editorials
6. Krawiec ME, Westcott JY, Chu HW, et al. Persistent wheezing
in very young children is associated with lower respiratory in-
flammation. Am J Respir Crit Care Med 2001;163:1338-43.
7. Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood
asthma after bacterial colonization of the airway in neonates.
N Engl J Med 2007;357:1487-95.
8. Schaub B, Campo M, He H, et al. Neonatal immune respons-
es to TLR2 stimulation: influence of maternal atopy on Foxp3
and IL-10 expression. Respir Res 2006;7:40.
9. Holt PG, Upham JW, Sly PD. Contemporaneous maturation of
immunologic and respiratory functions during early childhood:
implications for development of asthma prevention strategies.
J Allergy Clin Immunol 2005;116:16-24.
Breast-Cancer Therapy Looking Back to the Future
Anne Moore, M.D.
Adjuvant therapy for breast cancer treatment
after surgical removal of the tumor is a major
therapeutic advance that has had a considerable
effect on prolonging disease-free and overall sur-
vival. Not all patients benefit from adjuvant ther-
apy, however, and certain types of adjuvant therapy
are not appropriate for some patients. For exam-
ple, adjuvant treatment with tamoxifen, a selec-
tive estrogen-receptor modulator, has improved the
15-year survival rate among women with estrogen-
receptorpositive breast cancer by 31%, but it does
not benefit women with estrogen-receptornega-
tive disease.1 Trastuzumab, a monoclonal anti-
body against the human epidermal growth factor
receptor type 2 (HER2), is associated with an im-
provement of approximately 50% in disease-free
survival among the 15 to 20% of women with
HER2-positive disease.2,3
In addition to these targeted approaches, adju-
vant chemotherapy that includes alkylating agents,
antimetabolites, anthracyclines, and taxanes in
various combinations has contributed to the over-
all improvement in outcomes among women with
operable breast cancer. As compared with women
with estrogen-receptorpositive disease, women
with estrogen-receptornegative breast cancer ben
efit more from chemotherapy. A recent retrospec-
tive analysis of three trials by the Cancer and
Leukemia Group B (CALGB) suggests very little
overall benefit of adjuvant chemotherapy for wom
en with estrogen-receptorpositive breast cancer
who received tamoxifen for 5 years after receiving
chemotherapy.4
Is it possible to define an optimal adjuvant
chemotherapy program for individual patients
with either estrogen-receptorpositive or estro-
n engl j med 357;15 www.nejm.org october 11, 2007
Downloaded from www.nejm.org on June 13, 2010 . Copyright 2007 Massachusetts Medical Society. All rights reserved.
10. van Rossum AM, Lysenko ES, Weiser JN. Host and bacterial
factors contributing to the clearance of colonization by Strepto-
coccus pneumoniae in a murine model. Infect Immun 2005;73:
7718-26.
11. Eder W, Klimecki W, Yu L, et al. Toll-like receptor 2 as a major
gene for asthma in children of European farmers. J Allergy Clin
Immunol 2004;113:482-8.
12. Johnston SL. Innate immunity in the pathogenesis of virus-
induced asthma exacerbations. Proc Am Thorac Soc 2007;4:267-70.
13. Celedn JC, Fuhlbrigge A, Rifas-Shiman S, Weiss ST, Finkel-
stein JA. Antibiotic use in the first year of life and asthma in
early childhood. Clin Exp Allergy 2004;34:1011-6.
Copyright 2007 Massachusetts Medical Society.
gen-receptornegative breast cancer to maximize
the benefit and minimize toxic effects? The arti-
cle by Hayes et al.5 in this issue of the Journal
addresses this question.
Hayes et al. report their retrospective analysis
of an adjuvant-chemotherapy trial, CALGB 9344/
INT0148 (referred to below as CALGB 9344), for
women with lymph nodepositive breast cancer.6
The trial began in 1994 to test the benefit of add-
ing four cycles of the taxane paclitaxel after four
cycles of doxorubicin plus cyclophosphamide. The
trial also investigated whether doxorubicin at
higher than standard doses was beneficial, and
the answer was that escalating the dose of doxo-
rubicin did not benefit any subgroup of patients.
Women with estrogen-receptorpositive breast
cancer received tamoxifen for 5 years after che-
motherapy. When the results of the trial were
first presented at the American Society of Clinical
Oncology meeting in May 1998, a small but sta-
tistically significant benefit from the addition of
four cycles of paclitaxel every 3 weeks after doxo-
rubicin plus cyclophosphamide was reported.7
This result changed clinical practice, and the use
of adjuvant paclitaxel rose dramatically well be-
fore the publication of the results in 2003.
