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The new england journal of medicine 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., b a c k g r o u n d
The likelihood of distant recurrence in patients with breast cancer who have no involved From the Division of Pathology, Operation Center, and the Biostatistics Center, Na- lymph nodes and estrogen-receptor–positive tumors is poorly defined by clinical and tional 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 Statis- We tested whether the results of a reverse-transcriptase–polymerase-chain-reaction tics, University of Pittsburgh, Pittsburgh (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue (G.T., J.B.); and the University of Califor-would correlate with the likelihood of distant recurrence in patients with node-nega- nia, San Francisco, San Francisco (F.L.B.).
Address reprint requests to Dr. Paik at the tive, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adju- Division of Pathology, NSABP, 4 Allegheny vant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancer- Center, 5th Fl., East Commons Profession-related genes and 5 reference genes were used in a prospectively defined algorithm to al Bldg., Pittsburgh, PA 15212, or at spaik.
calculate a recurrence score and to determine a risk group (low, intermediate, or high)for each patient.
N Engl J Med 2004;351:2817-26.
Copyright 2004 Massachusetts Medical Society. Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportionsof patients categorized as having a low, intermediate, or high risk by the RT-PCR assaywere 51, 22, and 27 percent, respectively. The Kaplan–Meier estimates of the rates ofdistant recurrence at 10 years in the low-risk, intermediate-risk, and high-riskgroups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence in-terval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that inthe high-risk group (P<0.001). In a multivariate Cox model, the recurrence score pro-vided significant predictive power that was independent of age and tumor size(P<0.001). The recurrence score was also predictive of overall survival (P<0.001) andcould be used as a continuous function to predict distant recurrence in individual pa-tients.
c o n c l u s i o n s
The recurrence score has been validated as quantifying the likelihood of distant re-currence in tamoxifen-treated patients with node-negative, estrogen-receptor–positivebreast cancer.
Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ly defined, 21-gene RT-PCR assay and recurrence- lecular dissection of cancer has increased score algorithm to quantify the likelihood of distant oour understanding of the pathways that recurrence in patients with node-negative, estrogen- are altered in neoplastic cells.1,2 Nevertheless, the receptor–positive breast cancer who had been treat-diagnosis of cancer and decisions about its treat- ed with tamoxifen in the large, multicenter NSABPment still rely largely on classic histopathological trial B-14.
and immunohistochemical techniques. A morequantitative approach to diagnosis and rational in- dividualization of treatment are needed.
Large clinical trials, such as National Surgical patients
Adjuvant Breast and Bowel Project (NSABP) trials NSABP trial B-14 (entitled “A Clinical Trial to Assess
B-14 and B-20, have demonstrated the benefit of Tamoxifen in Patients with Primary Breast Cancer
tamoxifen and chemotherapy in women who have and Negative Axillary Nodes Whose Tumors Are
node-negative, estrogen-receptor–positive breast Positive for Estrogen Receptors”) enrolled 2892 pa-
cancer.3-5 However, since the likelihood of distant tients who were randomly assigned to receive place-
recurrence in patients treated with tamoxifen alone bo or tamoxifen between January 4, 1982, and Janu-
after surgery is about 15 percent at 10 years, at least ary 25, 1988, and enrolled 1235 additional patients,
85 percent of patients would be overtreated with all treated with tamoxifen, between January 26,
chemotherapy if it were offered to everyone. Numer- 1988, and October 17, 1988. The current study of
ous attempts have been made to identify biomark- the recurrence score was approved by the Essex In-
ers of residual risk,6-9 but none of them have been stitutional Review Board (Lebanon, N.J.) and by the
recommended for guiding treatment.10-15 Molecu- institutional review boards of Allegheny General
lar signatures of gene expression in tumor tissue Hospital and the University of Pittsburgh (both in
that correlate with recurrence of breast cancer have Pittsburgh). The need for additional informed con-
been identified by methods based on the use of DNA sent was waived by the institutional review boards.
arrays.16-21 However, the requirement for fresh or
snap-frozen tissue and uncertainties about the re- sample preparation
producibility of such methods have limited their Paraffin blocks with cancer cells occupying less
clinical application.
