Correspondence
The authors reply: Timing of the induction of
therapeutic hypothermia after traumatic brain
injury can be early (<6 hours) to provide prophy-
lactic “neuroprotection” or later to reduce intra-
cranial pressure. Early induction is well tested in
trials with a low risk of bias involving adults and
children with a signal toward harm and is being
further tested in POLAR. Therapeutic hypother-
mia for the reduction of intracranial pressure has
not been extensively tested before,1 but our trial
presents evidence against the intervention.
We see no plausible explanation why waiting
until all other therapies have failed to control in-
tracranial pressure would result in benefit from
therapeutic hypothermia, when the pathophysiol-
ogy of brain swelling is similar.
The threshold for therapy to reduce intracra-
nial pressure is based on level II evidence, and
20 mm Hg is the threshold recommended by the
current guidelines.2 There are even fewer data
supporting a permissive strategy of an intracra-
nial pressure of less than 25 mm Hg or less than
30 mm Hg, even with management of cerebral
perfusion pressure.
Stage 2 treatments failed to control intracra-
nial pressure in more than half the participants
in the Eurotherm3235 Trial. This was more com-
mon in the control group, which suggests pre-
vention of refractory raised intracranial pressure
with therapeutic hypothermia. The lessons learned
from the DECRA trial3 and the BEST:TRIP trial4
are that intracranial-pressure monitoring and
reduction does not improve outcomes after trau-
matic brain injury and are consistent with the
Eurotherm3235 Trial results. The results of the
RESCUEicp trial are eagerly awaited.
Because the Eurotherm3235 Trial was stopped
on the basis of a recommendation by the data
and safety monitoring committee, it is irrelevant
whether the target sample size was 1800 or 600.
The committee requested calculation of risk with
the use of the IMPACT model, and these data
A 21-Gene Expression Assay in Breast Cancer
To the Editor: Sparano et al. (Nov. 19 issue)1
report on the results of their Trial Assigning Indi-
vidualized Options for Treatment (TAILORx). In
their trial, the clinicopathologic features selected
16% of patients with breast cancer who had a
n engl j med 374;14 nejm.org  April 7, 2016
The New England Journal of Medicine
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Copyright © 2016 Massachusetts Medical Society. All rights reserved.
show that the increase in the rates of death and
poor outcome was consistent over time and was
greatest among the patients with the lowest
risks of death and disability in the hypothermia
group (see the Supplementary Appendix, avail-
able with the full text of the article at NEJM.org)
but were not prespecified in our statistical
analysis plan. Baseline data were assessed for
differences between groups, and there were no
significant differences detected, including in the
Marshall classification and mass lesions.
It remains unclear whether the Eurotherm3235
Trial results were due to a biologic effect of hy-
pothermia or the effect of an imbalance between
groups in the various but necessary cointerven-
tions. We believe that therapeutic hypothermia
should not be used after traumatic brain injury,
except in clinical trials.
Thresholds for intracranial-pressure interven-
tion after traumatic brain injury urgently require
reconsideration. Otherwise, the fate of the intra-
cranial-pressure monitor will emulate the de-
mise of the pulmonary-artery catheter.
Peter J.D. Andrews, M.D., M.B., Ch.B.
Bridget A. Harris, R.G.N., Ph.D.
Gordon D. Murray, Ph.D.
University of Edinburgh
Edinburgh, United Kingdom
p​.­andrews@​­ed​.­ac​.­uk
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Shiozaki T, Sugimoto H, Taneda M, et al. Effect of mild hypo-
thermia on uncontrollable intracranial hypertension after severe
head injury. J Neurosurg 1993;​79:​363-8.
2. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the
management of severe traumatic brain injury. VIII. Intracranial
pressure thresholds. J Neurotrauma 2007;​24:​Suppl 1:​S55-8.
3. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive cra-
niectomy in diffuse traumatic brain injury. N Engl J Med 2011;​
364:​1493-502.
4. Chesnut RM, Temkin N, Carney N, et al. A trial of intracra-
nial-pressure monitoring in traumatic brain injury. N Engl J Med
2012;​367:​2471-81.
DOI: 10.1056/NEJMc1600339
very good outcome at 5 years even though they
did not receive adjuvant chemotherapy.
To cross-validate their findings, we performed
a retrospective analysis involving a cohort of
1235 patients from our database from 2000
1385
 The n e w e ng l a n d j o u r na l
through 2010. These patients had clinicopatho-
logic features that were similar to those of the
patients in the study by Sparano et al. (primary
tumor size, >5 mm or >10 mm if Scarff–Bloom–
Richardson grade I and axillary-node–negative
breast cancer that was positive for estrogen re-
ceptor, progesterone receptor, and human epider-
mal growth factor receptor 2 [HER2] or unknown
status). In our series, 1008 of the patients (82%)
did not receive chemotherapy on the basis of
standard clinicopathologic criteria.
