Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.

The new england
journal of medicine
n engl j med 379;2nejm.org July 12, 2018 111
established in 1812 July 12, 2018 vol. 379 no. 2
The authors’ full names, academic de-
grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
Sparano at Montefiore Medical Center,
1695 Eastchester Rd., Bronx, NY 10461,
or at jsparano@ montefiore . org.
A full list of the investigators in this trial
is provided in the Supplementary Appen-
dix, available at NEJM.org.
This article was published on June 3, 2018
at NEJM.org.
N Engl J Med 2018;379:111-21.
DOI: 10.1056/NEJMoa1804710
Copyright © 2018 Massachusetts Medical Society.
BACKGROUND
The recurrence score based on the 21-gene breast cancer assay predicts chemother-
apy benefit if it is high and a low risk of recurrence in the absence of chemotherapy
if it is low; however, there is uncertainty about the benefit of chemotherapy for most
patients, who have a midrange score.
METHODS
We performed a prospective trial involving 10,273 women with hormone-recep-
tor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary
node–negative breast cancer. Of the 9719 eligible patients with follow-up informa-
tion, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly
assigned to receive either chemoendocrine therapy or endocrine therapy alone. The
trial was designed to show noninferiority of endocrine therapy alone for invasive
disease–free survival (defined as freedom from invasive disease recurrence, second
primary cancer, or death).
RESULTS
Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of
invasive disease–free survival (hazard ratio for invasive disease recurrence, second
primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% con-
fidence interval, 0.94 to 1.24; P = 0.26). At 9 years, the two treatment groups had
similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group
and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence
at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and
92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for in-
vasive disease–free survival varied with the combination of recurrence score and
age (P = 0.004), with some benefit of chemotherapy found in women 50 years of
age or younger with a recurrence score of 16 to 25.
CONCLUSIONS
Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in
women with hormone-receptor–positive, HER2-negative, axillary node–negative
breast cancer who had a midrange 21-gene recurrence score, although some benefit
of chemotherapy was found in some women 50 years of age or younger. (Funded
by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number,
NCT00310180.)
a bs tr ac t
Adjuvant Chemotherapy Guided by a 21-Gene Expres
Assay in Breast Cancer
J.A. Sparano, R.J. Gray, D.F. Makower, K.I. Pritchard, K.S. Albain, D.F. Hayes, C.E. Geyer, Jr., E.C. Dees,
J.A. Olson, Jr., T. Lively, S.S. Badve, T.J. Saphner, L.I. Wagner, T.J. Whelan, M.J. Ellis, S. Paik, W.C. W
P.M. Ravdin, M.M. Keane, H.L. Gomez Moreno, P.S. Reddy, T.F. Goggins, I.A. Mayer, A.M. Brufsk
D.L. Toppmeyer, V.G. Kaklamani, J.L. Berenberg, J. Abrams, and G.W. Sledge, Jr.
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n engl j med 379;2nejm.org July 12, 2018112
T h en e w e ngl a nd j o u r na lo f m e dic i n e
Breast cancer is the most common
cancer in women in the United States and
worldwide.1 Hormone-receptor–positive, ax-
illary node–negative disease accounts for approxi-
mately half of all cases of breast cancer in the
United States.2 Adjuvant chemotherapy reduces
the risk of recurrence,3-5 with effects that are pro-
portionally greater in younger women but that are
little affected by nodal status, grade, or the use
of adjuvant endocrine therapy.6,7 These findings
led a National Institutes of Health consensus
panel to recommend adjuvant chemotherapy for
most patients,8 a practice that has contributed to
declining breast cancer mortality.9 However, the
majority of patients may receive chemotherapy un-
necessarily.
The 21-gene recurrence-score assay (Oncotype
DX, Genomic Health) is one of several commer-
cially available gene-expression assays that provide
prognostic information in hormone-receptor–pos-
itive breast cancer.10,11
The recurrence score based
on the 21-gene assay ranges from 0 to 100 and is
predictive of chemotherapy benefit when it is high,
whether a high score is defined as 31 or higher12,13
or 26 or higher12,14
; when the recurrence score is
low (0 to 10), it is prognostic for a very low rate of
distant recurrence (2%) at 10 years that is not
likely to be affected by adjuvant chemotherapy.12,14
Although expert panels recommend the use of the
21-gene assay,15,16
uncertainty remains as to wheth-
er chemotherapy is beneficial for the majority of
patients, who have a mid-range recurrence score.
The Trial Assigning Individualized Options
for Treatment (TAILORx) was designed to address
these gaps in our knowledge by determining
whether chemotherapy is beneficial for women
with a mid-range recurrence score of 11 to 25. It
was a prospective clinical trial, a type of trial that
provides the highest level of evidence supporting
the clinical usefulness of a biomarker.17 Another
objective of the trial was to prospectively confirm
that a low recurrence score of 0 to 10 is associated
with a low rate of distant recurrence when patients
are treated with endocrine therapy alone.18
Methods
Trial Oversight
We conducted a prospective clinical trial sponsored
by the National Cancer Institute that was coordi-
nated by the Eastern Cooperative Oncology Group
(ECOG) and subsequently by the ECOG–Ameri-
can College of Radiology Imaging Network (ACRIN)
Cancer Research Group, with other federally fund-
ed groups participating, including the Southwest
Oncology Group, Alliance for Clinical Trials in
Oncology, NRG Oncology, and Canadian Cancer
Trials Group. Women who participated in the
trial provided written informed consent, includ-
ing a statement of willingness to have treatment
assigned or randomly assigned on the basis of
the recurrence-score results. An Oncotype DX
recurrence-score assay was performed in a cen-
tral laboratory (Genomic Health) on samples
obtained from every woman who participated in
the trial.10 Additional details are provided in the
Supplementary Appendix and the protocol, both
of which are available with the full text of this
article at NEJM.org.