than 5 percent of the section area were excluded We used a multistep approach to develop an as- from the study. Macrodissection was performed say of the expression of tumor-related genes for with the use of a safety blade for cases involving
use with routinely prepared tumor blocks and to val- nontumor elements that were amenable to macro-
idate the assay clinically. First, a high-throughput, dissection and that constituted more than 50 per-
real-time, reverse-transcriptase–polymerase-chain- cent of the overall area of the tissue section. RNA
reaction (RT-PCR) method was developed to quanti- was extracted from three 10-µm sections when mac-
fy gene expression with the use of sections of fixed, rodissection had not been performed or from six
paraffin-embedded tumor tissue.22 Second, we se- 10-µm sections when macrodissection had been
lected 250 candidate genes from the published lit- performed.
erature, genomic databases, and experiments based
on DNA arrays performed on fresh-frozen tis- assay methods, gene selection,
sue.17-19,23 Third, we analyzed data from three inde- and recurrence-score algorithm
pendent clinical studies of breast cancer involving Gene expression in fixed, paraffin-embedded tu-
a total of 447 patients, including the tamoxifen-only mor tissue was measured as described by Cronin
group of NSABP trial B-20, to test the relation be- et al.22 The Oncotype DX assay (Genomic Health)
tween expression of the 250 candidate genes and was used. In brief, after RNA extraction and DNase
the recurrence of breast cancer.24-26 Fourth, we used I treatment, total RNA content was measured and
the results of the three studies to select a panel of 16 the absence of DNA contamination was verified (as
cancer-related genes and 5 reference genes and de- described in the Supplementary Appendix, available
signed an algorithm, based on the levels of expres- with the full text of this article at www.nejm.org).
sion of these genes, to compute a recurrence score Reverse transcription was performed and was fol-
for each tumor sample. The study reported here was lowed by quantitative TaqMan RT-PCR reactions in
performed to validate the ability of the prospective- 384-well plates, performed with the use of Prism
Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. m u l t i g e n e a s s a y t o p r e d i c t r e c u r r e n c e o f b r e a s t c a n c e r 7900HT instruments (Applied Biosystems). Theexpression of each gene was measured in triplicate Proliferation
Estrogen
and then normalized relative to a set of five refer- ence genes (ACTB [the gene encoding b-actin], GAPDH, GUS, RPLPO, and TFRC). Reference-nor- malized expression measurements ranged from 0 to 15, where a 1-unit increase reflected an approx- Reference
The list of 21 genes and the recurrence-score algorithm (Fig. 1) were designed by analyzing the Invasion
results of the three independent preliminary studies involving 447 patients and 250 candidate genes24-26 (as described in the Supplementary Appendix). The selection of the final 16 cancer-related genes wasbased primarily on the strength of their performance Figure 1. Panel of 21 Genes and the Recurrence-Score Algorithm.
in all three studies and the consistency of primer or The recurrence score on a scale from 0 to 100 is derived from the reference- probe performance in the assay. The range of pos- normalized expression measurements in four steps. First, expression for each sible recurrence scores was 0 to 100 (where higher gene is normalized relative to the expression of the five reference genes (ACTB scores indicated a greater likelihood of recurrence) [the gene encoding b-actin], GAPDH, GUS, RPLPO, and TFRC). Reference-nor-malized expression measurements range from 0 to 15, with a 1-unit increase and was derived from the reference-normalized ex- reflecting approximately a doubling of RNA. Genes are grouped on the basis pression measurements for the 16 cancer-related of function, correlated expression, or both. Second, the GRB7, ER, proliferation, and invasion group scores are calculated from individual gene-expression Cutoff points were prespecified to classify pa- measurements, as follows: GRB7 group score = 0.9 ¬ GRB7+0.1¬HER2 (if the tients into the following categories: low risk (re- result is less than 8, then the GRB7 group score is considered 8); ER group score = (0.8¬ER+1.2¬PGR+BCL2+SCUBE2)÷4; proliferation group score currence score, less than 18), intermediate risk (re- =Survivin+KI67+MYBL2+CCNB1 [the gene encoding cyclin B1]+STK15)÷5 currence score, 18 or higher but less than 31), and (if the result is less than 6.5, then the proliferation group score is considered high risk (recurrence score, 31 or higher). The cut- 6.5); and invasion group score=(CTSL2 [the gene encoding cathepsin L2] off points were chosen on the basis of the results of +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 Reproducibility within and between blocks was training studies24-26: RSU=+0.47¬GRB7 group score¡0.34¬ER group score assessed by performing the 21-gene assay in five +1.04¬proliferation group score+0.10¬invasion group score+0.05¬CD68 serial sections from six blocks in two patients. The ¡0.08¬GSTM1¡0.07¬BAG1. A plus sign indicates that increased expression is within-block standard deviation for the recurrence associated with an increased risk of recurrence, and a minus sign indicates score was 0.72 recurrence-score unit (95 percent that increased expression is associated with a decreased risk of recurrence. Fourth, the recurrence score (RS) is rescaled from the unscaled recurrence confidence interval, 0.55 to 1.04). The total within- score, as follows: RS=0 if RSU<0; RS=20¬(RSU¡6.7) if 0≤RSU≤100; and patient standard deviation (including between- block and within-block standard deviations) was2.2 recurrence-score units.