The characteristics of the patients who did not
receive chemotherapy versus those who did re-
ceive chemotherapy were as follows: median age,
61 years versus 48 years; median primary tumor
size, 14 mm versus 17 mm in the greatest di-
mension; Scarff–Bloom–Richardson grades I, II,
and III, 24%, 68%, and 8% versus 5%, 53%, and
42%, respectively; and the presence of vascular
emboli, 11% versus 48%. With a median follow-
up of 6.9 years (≥5 years in 76% of the patients),
the rate of disease-free survival at 5 years was
98.6% (95% confidence interval [CI], 97.6 to 99.2)
among patients who received endocrine therapy
only and 97.6% (95% CI, 94.3 to 99.0) among
those who also received chemotherapy.
These results show that standard clinico-
pathologic criteria are sufficient to spare the use
of chemotherapy in a large majority of patients
with breast cancer. We disagree that the study by
Sparano and colleagues adds evidence for the
use of the Oncotype DX Recurrence Score in this
population.
Marc Debled, M.D.
Christine Tunon de Lara, M.D.
Gaëtan MacGrogran, M.D.
Institut Bergonié
Bordeaux, France
m​.­debled@​­bordeaux​.­unicancer​.­fr
No potential conflict of interest relevant to this letter was re-
ported.
1. Sparano JA, Gray RJ, Makower DF, et al. Prospective valida-
tion of a 21-gene expression assay in breast cancer. N Engl J Med
2015;​373:​2005-14.
DOI: 10.1056/NEJMc1515988
To the Editor: Sparano et al. report that pa-
tients with hormone receptor–positive, node-
negative breast cancer who had a recurrence
score of 10 or lower (on a scale of 1 to 100, with
higher scores indicating a greater risk of recur-
rence) had an excellent prognosis without the use
1386 n engl j med 374;14 nejm.org  April 7, 2016
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Copyright © 2016 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
of adjuvant chemotherapy, irrespective of tumor
grade. Notably, although the recurrence score is
mainly determined by cell proliferation,1 classic
proliferation markers were not evaluated in this
study.
The Ki-67 proliferation index (the percentage
of cells that are positive for Ki-67) is widely used
internationally and recommended by the St. Gal-
len guidelines.2 We and others have shown that
the prognostic value of the Ki-67 proliferation
index is similar to that of genomic signatures.3,4
Despite reported analytic shortcomings, the
analytic validity of the Ki-67 proliferation index
has been confirmed in a Swedish nationwide
study.5
Using data from a population-based regional
registry, we identified all 908 patients who re-
ceived a diagnosis of breast cancer in Stockholm
in 2005 and 2006, who fulfilled the inclusion
criteria of the TAILORx study, and in whom the
Ki-67 proliferation index was assessed. A total of
247 patients had a very low Ki-67 index (≤10%),
and 229 of these patients (92.7%) did not receive
adjuvant chemotherapy. The prognosis in these
patients (Table 1) was in the same range as that
in patients in the study by Sparano et al. Thus,
Table 1. Characteristics and Outcomes of Patients with a
Very Low Ki-67 Proliferation Index (≤10%) Who Received
Adjuvant Endocrine Therapy.*
Variable Patients (N = 229)
Median age (interquartile range) — yr 60 (54–65)
Histologic grade of tumor — no.
1 94
2 125
3 5
Not available 5
Events — no. (%)
Freedom from recurrence 219 (95.6)†
Breast cancer–specific survival 226 (98.7)
Overall survival 211 (92.1)
* Data are from patients who received the primary diagno-
sis in 2005 or 2006. The follow-up analysis for survival
occurred in July 2015. The main selection criteria were
an age of 18 to 75 years and hormone receptor–positive,
human epidermal growth factor receptor 2–negative,
lymph node–negative tumors measuring 1 to 5 cm in
the greatest dimension. The Ki-67 proliferation index
is the percentage of cells that are positive for Ki-67.
† Six patients had locoregional relapse, and four patients
had distant relapse.
 Correspondence

the Ki-67 index may be an alternative to the re- Breast cancer–specific mortality was higher
currence score for the identification of patients among patients with a recurrence score of 11 to
with a low risk of recurrence. 18, 18 to 30, or greater than 30 (hazard ratio,
Theodoros Foukakis, M.D., Ph.D. 2.0, 3.0, and 10.7, respectively) than among pa-
Claudette Falato, M.D. tients with a recurrence score of less than 11.