The authors performed the statistical analysis
and wrote the first draft of the manuscript; the
final submitted manuscript, which incorporated
changes recommended by the coauthors and by
Genomic Health, was reviewed and approved by
all the authors, who vouch for the accuracy and
completeness of the data and for adherence of
the trial to the protocol. No one who is not an
author contributed to the manuscript. Commer-
cial support was not provided for the planning and
execution of the trial but was provided by Ge-
nomic Health for the collection of follow-up in-
formation from the treating sites.
Trial Population, Treatment, and End Points
We enrolled women who were 18 to 75 years of
age; had hormone-receptor–positive, human epi-
dermal growth factor receptor 2 (HER2)–negative,
axillary node–negative breast cancer; and met Na-
tional Comprehensive Cancer Network guidelines
for the recommendation or consideration of ad-
juvant chemotherapy (the full list of inclusion
and exclusion criteria is provided in the Supple-
mentary Appendix). On the basis of the 21-gene
recurrence score, women were assigned to one of
four treatment groups. Women with a recurrence
score of 10 or lower were assigned to receive
endocrine therapy only, and women with a score
of 26 or higher were assigned to receive chemo-
therapy plus endocrine (chemoendocrine) therapy.
Women with a midrange score of 11 to 25 under-
went randomization and were assigned to receive
either endocrine therapy alone or chemoendocrine
therapy. Additional details are provided in the
Supplementary Appendix.
A Quick Take is
available at
NEJM.org
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n engl j med 379;2nejm.org July 12, 2018 113
21-Gene Expression Assay in Breast Cancer
The standardized definitions for efficacy end
points (STEEP) criteria were used for end-point
definitions (Section 6B in the Supplementary
Appendix).19 The primary end point was invasive
disease–free survival, defined as freedom from
invasive disease recurrence, second primary can-
cer, or death. Key secondary end points included
freedom from recurrence of breast cancer at a
distant site (which corresponds to the STEEP defi-
nition of distant recurrence–free interval), free-
dom from recurrence of breast cancer at a dis-
tant or local–regional site (which corresponds to
the STEEP definition of recurrence-free interval),
and overall survival. Full definitions of all the end
points are provided in the Supplementary Ap-
pendix.
Statistical Analysis
The overall sample size was driven by the need
to include a sufficient number of patients with a
recurrence score of 11 to 25 to test the noninfe-
riority of endocrine therapy alone (the experimen-
tal group) to chemoendocrine therapy (the stan-
dard group) in this cohort of patients. Because
of concern that nonadherence to the assigned
treatment could make determination of an ap-
propriate noninferiority margin problematic, the
test of noninferiority used a null hypothesis of
no difference, as when testing for superiority, but
with a larger type I error (one-sided 10%) and
smaller type II error (5%) than usual. In this ap-
proach, controlling the type II error is critical,
so failure to reject equality provides evidence for
a conclusion of noninferiority. A 5-year rate of
invasive disease–free survival of 90% with che-
moendocrine therapy and of 87% or less with
endocrine therapy alone, which corresponds to a
32.2% higher risk of an invasive disease recur-
rence, second primary cancer, or death as a result
of not administering chemotherapy (hazard ratio,
1.322), was prespecified as unacceptable.12,14
The primary analysis was a comparison ac-
cording to the assigned treatment. Because of a
rate of nonadherence (12%) that was larger than
had originally been projected (5%), the sample
size of the group that underwent randomization
(i.e., women with a recurrence score of 11 to 25)
was increased by 73% (relative to a design with
100% adherence, based on the Lachin–Foulkes
correction),20 which resulted in a target sample size
of 6517 eligible patients undergoing randomiza-
tion. The analysis was also performed according
to the actual treatment given in order to explore
the effect of nonadherence. The final analysis took
place on March 2, 2018, at which time the pre-
specified number of events required for full in-
formation (835 events) had occurred. The analysis
methods are further described in Section 6B in
the Supplementary Appendix.
R esult s
Characteristics of the Patients
A total of 10,273 women were registered between
April 7, 2006, and October 6, 2010, of whom
10,253 were eligible for participation. Among the
9719 eligible patients with follow-up information
who were included in the main analysis set, 6711
(69%) had a recurrence score of 11 to 25, 1619
(17%) had a recurrence score of 10 or lower, and
1389 (14%) had a recurrence score of 26 or high-
er (Fig. 1). The median duration of follow-up in
the cohort of patients with a recurrence score of
11 to 25 was 90 months for invasive disease–free
survival and 96 months for overall survival. The
characteristics of the trial population that was
included in the main analysis are shown in Ta-
ble 1, and in Table S1 in the Supplementary Ap-
pendix.
Adjuvant Therapy in the Cohort
with a Recurrence Score of 11 to 25
The median duration of endocrine therapy was
5.4 years, with similar distributions of durations
in the two randomly assigned treatment groups,
including approximately 35% rates of adjuvant
endocrine therapy extending beyond 5 years (Fig.