were free of a distant recurrence for more than 10 s t u d y d e s i g n a n d e n d p o i n t s
years after surgery was significantly greater in the Patients were eligible if they had been randomly low-risk group than in the high-risk group. Theassigned to receive tamoxifen or had received ta- second prespecified primary objective was to deter-moxifen as a member of the registration group of mine whether there was a statistically significantNSABP trial B-14 and if a tumor block was available relation between the recurrence score and the riskin the NSABP Tissue Bank. Exclusion criteria were of distant recurrence — one that went beyond theinsufficient tumor tissue (less than 5 percent of the relation between recurrence and the standard mea-overall tissue sample) as assessed by histopatho- sures of the patient’s age and the size of the tumor.
logical analysis, insufficient RNA (less than 0.5 µg), Contralateral disease, other second primary can-or a weak RT-PCR signal (average cycle threshold cers, and death before distant recurrence were con-for the reference genes, greater than 35).
sidered censoring events. Recurrence in the ipsilat- The first prespecified primary objective was to eral breast, local recurrence, and regional recurrence determine whether the proportion of patients who were not considered events or censoring events.
Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Prespecified secondary objectives included de- year rate of distant recurrence was then estimated termination of the relapse-free interval (the time by a Breslow-type function.29 The NSABP designedfrom surgery to any recurrence) over a 10-year peri- the study, collected the clinical data, and analyzedod and the 10-year overall mortality from any cause the results. The assay was carried out by Genomicin the low-risk and high-risk groups; the degree Health. The NSABP held the combined clinical andof agreement in the assignment of tumor grade laboratory data (after the removal of identifying in-among three pathologists; and the performance of formation) and performed the data analyses. Thethe recurrence score in the context of the interob- manuscript was written by the NSABP, with inputserver 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 were finalized in a proto-
col signed on August 27, 2003. RT-PCR analysis characteristics of the patients
was initiated on September 5, 2003, and RT-PCR Paraffin blocks containing sufficient specimens of
data were transferred to the NSABP for analysis on tissue involved by invasive breast cancer were avail-
September 29, 2003.
able from 675 of 2617 tamoxifen-treated patients Estrogen- and progesterone-receptor proteins in trial B-14. RT-PCR was successful in 668 of the were measured by ligand-binding assays. HER2 DNA 675 blocks. The 668 patients who corresponded towas measured by a fluorescence in situ hybridiza- these blocks were similar in terms of age distribu-tion assay (PathVysion, Vysis). Tumor grade was tion and the distribution of tumor size to the over-determined independently by three pathologists all group of 2617 tamoxifen-treated patients (Tablefrom the NSABP, Stanford University Medical Cen- 1 of the Supplementary Appendix). For the groupter, and the University of California, San Francisco, of 668 patients whose tumor sample could be eval-School of Medicine with use of a modification of uated, the Kaplan–Meier estimate for the propor-the Bloom–Richardson grading criteria.27 tion who had no distant recurrence 10 years aftersurgery was 85 percent.