Jonas Bergh, M.D., Ph.D. Furthermore, in an evaluation of the TAILORx
Karolinska Institutet cohort, the distribution of clinicopathologic fea-
Stockholm, Sweden tures did not allow a clinician to reliably distin-
theodoros​.­foukakis@​­ki​.­se
guish patients who had a very low recurrence
No potential conflict of interest relevant to this letter was re-
ported. score from those with a higher recurrence score.
These findings provide clear evidence that the
1. Sotiriou C, Pusztai L. Gene-expression signatures in breast recurrence score provides prognostic informa-
cancer. N Engl J Med 2009;​360:​790-800.
2. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the tion that is independent of clinicopathologic
treatment of women with early breast cancer: highlights of the features, but they do not indicate the most ap-
St Gallen International Expert Consensus on the Primary Therapy propriate recurrence-score cutoff point for ob-
of Early Breast Cancer 2013. Ann Oncol 2013:​9:​2206-23.
3. Ignatiadis M, Azim HA Jr, Desmedt C, et al. The genomic serving a benefit from chemotherapy.
grade assay compared with Ki67 to determine risk of distant Foukakis et al. suggest that despite known
breast cancer recurrence. JAMA Oncol 2016;​2:​217-24. “analytic shortcomings,” evaluation of the Ki-67
4. Tobin NP, Lindström LS, Carlson JW, Bjöhle J, Bergh J, Wenn­
malm K. Multi-level gene expression signatures, but not binary, proliferation index in a central laboratory pro-
outperform Ki67 for the long term prognostication of breast vided prognostic information that was similar to
cancer patients. Mol Oncol 2014;​8:​741-52. that provided by the recurrence score in a cohort
5. Ekholm M, Grabau D, Bendahl PO, et al. Highly reproducible
results of breast cancer biomarkers when analysed in accor- of 908 patients, of whom 247 had a very low
dance with national guidelines — a Swedish survey with central Ki-67 index (≤10%). However, use of the Ki-67
re-assessment. Acta Oncol 2015;​54:​1040-8. proliferation index is not currently recommend-
DOI: 10.1056/NEJMc1515988 ed by expert panels,2 including the International
Ki-67 in Breast Cancer Working Group, because
The author replies: Debled and colleagues as- of intraobserver and interobserver discrepancies
sert that “standard clinicopathologic criteria are regarding clinically relevant cutoff points, despite
sufficient to spare the use of chemotherapy in a standardization.3 In contrast, the 21-gene recur-
large majority of patients.” They report excellent rence-score assay has a high degree of reproduc-
outcomes at 5 years in 1235 low-risk patients ibility and analytic validity, in addition to clini-
identified in their institutional database. cal validity and clinical utility.4
The characteristics of their cohort are similar Joseph A. Sparano, M.D.
to those of 38,568 patients with node-negative,
Montefiore Medical Center
hormone receptor–positive, HER2-negative inva- Bronx, NY
sive breast cancer who were identified in the Sur- jsparano@​­montefiore​.­org
veillance, Epidemiology, and End Results data- Since publication of his article, the author reports no further
base and in whom the 21-gene recurrence-score potential conflict of interest.
assay was performed.1 In this large population-
1. Shak S, Petkov VI, Miller DP, et al. Breast cancer specific
based cohort, the percentages of patients who survival in 38,568 patients with node negative hormone receptor
had low-grade, intermediate-grade, and high- positive invasive breast cancer and Oncotype DX Recurrence
grade tumors were 29%, 54%, and 17%, respec- Score results in the SEER database. Presented at the San Antonio
Breast Cancer Symposium, San Antonio, TX, December 8–12,
tively. Tumor measurements were 1.0 cm or 2015. abstract.
smaller in 25% of the patients, 1.1 to 2.0 cm in 2. Harris L, Fritsche H, Mennel R, et al. American Society of
53%, and larger than 2.0 cm in 27%. Clinical Oncology 2007 update of recommendations for the use
of tumor markers in breast cancer. J Clin Oncol 2007;​25:​5287-
In a multivariate model that included tumor 312.
size and grade and the patients’ age and race, 3. Polley MY, Leung SC, Gao D, et al. An international study to
the recurrence score, when evaluated as a con- increase concordance in Ki67 scoring. Mod Pathol 2015;​28:​778-
86.
tinuous or categorical variable, was associated 4. Sparano JA, Paik S. Development of the 21-gene assay and its
with significantly higher breast cancer–specific application in clinical practice and clinical trials. J Clin Oncol
mortality at 5 years among patients who were 2008;​26:​721-8.
not known to be treated with chemotherapy. DOI: 10.1056/NEJMc1515988

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