S1 in the Supplementary Appendix). The most
common chemotherapy regimens among the pa-
tients who were randomly assigned to and treated
with chemotherapy were docetaxel–cyclophospha-
mide (56%) and anthracycline-containing regi-
mens (36%). The endocrine therapy regimens
among postmenopausal women most commonly
included an aromatase inhibitor (91%); among
premenopausal women, endocrine therapy regi-
mens most commonly included either tamoxifen
alone or tamoxifen followed by an aromatase
inhibitor (78%), and suppression of ovarian func-
tion was used in 13% of premenopausal women
(Table S2 in the Supplementary Appendix). The
rate of nonadherence to the assigned treatment
was 11.8% overall, including 5.4% among patients
who were randomly assigned to receive endo-
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n engl j med 379;2nejm.org July 12, 2018114
T h en e w e ngl a nd j o u r na lo f m e dic i n e
crine therapy alone and 18.4% among those
who were randomly assigned to receive chemo-
endocrine therapy (Table 1). In the as-treated
population, some of the differences in baseline
characteristics between the treatment groups
were significant (Table S3 in Supplementary Ap-
pendix).
Invasive Disease–free Survival
and Other End Points in the Cohort
with a Recurrence Score of 11 to 25
There had been 836 events of invasive disease
recurrence, second primary cancer, or death (the
components of invasive disease–free survival,
the primary end point) in the two randomly as-
Figure 1. Registration, Randomization, and Follow-up.
All the patients who met the eligibility criteria and provided written informed consent were preregistered; a primary tumor specime
was subsequently obtained and sent to the Genomic Health laboratory for the 21-gene assay. On receipt of the assay report and rec
rence-score result by the treating physician, the enrolling site then assigned patients to a treatment group. If the recurrence score w
10 or lower, the patient was assigned to receive endocrine therapy alone. If the recurrence score was 26 or higher, the patient was
signed to receive chemoendocrine therapy. If the recurrence score was 11 to 25, the patient underwent randomization and was ass
to receive either endocrine therapy or chemoendocrine therapy. The stratification factors that were used in randomization were tum
size (≤2 cm vs. >2 cm), menopausal status (pre- vs. postmenopausal), planned chemotherapy (taxane-containing vs. not), planned
ation therapy (whole breast and no boost irradiation planned vs. whole breast and boost irradiation planned vs. partial breast irradi
planned vs. no planned radiation therapy for patients who had undergone a mastectomy), and recurrence-score group (11 to 15 vs.
16 to 20 vs. 21 to 25), which was added midway through the trial.
10,273 Registered and were assigned
to a treatment group
11,232 Patients were preregistered
959 Did not register
182 Were ineligible
551 Withdrew
33 Had medical reason
159 Had other reasons
34 Did not report a reason
1629 Had recurrence score ≤10
and were assigned to receive
endocrine therapy alone
10 Were excluded
3 Were ineligible
7 Did not have
trial-period infor-
mation, follow-
up information,
or either
1619 Were included in the main
analysis
56 Withdrew consent for
continued follow-up
93 Were lost to follow-up
3458 Had recurrence score 11–25
and were randomly assigned to
receive endocrine therapy alone
59 Were excluded
4 Were ineligible
55 Did not have
trial-period infor-
mation, follow-
up information,
or either
3399 Were included in the main
analysis
3214 Received assigned treat-
ment with endocrine
therapy only
185 Received adjuvant
chemotherapy
116 Withdrew consent for
continued follow-up
224 Were lost to follow-up
3449 Had recurrence score 11–25
and were randomly assigned to
receive chemoendocrine therapy
137 Were excluded
6 Were ineligible
131 Did not have
trial-period infor-
mation, follow-
up information,
or either
3312 Were included in the main
analysis
2704 Received assigned treat-
ment with adjuvant
chemotherapy
608 Did not receive chemo-
therapy
148 Withdrew consent for
continued follow-up
208 Were lost to follow-up
1737 Had recurrence score ≥26
and were assigned to receive
chemoendocrine therapy
348 Were excluded
7 Were ineligible
341 Did not have
trial-period infor-
mation, follow-
up information,
or either
1389 Were included in the main
analysis
25 Withdrew consent for
continued follow-up
25 Were lost to follow-up
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n engl j med 379;2nejm.org July 12, 2018 115
21-Gene Expression Assay in Breast Cancer
Characteristic Recurrence Score of ≤10 Recurrence Score of 11–25Recurrence Score of ≥26
Endocrine Therapy
(N = 1619)
Endocrine Therapy
(N = 3399)
Chemoendocrine
Therapy
(N = 3312)
Chemoendocrine
Therapy
(N = 1389)
Median age (range) — yr 58 (25–75) 55 (23–75) 55 (25–75) 56 (23–75)
Age ≤50 yr — no. (%) 429 (26) 1139 (34) 1077 (33) 409 (29)
Menopausal status — no. (%)†
Premenopausal 478 (30) 1212 (36) 1203 (36) 407 (29)
Postmenopausal 1141 (70) 2187 (64) 2109 (64) 982 (71)
Tumor size in the largest dimension —
cm‡
Median (IQR) 1.5 (1.2–2.0) 1.5 (1.2–2.0) 1.5 (1.2–2.0) 1.7 (1.3–2.3)
Mean 1.74±0.76 1.71±0.81 1.71±0.77 1.88±0.99
Histologic grade of tumor — no./total
no. (%)
Low 530/1572 (34) 959/3282 (29) 934/3216 (29) 89/1363 (7)
Intermediate 931/1572 (59) 1884/3282 (57) 1837/3216 (57) 590/1363 (43)
High 111/1572 (7) 439/3282 (13) 445/3216 (14) 681/1363 (50)
Estrogen-receptor expression — no. (%)
Negative 5 (<1) 6 (<1) 3 (<1) 40 (3)
Positive 1614 (>99) 3393 (>99) 3309 (>99) 1349 (97)
Progesterone-receptor expression —
no./total no. (%)
Negative 28/1583 (2) 267/3339 (8) 251/3240 (8) 405/1353 (30)
Positive 1555/1583 (98) 3072/3339 (92) 2989/3240 (92) 948/1353 (70)
Clinical risk — no./total no. (%)§
Low 1227/1572 (78) 2440/3282 (74) 2359/3214 (73) 589/1359 (43)
High 345/1572 (22) 842/3282 (26) 855/3214 (27) 770/1359 (57)
Primary surgery — no. (%)
Mastectomy 516 (32) 935 (28) 917 (28) 368 (26)
Breast conservation 1103 (68) 2464 (72) 2395 (72) 1021 (74)
Adjuvant chemotherapy — no. (%)
Yes 8 (0.5) 185 (5.4) 2704 (81.6) 1300 (93.6)
No 1611 (99.5) 3214 (94.6) 608 (18.4) 89 (6.4)
* Plus–minus values are means ±SD. The characteristics were well balanced between the two randomly assigned groups (i.e.