The study by Hayes et al.5 was designed to
determine whether paclitaxel administered after
doxorubicin plus cyclophosphamide was equally
beneficial to all subgroups of women enrolled in
the CALGB 9344 trial. New information was add-
ed by testing the tissue blocks from the original
tumors for HER2 positivity with the use of assays
for overexpression and gene amplification. The
results are noteworthy. There was a significant
clinical benefit from the addition of paclitaxel
1547
 The n e w e ng l a n d j o u r na l
to the treatment of women with HER2-positive
breast cancer. Most of these women had HER2-
positive, estrogen-receptornegative breast can-
cer, a profile associated with a relatively poor
prognosis, but the small subgroup of women
with HER2-positive, estrogen-receptorpositive
disease also benefited from paclitaxel. However,
women with HER2-negative, estrogen-receptor
positive breast cancer, the most common cate-
gory of the disease, did not benefit from the
addition of paclitaxel to doxorubicin plus cyclo-
phosphamide.
Why should we spare our patients from pacli-
taxel? The toxicity profile of this drug is unique.
Hypersensitivity reactions (including, rarely, ana-
phylaxis) occur during the infusion of paclitaxel,
despite premedication with corticosteroids. Such
reactions were reported in 6% of patients in the
CALGB 9344 trial. A transient symptom complex
of myalgia, arthralgia, and neuralgia is common
within 2 to 3 days after the infusion. Neurotoxic-
ity, the predominant side effect, was reported
in 18% of patients in the CALGB 9344 trial. For
some patients, numbness and tingling in the
hands and feet last for months or even years after
treatment is completed.8
Thirteen years have passed since the first pa-
tient was enrolled in the CALGB 9344 trial. Dur-
ing this time, important changes in practice may
have diminished the value of adding paclitaxel to
chemotherapy for women with HER2-negative,
estrogen-receptorpositive breast cancer. For in-
stance, advances in adjuvant endocrine therapy
reduce the proportional benefit of adjuvant che-
motherapy for women with estrogen-receptor
positive breast cancer. In postmenopausal women,
the incorporation of an aromatase inhibitor (anas
trozole, exemestane, or letrozole) into adjuvant
therapy prolongs disease-free survival more than
does treatment with tamoxifen for 5 years.9
Hayes and his coauthors caution us not to
change clinical practice on the basis of their retro
spective analysis, but oncologists have a responsi-
bility to their patients to be aware of this report.
A similar trial of doxorubicin plus cyclophospha-
mide followed by paclitaxel involving 3100 pa-
tients was published by the National Surgical
Adjuvant Breast and Bowel Project in 2005. The
results showed a small benefit in 5-year disease-
free survival but no difference in overall survival
as a result of the addition of paclitaxel in women
1548 n engl j med 357;15 www.nejm.org october 11, 2007
Downloaded from www.nejm.org on June 13, 2010 . Copyright 2007 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
with estrogen-receptornegative or estrogen-recep
torpositive disease. There was no analysis of
outcome according to HER2 status.10
In the analysis by Hayes et al., women with
HER2-positive breast cancer benefited from receiv
ing four cycles of paclitaxel every 3 weeks after
receiving doxorubicin plus cyclophosphamide, re-
gardless of the estrogen-receptor status of the
tumor. How does this treatment fit into contem-
porary adjuvant-chemotherapy programs that in-
corporate trastuzumab into the treatment of
HER2-positive breast cancer? Most such programs
include a taxane. However, in a pivotal trial that
showed clinically significant improvement in dis-
ease-free survival from administration of trastu-
zumab after adjuvant chemotherapy, 74% of the
patients were treated without a taxane and still
benefited from trastuzumab.3
More difficult to define is the effect of the re-
port by Hayes and colleagues on the treatment of
women with HER2-negative, estrogen-receptor
positive breast cancer. According to this report,
the addition of four cycles of paclitaxel every
3 weeks after treatment with doxorubicin plus cy-
clophosphamide is unlikely to benefit these pa-
tients. However, this is not a call to abandon
taxanes for this group of patients. The 3-week
schedule of treatment with paclitaxel is not the
only way to include a taxane in adjuvant therapy.
In more recent trials, dose-dense therapy using
the same doses of doxorubicin plus cyclophospha
mide and paclitaxel every 2 weeks has been shown
to be more effective than the same regimen every
3 weeks.11 Adjuvant trials that use paclitaxel week-
ly instead of every 3 weeks and the adoption of the
alternative taxane, docetaxel, for adjuvant therapy
point to more choices.12,13 It would be of great
value if the investigators in charge of these more
recent trials analyzed their results retrospectively
with respect to HER2 and estrogen-receptor status.