s t a t i s t i c a l a n a l y s i s
We tested the hypothesis that the proportion of recurrence rates in the low-risk
patients who are free of a distant recurrence at 10 and high-risk groups
years would be significantly higher in the low-risk The Kaplan–Meier estimate for the proportion of
group (recurrence score, less than 18) than in the patients in the low-risk group who were free of a
high-risk group (recurrence score, 31 or higher). distant recurrence at 10 years (93.2 percent) was sig-
The test statistic was derived by adjusting the dif- nificantly greater than the proportion in the high-
ference between the Kaplan–Meier estimates of risk category (69.5 percent) (P<0.001) (Table 1 and
the 10-year rate of distant recurrence in the two
groups by the corresponding Greenwood variance
estimates. A P value of less than 0.05 (two-sided) was
Table 1. Kaplan–Meier Estimates of the Rate of Distant
considered to indicate a significant result. We also Recurrence at 10 Years, According to Recurrence-Score
Risk Categories.*

tested the hypothesis that there would be a signifi-cant difference between a (reduced) Cox proportion- Rate of Distant
Percentage
Recurrence at 10 Yr
al-hazards model for distant recurrence based only Risk Category
of Patients
(95% CI)†
on age and clinical tumor size and a (full) propor- tional-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 significant result. To de-fine the continuous relation between the recurrence * A low risk was defined as a recurrence score of less than score and the 10-year risk of distant recurrence, the 18, an intermediate risk as a score of 18 or higher but data were fitted by a time-varying, piecewise, log- less than 31, and a high risk as a score of 31 or higher.
hazard ratio model with the recurrence score and ‡ P<0.001 for the comparison with the low-risk category.
its quadratic term included as covariates.28 The 10- Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved.
m u l t i g e n e a s s a y t o p r e d i c t r e c u r r e n c e o f b r e a s t c a n c e r Fig. 2). The recurrence score was also significantlycorrelated with two secondary end points: the re- lapse-free interval and overall survival (P<0.001 for both) (Fig. 2B and 2C of the Supplementary Ap- r e c u r r e n c e s c o r e , a g e , t u m o r s i z e ,
a n d r i s k o f d i s t a n t r e c u r r e n c e
As expected, younger patients (those less than 50 (% of patients)
years of age) had higher rates of distant recurrence at 10 years than older patients (21.1 percent [95 Freedom from Distant Recurrence
percent confidence interval, 15.1 to 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 estimat- No. at Risk
ed rates of distant recurrence at 10 years than those with larger tumors (13.3 percent [95 percent confi- dence interval, 9.9 to 16.8 percent] vs. 17.5 percent [95 percent confidence interval, 12.6 to 22.3 per-cent]). In a multivariate Cox model in which distant Figure 2. Likelihood of Distant Recurrence, According to Recurrence-Score
recurrence was evaluated in relation to both age Categories.
and tumor size, age alone was significantly corre- 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 lated with distant recurrence (P=0.004, with young- 31 or higher. There were 28 recurrences in the low-risk group, 25 in the inter- er patients more likely to have recurrence), where- mediate-risk group, and 56 in the high-risk group. The difference among the as tumor size trended toward significance (P=0.06, with larger tumors more likely to recur) (Table 2).
In a multivariate Cox model in which distant recur-rence was evaluated in relation to the recurrencescore, age, and tumor size, the recurrence score pro-vided significant predictive power that was inde- Table 2. Multivariate Cox Proportional Analysis of Age, Tumor Size,
and Recurrence Score in Relation to the Likelihood of Distant Recurrence.*

pendent of age and tumor size (P<0.001) (Table 2).
