2 to 86.9 percent), and 86.0percent (95 percent confidence interval, 83.1 to 88.9 percent)among patients with tumors in which HER2 was not amplified (P=0.08)(Fig. 2A of the Supplementary Appendix). In Cox models thatincluded the recurrence score and traditional measures (estrogenreceptor, progesterone receptor, or DNA amplification of HER2),only the recurrence score was a significant predictor of distantrecurrence (data not shown).
Recurrence Score, Tumor Grade, and Risk of Distant Recurrence
The assessment of tumor grade by each of the three pathologistscorrelated with the risk of distant recurrence (Tables 2A, 2B,and 2C of the Supplementary Appendix). The recurrence scoreprovided significant information beyond tumor grade for eachof the three pathologists (P<0.001). The concordance in assessmentof grade between any two pathologists was 59 to 65 percent,and the overall concordance among all the three pathologistswas 43 percent (Table 3 of the Supplementary Appendix). Agreementamong the three pathologists was lowest for well-differentiatedand moderately differentiated tumor grades (kappa, 0.36 and0.23, respectively) and highest for a poorly differentiatedgrade (kappa, 0.61).
Finally, multivariate Cox proportional-hazards analyses wereperformed to explore the relation between distant recurrenceand age, tumor size, tumor grade, HER2 amplification, amountsof estrogen- and progesterone-receptor protein, and recurrencescore (Table 3). The recurrence score and poor tumor grade weresignificant predictors of distant recurrence.
Table 3. Multivariate Cox Proportional Analysis of Age, Tumor Size, Tumor Grade, and Recurrence Score in Relation to the Likelihood of Distant Recurrence.
Risk of Distant Recurrence in Subgroups of Patients
The recurrence score predicted distant recurrence for all agecategories and all categories of tumor size (Figure 3). Patientswith a low-risk recurrence score (less than 18) had less frequentdistant recurrences at 10 years than patients with a high-riskscore (31 or higher). Moreover, not all patients with smalltumors (109 patients with a tumor 1 cm in diameter or smaller)were at low risk; the recurrence score identified 44 of thosepatients as having an intermediate or high risk and a 15 to20 percent risk of distant recurrence at 10 years.
Figure 3. Kaplan–Meier Estimates of the Proportion of Patients Free of Distant Recurrences at 10 Years, According to Age, Tumor Size, and Tumor Grade.
For each group of patients, the results for low-, intermediate-, and high-risk recurrence-score categories (scores of less than 18, 18 or higher but less than 31, and 31 or higher, respectively) are shown. The tumor grades are those of one of the three pathologists. The size of each square corresponds to the size of the subgroup; the horizontal lines represent the 95 percent confidence interval.
The subgroup of patients with moderately differentiated tumors(the most common grade) could be distinguished to be at lowor high risk by the recurrence score (Figure 3). A subgroupof patients with well-differentiated tumors had high recurrencescores and high rates of distant recurrence. For two of thethree pathologists, a subgroup of patients with poorly differentiatedtumors had low recurrence scores and low rates of distant recurrence(Fig. 3A and 3B of the Supplementary Appendix).
Recurrence Score as a Continuous Predictor of Distant Recurrence
The likelihood of distant recurrence at 10 years increased continuouslyas the recurrence score increased (Figure 4). Two-sided confidenceintervals for the likelihood of distant recurrence are generally±2 to 3 percent for recurrence scores of less than 30and ±3 to 5 percent for recurrence scores of 30 to 50.For recurrence scores greater than 50, the likelihood of distantrecurrence increases only slightly as the score increases. Onaverage, patients with recurrence scores greater than 50 (12percent of the 668 patients) had a risk of distant recurrenceat 10 years of 33.8 percent (95 percent confidence interval,23.4 to 44.2 percent).
Figure 4. Rate of Distant Recurrence as a Continuous Function of the Recurrence Score.
The continuous function was generated with use of a piecewise log-hazard-ratio model.28 The dashed curves indicate the 95 percent confidence interval. The rug plot on top of the x axis shows the recurrence score for individual patients in the study.
Discussion
Using a prospectively defined gene-expression assay and an algorithmfor calculating recurrence scores, we were able to quantifythe likelihood of distant recurrence in patients with node-negative,estrogen-receptor–positive breast cancer who had beentreated with tamoxifen. The difference in the risk of distantrecurrence between patients with low recurrence scores and thosewith high recurrence scores was large and statistically significant.Many patients (51 percent of the patients in the study) werecategorized as having a low risk, and their rate of distantrecurrence at 10 years was 6.8 percent. A smaller group of patients(27 percent) was categorized as having a high risk; their rateof distant recurrence at 10 years was 30.5 percent — arisk similar to that observed among patients with node-positivedisease.30 The use of the recurrence score as a continuous predictorprovides an accurate estimate of the risk of distant recurrencein individual patients.
The recurrence score can also predict overall survival. Thisfeature is notable, since approximately 50 percent of the deathsoccurred in the absence of recurrent breast cancer. In addition,the recurrence score predicts the relapse-free interval (includingthe interval free of local and regional recurrences). Thus,the recurrence score correlates in a statistically significantmanner with all the end points we examined.