with a recurrence score of 11 to 25) for all the factors listed. The differences between the group with a recurrence score of 1
the combined randomly assigned groups were significant for age, menopausal status, histologic grade, progesterone recept
surgical procedure (P<0.001 for all comparisons). The differences between the group with a recurrence score of 26 or highe
bined randomly assigned groups were significant for the distributions of age (P = 0.003), menopausal status (P<0.001), tum
(P<0.001), histologic grade (P<0.001), and progesterone receptor status (P<0.001).
† Among the 14 patients for whom menopausal status was not reported, those who were 50 years of age or younger were cla
menopausal.
‡ There were 86 patients with a tumor size recorded as 0.5 cm or less and 20 patients with a tumor size greater than 5 cm. In
mor size was missing for 2 patients with a recurrence score of 11 to 25 in the chemoendocrine-therapy group and for 1 patie
rence score of 26 or higher.
§ Clinical risk was defined as in the MINDACT (Microarray in Node Negative Disease May Avoid Chemotherapy) trial (i.e., with
fined as low histologic grade and tumor size ≤3 cm, intermediate histologic grade and tumor size ≤2 cm, or high histologic g
mor size ≤1 cm; and with high risk defined as all other cases with known values for grade and tumor size).
Table 1. Characteristics of the Patients in the Intention-to-Treat Population at Baseline.*
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n engl j med 379;2nejm.org July 12, 2018116
T h en e w e ngl a nd j o u r na lo f m e dic i n e
signed treatment groups at the time of the final
analysis, including 338 (40.4%) recurrences of
breast cancer as the first event, of which 199
(23.8% of the total events) were distant recur-
rences (Tables S4 and S5 in the Supplementary
Appendix). In the intention-to-treat population,
endocrine therapy was noninferior to chemoen-
docrine therapy in the analysis of invasive dis-
ease–free survival (hazard ratio for invasive dis-
ease recurrence, second primary cancer, or death
[endocrine vs. chemoendocrine therapy], 1.08;
95% confidence interval [CI], 0.94 to 1.24; P = 0.26)
(Fig. 2A). Endocrine therapy was likewise nonin-
ferior to chemoendocrine therapy in the analyses
of other end points, including freedom from
recurrence of breast cancer at a distant site (haz-
ard ratio for recurrence, 1.10; P = 0.48) (Fig. 2B),
freedom from recurrence of breast cancer at a
distant or local–regional site (hazard ratio for
recurrence, 1.11; P = 0.33), and overall survival
(hazard ratio for death, 0.99; P = 0.89). Additional
details regarding these end points are provided
in Figure S2 and Section 6B in the Supplemen-
tary Appendix.
The results of the as-treated analyses were
consistent with those of the intention-to-treat
analyses for invasive disease–free survival (haz-
ard ratio for invasive disease recurrence, second
primary cancer, or death [endocrine vs. chemo-
endocrine therapy], 1.14; 95% CI, 0.99 to 1.31;
P = 0.06), freedom from recurrence of breast
cancer at a distant site (hazard ratio for recur-
rence, 1.03; P = 0.81), freedom from recurrence
of breast cancer at a distant or local–regional
site (hazard ratio for recurrence, 1.12; P = 0.28),
and overall survival (hazard ratio for death, 0.97;
P = 0.78) (Fig. S3 in the Supplementary Appendix).
The estimated 9-year rates of invasive disease–
free survival in the as-treated population were
83.1% for patients who received endocrine ther-
apy alone and 84.7% for those who received che-
moendocrine therapy. The outcomes were unlikely
to have been affected by incomplete follow-up in-
formation (Section 6E in the Supplementary Ap-
pendix).