When recurrence score was added to the model, Hazard Ratio
age and tumor size were no longer statistically sig- Variable
(95% CI)†
nificant. Similar results were observed when more Analysis without recurrence score
than two categories of age and tumor size were used e s t r o g e n - a n d p r o g e s t e r o n e - r e c e p t o r
Analysis with recurrence score‡
p r o t e i n s a n d a m p l i f i c a t i o n o f h e r 2
No relation was observed between the levels of es- trogen- or progesterone-receptor proteins and therisk of distant recurrence (Fig. 1 of the Supplemen- tary Appendix). HER2 was amplified in 55 of the * Age at surgery was a binary variable (0 for an age of less than 50 years and 1 for 668 tumors (8.2 percent) and not amplified in 605 an age of 50 years or more); clinical tumor size was a binary variable (0 for a diam- tumors (90.6 percent); the result was indetermi- eter of 2 cm or less and 1 for a diameter greater than 2 cm); and the recurrence nate in 8 (1.2 percent). The Kaplan–Meier estimate score was a continuous variable, with the hazard ratio for distant recurrence calculated relative to an increment of 50 units (chosen to dichotomize the re- of the proportion of patients free of distant re- currence score and thus improve comparability of the hazard ratio with the currence at 10 years among those with tumors in hazard ratios based on the clinical covariates).
which HER2 was amplified was 75.0 percent (95 † CI denotes confidence interval.
‡ P<0.001 and chi-square=33.7 for the comparison with the analysis without the percent confidence interval, 63.2 to 86.9 percent), recurrence score (by the likelihood-ratio test).
and 86.0 percent (95 percent confidence interval, Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 83.1 to 88.9 percent) among patients with tumors rence score was a significant predictor of distant
in which HER2 was not amplified (P=0.08) (Fig. recurrence (data not shown).
2A of the Supplementary Appendix). In Cox models
that included the recurrence score and traditional recurrence score, tumor grade,
measures (estrogen receptor, progesterone recep- and risk of distant recurrence
tor, or DNA amplification of HER2), only the recur- The assessment of tumor grade by each of the three
pathologists correlated with the risk of distant re-currence (Tables 2A, 2B, and 2C of the Supplemen- Table 3. Multivariate Cox Proportional Analysis of Age, Tumor Size, Tumor
tary Appendix). The recurrence score provided sig- Grade, and Recurrence Score in Relation to the Likelihood of Distant
nificant information beyond tumor grade for each Recurrence.*
of the three pathologists (P<0.001). The concor- Hazard Ratio
dance in assessment of grade between any two pa- Variable
(95% CI)†
thologists was 59 to 65 percent, and the overall con- Analysis without recurrence score
cordance among all the three pathologists was 43percent (Table 3 of the Supplementary Appendix).
Agreement among the three pathologists was low- est for well-differentiated and moderately differ- entiated tumor grades (kappa, 0.36 and 0.23, respec- tively) and highest for a poorly differentiated grade Finally, multivariate Cox proportional-hazards analyses were performed to explore the relation be- tween distant recurrence and age, tumor size, tumor grade, HER2 amplification, amounts of estrogen- and progesterone-receptor protein, and recurrence score (Table 3). The recurrence score and poor tu- Analysis with recurrence score‡
mor grade were significant predictors of distant re- r i s k o f d i s t a n t r e c u r r e n c e
i n s u b g r o u p s o f p a t i e n t s
The recurrence score predicted distant recurrence for all age categories and all categories of tumor size (Fig. 3). Patients with a low-risk recurrence score (less than 18) had less frequent distant recur-rences at 10 years than patients with a high-risk score (31 or higher). Moreover, not all patients with small tumors (109 patients with a tumor 1 cm in di- ameter or smaller) were at low risk; the recurrence score identified 44 of those patients as having anintermediate or high risk and a 15 to 20 percent risk * The tumor grades were those of one of the three pathologists. Age at surgery was a binary variable (0 for an age of less than 50 years and 1 for an age of 50 years or more); clinical tumor size was a binary variable (0 for a diameter of The subgroup of patients with moderately dif- 2 cm or less and 1 for a diameter greater than 2 cm); grade was a binary variable ferentiated tumors (the most common grade) could (poorly differentiated relative to well differentiated and moderately differenti- be distinguished to be at low or high risk by the ated relative to well differentiated); HER2 amplification was a binary variable (0 for no amplification on fluorescence in situ hybridization and 1 for amplifi- recurrence score (Fig. 3). A subgroup of patients cation); the amount of estrogen-receptor protein was an ordinal variable, with with well-differentiated tumors had high recurrence the baseline level being 10 to 49 fmol per milligram; and recurrence score was scores and high rates of distant recurrence. For two a continuous variable, with the hazard ratio for distant recurrence calculated relative to an increment of 50 units.
of the three pathologists, a subgroup of patients with poorly differentiated tumors had low recur- ‡ P<0.001 and chi-square=15.2 for the comparison with the analysis without the rence scores and low rates of distant recurrence (Fig. 3A and 3B of the Supplementary Appendix).
Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. m u l t i g e n e a s s a y t o p r e d i c t r e c u r r e n c e o f b r e a s t c a n c e r Figure 3. Kaplan–Meier Estimates of the Proportion
of Patients Free of Distant Recurrences at 10 Years,
Subgroup
Patients
According to Age, Tumor Size, and Tumor Grade.
For each group of patients, the results for low-, interme- diate-, 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 hor- izontal lines represent the 95 percent confidence interval.
r e c u r r e n c e s c o r e a s a c o n t i n u o u s
p r e d i c t o r o f d i s t a n t r e c u r r e n c e
The likelihood of distant recurrence at 10 years increased continuously as the recurrence score in- creased (Fig. 4). Two-sided confidence intervals for the likelihood of distant recurrence are generally ±2 to 3 percent for recurrence scores of less than 30 and ±3 to 5 percent for recurrence scores of 30 to 50. For recurrence scores greater than 50, the like- lihood of distant recurrence increases only slightly as the score increases. On average, patients with re- currence scores greater than 50 (12 percent of the 668 patients) had a risk of distant recurrence at 10 years of 33.8 percent (95 percent confidence inter- Using a prospectively defined gene-expression assay and an algorithm for calculating recurrence scores, we were able to quantify the likelihood of distant recurrence in patients with node-negative, estrogen-receptor–positive breast cancer who had been treated with tamoxifen. The difference in the risk of distant recurrence between patients with low recurrence scores and those with high recurrence scores was large and statistically significant. Many patients (51 percent of the patients in the study) were categorized as having a low risk, and their rate of distant recurrence at 10 years was 6.8 percent.
A smaller group of patients (27 percent) was cate- gorized as having a high risk; their rate of distant recurrence at 10 years was 30.5 percent — a risk similar to that observed among patients with node- positive disease.30 The use of the recurrence score as a continuous predictor provides an accurate esti- mate of the risk of distant recurrence in individual Percentage of Patients Free
of Distant Recurrence at 10 Yr
The recurrence score can also predict overall sur- Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine all tumor-size categories. For example, more than a Intermediate-
third of the patients with small tumors (1 cm in di- Low-Risk Group
Risk Group
High-Risk Group
ameter or smaller) had intermediate-risk or high-risk recurrence scores and a 15 to 20 percent risk of We evaluated the recurrence score in the context of the interobserver variability in tumor grading that is typical in oncology practice. Tumor grade cor- relates with the likelihood of recurrence when an-alyzed in large populations of patients. However, previous studies have also documented that the grading of breast cancer entails a degree of subjec-tive judgment, leading to low concordance among pathologists. Robbins et al.33 compared the inter- observer reproducibility in their study to the pub- Rate of Distant Recurrence at 10 Yr (% of patients)
lished results of four other groups.34-36 Complete Recurrence Score
agreement in those five studies ranged from 54 per-cent to 83 percent (kappa, 0.17 to 0.73). We found Figure 4. Rate of Distant Recurrence as a Continuous Function of the Recur-
that the concordance among pathologists for the rence Score.
poorly differentiated grade is moderate (kappa, The continuous function was generated with use of a piecewise log-hazard- 0.61) and for the well-differentiated and moderately 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 pa- differentiated grades is low (kappa, 0.23 and 0.36, respectively). Recently, a Breast Task Force serv-ing the American Joint Committee on Cancer didnot add tumor grade to its staging criteria because vival. This feature is notable, since approximately of the sparseness and variability of the data.3750 percent of the deaths occurred in the absence of Traditional measures of estrogen-receptor pro- recurrent breast cancer. In addition, the recurrence tein (by ligand-binding assay) and HER2 (by fluo-score predicts the relapse-free interval (including rescence in situ hybridization) in this study werethe interval free of local and regional recurrences). only weakly predictive of the risk of distant recur-Thus, the recurrence score correlates in a statisti- rence. The quantitative information that the RT-PCRcally significant manner with all the end points we assay provides for ER, HER2, and the other 14 can-examined.
cer-related genes is clearly important.