The patient's age and the size of the tumor are routinely usedas predictors of recurrence in breast cancer and are incorporatedinto current treatment guidelines.13,14,15 When the recurrencescore was combined with data pertaining to age and tumor sizeto predict the risk of distant recurrence, only the recurrencescore remained statistically significant in a multivariate analysis.It is likely that the decreased risk of recurrence in olderpatients is not related to age itself but instead, at leastin part, to the higher amount of estrogen-receptor protein inolder patients' tumors.31,32 The contribution of ER expressionto the recurrence score captures this factor.
The subgroup analysis of patients according to age and tumorsize was exploratory, and the results should be interpretedcautiously. Nevertheless, the recurrence score was a consistentpredictor of distant recurrence in patients of all age categoriesand all tumor-size categories. For example, more than a thirdof the patients with small tumors (1 cm in diameter or smaller)had intermediate-risk or high-risk recurrence scores and a 15to 20 percent risk of distant recurrence.
We evaluated the recurrence score in the context of the interobservervariability in tumor grading that is typical in oncology practice.Tumor grade correlates with the likelihood of recurrence whenanalyzed in large populations of patients. However, previousstudies have also documented that the grading of breast cancerentails a degree of subjective judgment, leading to low concordanceamong pathologists. Robbins et al.33 compared the interobserverreproducibility in their study to the published results of fourother groups.34,35,36 Complete agreement in those five studiesranged from 54 percent to 83 percent (kappa, 0.17 to 0.73).We found that the concordance among pathologists for the poorlydifferentiated grade is moderate (kappa, 0.61) and for the well-differentiatedand moderately differentiated grades is low (kappa, 0.23 and0.36, respectively). Recently, a Breast Task Force serving theAmerican Joint Committee on Cancer did not add tumor grade toits staging criteria because of the sparseness and variabilityof the data.37
Traditional measures of estrogen-receptor protein (by ligand-bindingassay) and HER2 (by fluorescence in situ hybridization) in thisstudy were only weakly predictive of the risk of distant recurrence.The quantitative information that the RT-PCR assay providesfor ER, HER2, and the other 14 cancer-related genes is clearlyimportant.
It is important to emphasize that we do not know whether thegenes used in the calculation of the recurrence score correlatewith recurrence in the population we studied because they showa relation with the natural history of breast cancer, becausethey predict responsiveness to tamoxifen, or both. Esteva etal.38 found no correlation between the recurrence score andthe rate of distant recurrence in 149 selected patients withnode-negative breast cancer who did not receive adjuvant systemictherapy. However, in that cohort, patients with well-differentiatedtumors (i.e., those with a low nuclear grade) had a surprisinglyworse survival rate than patients with moderately differentiatedor poorly differentiated tumors. The current data cannot beused to select women for tamoxifen therapy.
Few assays have been rigorously validated for use as prognosticor predictive tests in oncology. We conducted a prospectivelydesigned validation study of a multigene-expression assay ina large, multicenter clinical trial. It is of practical importancethat this assay involves the use of very small amounts of thetumor tissue that is routinely prepared after surgery.
Supported by the National Surgical Adjuvant Breast and BowelProject and Genomic Health. Genomic Health paid the costs ofshipping the paraffin-embedded tissue sections and performingall RT-PCR assays.
Drs. Paik, Shak, Baker, Cronin, Walker, and Bryant report holdinga patent for the RT-PCR assay used in this study. Drs. Shak,Baker, Cronin, and Watson report holding equity ownership orstock options in Genomic Health and being employed by GenomicHealth, the commercial entity that sponsored the study. Dr.Walker reports having received consulting fees from GenomicHealth and owning stock options. Dr. Baehner reports havingreceived consulting fees from Genomic Health; Dr. Paik, lecturefees from Genomic Health; and Dr. Wickerham, consulting feesfrom AstraZeneca.
We are indebted to Tracy George (Stanford University); to TerryMamounas (NSABP) for his comments; to Randy Scott, Debjani Dutta,Daniel Klaus, Mylan Pho, Anhthu Nguyen, Jennie Jeong, StephanieButler, Joel Robertson, Ken Stineman, Marti Haskins, and ClaireAlexander (all of Genomic Health); and to Clifford Hudis, TomFleming, David Botstein, David Agus, and Fred Cohen for theirhelpful advice and suggestions.
Source Information
From the Division of Pathology, Operation Center, and the Biostatistics Center, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh (S.P., G.T., C.K., T.P., W.H., E.R.F., D.L.W., J.B., N.W.); Genomic Health, Redwood City, Calif. (S.S., J.B., M.C., M.G.W., D.W.); the Department of Statistics, University of Pittsburgh, Pittsburgh (G.T., J.B.); and the University of California, San Francisco, San Francisco (F.L.B.).
Address reprint requests to Dr. Paik at the Division of Pathology, NSABP, 4 Allegheny Center, 5th Fl., East Commons Professional Bldg., Pittsburgh, PA 15212, or at spaik.nejm{at}nsabp.org.
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