Survival Rates in All Recurrence-Score
Cohorts and Treatment Groups
The estimated survival rates at 5 and 9 years for
all treatment groups and end points are shown
in Table 2. At 9 years in the intention-to-treat
population, among patients with a recurrence
score of 11 to 25, the rate of invasive disease–
free survival was 83.3% in the endocrine-therapy
group and 84.3% in the chemoendocrine-therapy
group; the corresponding rates were 94.5% and
95.0% for freedom from recurrence of breast
cancer at a distant site, 92.2% and 92.9% for
freedom from recurrence of breast cancer at a
distant or local–regional site, and 93.9% and
93.8% for overall survival. When all recurrence-
score cohorts (≤10, 11 to 25, and ≥26) and treat-
ment-group assignments were considered, there
were significant differences in the rates of inva-
sive disease–free survival, recurrence, and death
(P<0.001), driven largely by the higher likelihood
of having an event in the cohort with a recur-
rence score of 26 or higher (Fig. S4 in the Sup-
plementary Appendix). Distant recurrence was
associated with recurrence score as a continuous
variable between 11 and 25, but there was no sig-
nificant interaction between chemotherapy treat-
ment and recurrence score in this range (Figs. S5
through S10 in the Supplementary Appendix).
Interactions According to Subgroup in the
Cohorts with a Recurrence Score of 11 to 25
We performed exploratory analyses to determine
whether any subgroups might have derived some
benefit from chemotherapy in the intention-to-
treat population, with a focus on covariates that
were prognostic or associated with greater benefit
from chemotherapy, such as younger age (Section
6F and Fig. S11 in the Supplementary Appendix).6
There were no significant interactions between
chemotherapy treatment and most of the prog-
nostic covariates examined, including recurrence-
score category (either 11 to 15 vs. 16 to 20 vs. 21
to 25, or 11 to 17 vs. 18 to 25), tumor size (≤2 cm
vs. >2 cm), histologic grade (low vs. intermediate
vs. high), clinical risk category (high vs. low), and
menopausal status (pre- vs. postmenopausal).
There were significant interactions between che-
motherapy treatment and age (≤50 vs. 51 to 65 vs.
>65 years)for invasivedisease–freesurvival
(P = 0.03) and for freedom from recurrence of
breast cancer at a distant or local–regional site
(P = 0.02) but not at a distant site (P = 0.12). The
effect of treatment also varied significantly over
the six combinations of menopausal status and
recurrence-score category (11 to 15 vs. 15 to 20
vs. 21 to 25) (P = 0.02) and over the nine combina-
tions of age and recurrence-scorecategory
(P = 0.004) for invasive disease–free survival (Figs.
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n engl j med 379;2nejm.org July 12, 2018 117
21-Gene Expression Assay in Breast Cancer
S12 and S13 in the Supplementary Appendix) but
not for freedom of recurrence of breast cancer at
a distant site or distant or local–regional site. In
women 50 years of age or younger, chemotherapy
was associated with a lower rate of distant recur-
rence than endocrine therapy if the recurrence
score was 16 to 20 (percentage-point difference,
0.8 at 5 years and 1.6 at 9 years) or 21 to 25 (per-
centage-point difference, 3.2 at 5 years and 6.5 at
9 years), although the rates of overall survival
were similar (Table 3). Conversely, in the 40% of
women 50 years of age or younger who had a re-
currence score of 0 to 15, the rate of distant re-
currence was approximately 2% at 9 years among
those who had been assigned (either randomly or
nonrandomly) to endocrine therapy alone.
Figure 2. Clinical Outcomes among Patients with a Recurrence Score of 11 to 25.
Kaplan–Meier estimates of survival rates in the analysis according to the assigned treatment group are shown for
the group that received endocrine therapy alone and the group that received chemoendocrine therapy in the inten-
tion-to-treat analysis of invasive disease–free survival (defined as freedom from invasive disease recurrence, second
primary cancer, or death) and freedom from recurrence of breast cancer at a distant site. The hazard ratios are for
the endocrine-therapy group versus the chemoendocrine-therapy group.
B Freedom from Recurrence at a Distant Site
A Invasive Disease–free Survival
1.0
1.0
Probability of Invasive
Disease–free Survival
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 24 36 48 84 108
Months
Hazard ratio for invasive-disease recurrence, second primary cancer,
or death, 1.08 (95% CI, 0.94–1.24)
P=0.26
No. at Risk
Chemoendocrine therapy
Endocrine therapy
3312
3399
3104
3194
12
3204
3293
2993
3081
2849
2953
60
2645
2741
1781
1859
72
2335
2431
96
1130
1197
523
537
Probability of Freedom from
Recurrence at a Distant Site
0.8
0.9
0.7
0.6
0.4
0.3
0.1
0.5
0.2
0.0
0 24 36 48 84 108
Months
Hazard ratio for recurrence at a distant site, 1.10 (95% CI, 0.85–1.41)
P=0.48
No. at Risk
Chemoendocrine therapy
Endocrine therapy
3312
3399
3142
3239
12
3215
3318
3059
3147
2935
3033
60
2734
2833
1866
1947
72
2432
2537
96
1197
1267
554
581
Endocrine therapy Chemoendocrine therapy
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n engl j med 379;2nejm.org July 12, 2018118
T h en e w e ngl a nd j o u r na lo f m e dic i n e
Discussion
In this prospective, randomized trial, we found
that among 6711 women with hormone-receptor–
positive, HER2-negative, axillary node–negative
breast cancer and a midrange recurrence score of
11 to 25 on the 21-gene assay, endocrine therapy
was not inferior to chemoendocrine therapy, which
provides evidence that adjuvant chemotherapy
was not beneficial in these patients. This find-
ing contrasts those of previous biomarker vali-
dation studies that were performed retrospec-
tively with the use of archival tumor specimens,
in which a substantial benefit for the prevention
of distant recurrence has been found for the com-
bination of chemotherapy and endocrine therapy
in patients with a recurrence score of 26 or
higher.12,13The 9-year rate of distant recurrence
in women with a recurrence score of 11 to 25 in
our trial was approximately 5%, irrespective of
chemotherapy use, a finding consistent with that
predicted from the original report showing a sig-
nificant treatment interaction between chemo-
therapy benefit and a recurrence score of 26 or
higher.14 Updated results for patients with a low
recurrence score of 10 or less, who were previ-
ously reported as having a 1% distant recurrence
rate at 5 years in our trial,18 now indicate a 9-year
rate of distant recurrence of approximately 3%.