The patient’s age and the size of the tumor are It is important to emphasize that we do not routinely used as predictors of recurrence in breast know whether the genes used in the calculation ofcancer and are incorporated into current treatment the recurrence score correlate with recurrence in theguidelines.13-15 When the recurrence score was population we studied because they show a relationcombined with data pertaining to age and tumor with the natural history of breast cancer, becausesize to predict the risk of distant recurrence, only they predict responsiveness to tamoxifen, or both.
the recurrence score remained statistically signif- Esteva et al.38 found no correlation between the re-icant in a multivariate analysis. It is likely that the currence score and the rate of distant recurrence indecreased risk of recurrence in older patients is 149 selected patients with node-negative breast can-not related to age itself but instead, at least in part, cer who did not receive adjuvant systemic therapy.
to the higher amount of estrogen-receptor protein However, in that cohort, patients with well-differ-in older patients’ tumors.31,32 The contribution of entiated tumors (i.e., those with a low nuclear grade)ER expression to the recurrence score captures had a surprisingly worse survival rate than patientsthis factor.
with moderately differentiated or poorly differenti- The subgroup analysis of patients according to ated tumors. The current data cannot be used to se- age and tumor size was exploratory, and the results lect women for tamoxifen therapy.
should be interpreted cautiously. Nevertheless, the Few assays have been rigorously validated for recurrence score was a consistent predictor of dis- use as prognostic or predictive tests in oncology.
tant recurrence in patients of all age categories and We conducted a prospectively designed validation Downloaded from www.nejm.org at Stanford University on December 14, 2004 . Copyright 2004 Massachusetts Medical Society. All rights reserved. m u l t i g e n e a s s a y t o p r e d i c t r e c u r r e n c e o f b r e a s t c a n c e r study of a multigene-expression assay in a large, ic Health and being employed by Genomic Health, the commercialmulticenter clinical trial. It is of practical impor- entity that sponsored the study. Dr. Walker reports having received consulting fees from Genomic Health and owning stock options.
tance that this assay involves the use of very small Dr. Baehner reports having received consulting fees from Genomicamounts of the tumor tissue that is routinely pre- Health; Dr. Paik, lecture fees from Genomic Health; and Dr. Wicker-pared after surgery.
ham, consulting fees from AstraZeneca.
We are indebted to Tracy George (Stanford University); to Terry Supported by the National Surgical Adjuvant Breast and Bowel Mamounas (NSABP) for his comments; to Randy Scott, Debjani Project and Genomic Health. Genomic Health paid the costs of Dutta, Daniel Klaus, Mylan Pho, Anhthu Nguyen, Jennie Jeong, shipping the paraffin-embedded tissue sections and performing all Stephanie Butler, Joel Robertson, Ken Stineman, Marti Haskins, and Claire Alexander (all of Genomic Health); and to Clifford Hudis, Drs. Paik, Shak, Baker, Cronin, and Walker report holding a patent Tom Fleming, David Botstein, David Agus, and Fred Cohen for their for the RT-PCR assay used in this study. Drs. Shak, Baker, Cronin, and Watson report holding equity ownership or stock options in Genom- r e f e r e n c e s
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In the last part of 2004, my husband Deanhours of healing are the most important in anyand myself were challenged with understandinginjury. Over the years I learned that my dadhow to medicate the body. On November 15,could see the energy field around the body. Dean had a second stroke which disabled the leftOften, he would just give sugar pills. He had theside of his body. Because he could

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DR. BERNSTEIN’S A COMPLETE GUIDE TO ACHIEVING NORMAL BLOOD SUGARS This document and its contents are Copyright 2000 by Richard K. Bernstein, M.D., Little, Brown & Company, and/orother copyright holders as may apply. No portion of this document may be reproduced in whole or in part without theexpress written consent of Little, Brown & Company and/or Richard K. Bernstein, M.D. and/

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