Population-based studies have shown a recur-
rence-score distribution similar to that observed
in this prospective trial, along with no apparent
benefit from chemotherapy in the recurrence-
score range of 11 to 25 and a significant asso-
ciation between recurrence score and recurrence
or 5-year breast cancer–specific mortality, which
indicates the generalizability of our findings to
clinical practice.21,22Although the rate of nonad-
herence to the assigned treatment was 12% over-
all, the sample size was adjusted to compensate
for this, and the as-treated analysis produced re-
sults similar to those of the intention-to-treat
analysis. The rate of nonadherence was similar
to those in previous trials evaluating breast con-
servation or high-dose chemotherapy.23,24 Only
24% of first events included in the primary end
point (invasive disease recurrence, second pri-
mary cancer, or death) were distant recurrences,
the type of recurrence that is most influenced by
adjuvant chemotherapy,7 which also has some ef-
fect in reducing other events, such as local–regional
recurrence or contralateral breast cancer.25,26
A total of 40% of women who were 50 years
of age or younger had a recurrence score of 15
or lower, which was associated with a low rate
of recurrence with endocrine therapy alone. Ex-
ploratory analyses indicated that chemotherapy
was associated with some benefit for women 50
years of age or younger who had a recurrence
score of 16 to 25 (a range of scores that was
found in 46% of women in this age group). A
greater treatment effect from adjuvant chemo-
therapy has been noted in younger women,7
which may be at least partly explained by an
antiestrogenic effect associated with premature
menopause induced by chemotherapy.27 We did
not collect data on chemotherapy-induced meno-
pause. It remains unclear whether similar bene-
fits could be achieved with ovarian suppression
End Point and Treatment Group Rate at 5 YrRate at 9 Yr
percent
Invasive disease–free survival†
Score of ≤10, endocrine therapy 94.0±0.6 84.0±1.3
Score of 11–25, endocrine therapy 92.8±0.5 83.3±0.9
Score of 11–25, chemoendocrine therapy93.1±0.5 84.3±0.8
Score of ≥26, chemoendocrine therapy87.6±1.0 75.7±2.2
Freedom from recurrence of breast cancer
at a distant site
Score of ≤10, endocrine therapy 99.3±0.2 96.8±0.7
Score of 11–25, endocrine therapy 98.0±0.3 94.5±0.5
Score of 11–25, chemoendocrine therapy98.2±0.2 95.0±0.5
Score of ≥26, chemoendocrine therapy93.0±0.8 86.8±1.7
Freedom from recurrence of breast cancer
at a distant or local–regional site
Score of ≤10, endocrine therapy 98.8±0.3 95.0±0.8
Score of 11–25, endocrine therapy 96.9±0.3 92.2±0.6
Score of 11–25, chemoendocrine therapy97.0±0.3 92.9±0.6
Score of ≥26, chemoendocrine therapy91.0±0.8 84.8±1.7
Overall survival
Score of ≤10, endocrine therapy 98.0±0.4 93.7±0.8
Score of 11–25, endocrine therapy 98.0±0.2 93.9±0.5
Score of 11–25, chemoendocrine therapy98.1±0.2 93.8±0.5
Score of ≥26, chemoendocrine therapy95.9±0.6 89.3±1.4
* Plus–minus values are Kaplan–Meier estimates ±SE.
† Invasive disease–free survival was defined as freedom from invasive disease
recurrence, second primary cancer, or death.
Table 2. Estimated Survival Rates According to Recurrence Score
and Assigned Treatment in the Intention-to-Treat Population.*
End Point and Treatment Group Rate at 5 YrRate at 9 Yr
percent
Invasive disease–free survival†
Score of ≤10, endocrine therapy 94.0±0.6 84.0±1.3
Score of 11–25, endocrine therapy 92.8±0.5 83.3±0.9
Score of 11–25, chemoendocrine therapy93.1±0.5 84.3±0.8
Score of ≥26, chemoendocrine therapy87.6±1.0 75.7±2.2
Freedom from recurrence of breast cancer
at a distant site
Score of ≤10, endocrine therapy 99.3±0.2 96.8±0.7
Score of 11–25, endocrine therapy 98.0±0.3 94.5±0.5
Score of 11–25, chemoendocrine therapy98.2±0.2 95.0±0.5
Score of ≥26, chemoendocrine therapy93.0±0.8 86.8±1.7
Freedom from recurrence of breast cancer
at a distant or local–regional site
Score of ≤10, endocrine therapy 98.8±0.3 95.0±0.8
Score of 11–25, endocrine therapy 96.9±0.3 92.2±0.6
Score of 11–25, chemoendocrine therapy97.0±0.3 92.9±0.6
Score of ≥26, chemoendocrine therapy91.0±0.8 84.8±1.7
Overall survival
Score of ≤10, endocrine therapy 98.0±0.4 93.7±0.8
Score of 11–25, endocrine therapy 98.0±0.2 93.9±0.5
Score of 11–25, chemoendocrine therapy98.1±0.2 93.8±0.5
Score of ≥26, chemoendocrine therapy95.9±0.6 89.3±1.4
* Plus–minus values are Kaplan–Meier estimates ±SE.
† Invasive disease–free survival was defined as freedom from invasive disease
recurrence, second primary cancer, or death.
Table 2. Estimated Survival Rates According to Recurrence Score
and Assigned Treatment in the Intention-to-Treat Population.*
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n engl j med 379;2nejm.org July 12, 2018 119
21-Gene Expression Assay in Breast Cancer
plus an aromatase inhibitor instead of chemo-
therapy.28,29
The MINDACT (Microarray in Node Negative
Disease May Avoid Chemotherapy) trial was also
a prospective trial integrating a gene-expression
assay (with 70 genes) and randomized assign-
ment of chemotherapy.30 The primary end point
in the trial focused on 644 patients with high
clinical risk (48% node-positive, 8% HER2-posi-
tive) and low genomic risk who were assigned to
receive no chemotherapy, and the prespecified
prognostic end point of a 5-year rate of distant
metastasis–free survival of more than 92% in
this group of patients was met. Evidence-based
guidelines recommend that the use of the assay
be considered in cases of hormone-receptor–
positive, HER2-negative breast cancer and high
clinical risk but not low clinical risk as defined
in that trial.31 When the same clinical risk defi-
nitions were applied in our trial, 73.9% of the
patients were at low clinical risk and 26.1% were
at high clinical risk in the randomized treatment
groups (Table 1), and we found no evidence sug-
gesting a chemotherapy benefit in either risk
group.
On the basis of previous information regard-
ing the clinical validity and usefulness of the
21-gene assay, the use of adjuvant chemotherapy
has declined substantially in hormone-receptor–
positive, HER2-negative, axillary node–negative
breast cancer.32 The results of our trial suggest
that the 21-gene assay may identify up to 85% of
women with early breast cancer who can be
spared adjuvant chemotherapy, especially those
who are older than 50 years of age and have a
recurrence score of 25 or lower, as well as
women 50 years of age or younger with a recur-
rence score of 15 or lower. Ongoing clinical tri-
als are obtaining additional information on the
clinical usefulnessof the 21-geneassayin
women with hormone-receptor–positive breast
cancer and positive axillary nodes33 and evaluat-
ing the clinical usefulness of the 50-gene assay
in this context.34
The content of this article is solely the responsibility of the
authors and does not necessarily represent the official views of
the National Institutes of Health, nor does mention of trade
names, commercial products, or organizations imply endorse-
ment by the United States government.
Supported by the National Cancer Institute of the National
Institutes of Health (award numbers CA180820, CA180794,
CA189828,CA180790,CA180795,CA180799,CA180801,
CA180816,CA180821,CA180838,CA180822,CA180844,
End Point and Treatment Group Rate at 5 YrRate at 9 Yr
percent
Invasive disease–free survival†
Score of ≤10, endocrine therapy 95.1±1.1 87.4±2.0
Score of 11–15, endocrine therapy 95.1±1.1 85.7±2.2
Score of 11–15, chemoendocrine therapy94.3±1.3 89.2±1.9
Score of 16–20, endocrine therapy 92.0±1.3 80.6±2.5
Score of 16–20, chemoendocrine therapy94.7±1.1 89.6±1.7
Score of 21–25, endocrine therapy 86.3±2.3 79.2±3.3
Score of 21–25, chemoendocrine therapy92.1±1.8 85.5±3.0
Score of ≥26, chemoendocrine therapy86.4±1.9 80.3±2.9
Freedom from recurrence of breast cancer at
a distant site
Score of ≤10, endocrine therapy 99.7±0.3 98.5±0.8
Score of 11–15, endocrine therapy 98.8±0.6 97.2±1.0
Score of 11–15, chemoendocrine therapy98.5±0.7 98.0±0.8
Score of 16–20, endocrine therapy 98.1±0.7 93.6±1.4
Score of 16–20, chemoendocrine therapy98.9±0.5 95.2±1.3
Score of 21–25, endocrine therapy 93.2±1.7 86.9±2.9
Score of 21–25, chemoendocrine therapy96.4±1.2 93.4±2.3
Score of ≥26, chemoendocrine therapy91.1±1.6 88.7±2.1
Freedom from recurrence of breast cancer at
a distant or local–regional site
Score of ≤10, endocrine therapy 98.4±0.6 95.4±1.3
Score of 11–15, endocrine therapy 97.5±0.8 93.3±1.6
Score of 11–15, chemoendocrine therapy97.2±0.9 94.4±1.5
Score of 16–20, endocrine therapy 95.7±1.0 89.6±1.9
Score of 16–20, chemoendocrine therapy97.2±0.8 93.0±1.5
Score of 21–25, endocrine therapy 89.8±2.0 82.0±3.2
Score of 21–25, chemoendocrine therapy94.2±1.6 90.7±2.5
Score of ≥26, chemoendocrine therapy88.6±1.8 86.1±2.2
Overall survival
Score of ≤10, endocrine therapy 100.0 98.6±0.9
Score of 11–15, endocrine therapy 99.3±0.4 96.8±1.0
Score of 11–15, chemoendocrine therapy98.9±0.6 97.5±0.9
Score of 16–20, endocrine therapy 98.6±0.6 95.8±1.2
Score of 16–20, chemoendocrine therapy99.8±0.2 96.1±1.2
Score of 21–25, endocrine therapy 98.2±0.9 92.7±2.0
Score of 21–25, chemoendocrine therapy98.3±0.8 93.9±1.9
Score of ≥26, chemoendocrine therapy95.6±1.1 92.4±1.9
* Plus–minus values are Kaplan–Meier estimates ±SE.
† Invasive disease–free survival was defined as freedom from invasive dis
recurrence, second primary cancer, or death.
Table 3. Estimated Survival Rates According to Recurrence Score
and Assigned Treatment among Women 50 Years of Age or Youn
in the Intention-to-Treat Population.*
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n engl j med 379;2nejm.org July 12, 2018120
T h en e w e ngl a nd j o u r na lo f m e dic i n e
CA180847,CA180857,CA180864,CA189867,CA180868,
CA189869,CA180888,CA189808,CA189859,CA189804,
CA190140, and CA180863), the Canadian Cancer Society Re-
search Institute (grants 015469 and 021039), the Breast Cancer
Research Foundation, the Komen Foundation, the Breast Cancer
Research Stamp issued by the U.S. Postal Service, and Genomic
Health.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org. Authors who reported
serving as paid consultants for Genomic Health within 36
months before publication include Drs. Goetz and Kaklamani;
Dr. Paik reports holding a patent issued and licensed to Ge-
nomic Health, with all rights transferred to the National Surgi-
cal Adjuvant Breast and Bowel Project (NSABP) Foundation.
We thank Sheila Taube, Ph.D., and JoAnne Zujewski, M.D.,
National Cancer Institute, for their support of the trial at its in-
ception and development; the staff at the Eastern Cooperative
Oncology Group (ECOG)–American College of Radiology Imag-
ing Network (ACRIN) Operations Office in Boston and the Can-
cer Trials Support Unit for their efforts; Una Hopkins, R.N.,
D.N.P., for serving as the study liaison for the trial; the late
Robert L. Comis, M.D., former chair of ECOG and cochair of
ECOG-ACRIN, for his prescient leadership in supporting bio-
marker-directed clinical trials; the thousands of women who
participated in the trial; the leadership of the National Breast
Cancer Coalition for endorsing the trial; and Mary Lou Smith,
J.D., M.B.A., for her work as a patient advocate for breast cancer
clinical research.
Appendix
The authors’ full names and academic degrees are as follows: Joseph A. Sparano, M.D., Robert J. Gray, Ph.D., Della F. Mako
Kathleen I. Pritchard, M.D., Kathy S. Albain, M.D., Daniel F. Hayes, M.D., Charles E. Geyer, Jr., M.D., Elizabeth C. Dees, M.D.,
thew P. Goetz, M.D., John A. Olson, Jr., M.D., Ph.D., Tracy Lively, Ph.D., Sunil S. Badve, M.B., B.S., M.D., Thomas J. Saphner,
Lynne I. Wagner, Ph.D., Timothy J. Whelan, B.M., B.Ch., Matthew J. Ellis, M.B., B.Chir., Ph.D., Soonmyung Paik, M.D., William
Wood, M.D., Peter M. Ravdin, M.D., Maccon M. Keane, M.D., Henry L. Gomez Moreno, M.D., Pavan S. Reddy, M.D., Timothy F
gins, M.D., Ingrid A. Mayer, M.D., M.S.C.I., Adam M. Brufsky, M.D., Ph.D., Deborah L. Toppmeyer, M.D., Virginia G. Kaklaman
M.D., D.Sc., Jeffrey L. Berenberg, M.D., Jeffrey Abrams, M.D., and George W. Sledge, Jr., M.D.
The authors’ affiliations are as follows: Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (J.A.S., D
Dana–Farber Cancer Institute, Boston (R.J.G.); Sunnybrook Research Institute, Toronto (K.I.P.), and McMaster University, Ha
ON (T.J.W.) — both in Canada; Loyola University Chicago Stritch School of Medicine, Maywood (K.S.A.), and Northwestern U
Chicago (L.I.W., V.G.K.) — both in Illinois; University of Michigan, Ann Arbor (D.F.H.); Virginia Commonwealth University Sch
Medicine and the Massey Cancer Center, Richmond (C.E.G.); University of North Carolina, Chapel Hill (E.C.D.), and Duke Un
Medical Center, Durham (J.A.O.) — both in North Carolina; Mayo Clinic, Jacksonville, FL (M.P.G.); National Institutes of Healt
tional Cancer Institute, Bethesda, MD (T.L., J.A.); Indiana University School of Medicine (S.S.B.) and Indiana University Hosp
(G.W.S.), Indianapolis; Vince Lombardi Cancer Clinic, Two Rivers (T.J.S.), and Fox Valley Hematology and Oncology, Appleto
— both in Wisconsin; Washington University, St. Louis (M.J.E.); National Surgical Adjuvant Breast and Bowel Project Patholo
(S.P.) and University of Pittsburgh (A.M.B.), Pittsburgh; Emory University, Atlanta (W.C.W.); University of Texas, San Antonio
Cancer Trials Ireland, Dublin (M.M.K.); Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru (H.L.G.M.); Cancer Cent
Kansas, Wichita (P.S.R.); Vanderbilt University, Nashville (I.A.M.); Rutgers Cancer Institute of New Jersey, New Brunswick (D
University of Hawaii Cancer Center, Honolulu (J.L.B.).
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