Leaders of clinical trials should continue to
look backward, when appropriate, for data such
as those presented by Hayes et al. In looking to
the future, correlative science must be incorporat
ed into modern clinical trials in breast cancer.
The days of one size fits all therapy for patients
with breast cancer are coming to an end.
No potential conflict of interest relevant to this article was
reported.
From the Division of HematologyOncology, Weill Cornell
Medical College, Cornell University Medical Center, New York.
 editorials
1. Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival. Lancet 2005;365:
1687-717.
2. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus
adjuvant chemotherapy for operable HER2-positive breast cancer.
N Engl J Med 2005;353:1673-84.
3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastu-
zumab after adjuvant chemotherapy in HER2-positive breast
cancer. N Engl J Med 2005;353:1659-72.
4. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-recep-
tor status and outcomes of modern chemotherapy for patients
with node-positive breast cancer. JAMA 2006;295:1658-67. [Erra-
tum, JAMA 2006;295:2356.]
5. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to
paclitaxel in node-positive breast cancer. N Engl J Med 2007;357:
1496-506.
6. Henderson IC, Berry DA, Demetri GD, et al. Improved out-
comes from adding sequential paclitaxel but not from escalating
doxorubicin dose in an adjuvant chemotherapy regimen for pa-
tients with node-positive primary breast cancer. J Clin Oncol
2003;21:976-83.
7. Henderson IC, Berry D, Demetri GD, et al. Improved disease-
free (DFS) and overall survival (OS) from the addition of sequen-
tial paclitaxel (T) but not from the escalation of doxorubicin (A)
dose level in the adjuvant chemotherapy of patients (pts) with
The Quality of Childrens Health Care Matters
Time to Pay Attention
James M. Perrin, M.D., and Charles J. Homer, M.D., M.P.H.
High-quality health care matters for all children
and is critically important for some. In many
ways, health care for children serves the same
function as health care for adults. For example,
the incidence of chronic illness in children is in-
creasing, resulting in a substantial illness burden
with a substantial cost.1 How well chronic con-
ditions are managed profoundly influences both
short-term and long-term outcomes, not only for
common diseases such as asthma but also for
rarer conditions such as cancer, cystic fibrosis,
and sickle cell disease.2
Many aspects of childrens health care have no
parallel in adult health services.3 The dispropor-
tionate rates of poverty among children and ado-
lescents mean that childrens health services must
address health needs despite limited resources.
Because children are dependent on caregivers and
community resources, providers of child health
care must enhance the competency of these care-
givers and coordinate a broad array of commu-
nity services. Childrens health care settings typ
ically involve developmental surveillance; the
identification of sensory, learning, and behavior-
al disorders; and monitoring for family violence
n engl j med 357;15 www.nejm.org october 11, 2007
Downloaded from www.nejm.org on June 13, 2010 . Copyright 2007 Massachusetts Medical Society. All rights reserved.
node-positive primary breast cancer (BC). Proc Am Soc Clin On-
col 1998;17:101a. abstract.
8. Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neu-
ropathy: pathogenesis and emerging therapies. Support Care
Cancer 2004;12:619-25.
9. Lin NU, Winer EP. Optimal use of aromatase inhibitors: to lead
or to follow? J Clin Oncol 2007;25:2639-41.
10. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after
doxorubicin plus cyclophosphamide as adjuvant chemotherapy
for node-positive breast cancer: results from NSABP B-28. J Clin
Oncol 2005;23:3686-96.
11. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial
of dose-dense versus conventionally scheduled and sequential
versus concurrent combination chemotherapy as postoperative
adjuvant treatment of node-positive primary breast cancer: first
report of Intergroup Trial C9741/Cancer and Leukemia Group B
Trial 9741. J Clin Oncol 2003;21:1431-9. [Erratum, J Clin Oncol
2003;21:2226.]
12. Sparano JA, Wang M, Martino S, et al. Phase III study of
doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel
given every 3 weeks or weekly in operable breast cancer: results
of Intergroup Trial E1199. J Clin Oncol 2007;25:Suppl:516. ab-
stract.
13. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel
for node-positive breast cancer. N Engl J Med 2005;352:2302-13.
Copyright 2007 Massachusetts Medical Society.
and child abuse. Optimally, such programs pro-
vide evidence-informed counseling that promotes
positive behaviors related to individual health,
family functioning, and psychological and devel-
opmental well-being all of which are beyond
traditional health care services with effects
that last for the rest of a childs life.
The article by Mangione-Smith et al.4 in this
issue of the Journal, although addressing tradition
al health care services and ambulatory care only,
nonetheless presents sobering findings. The au-
thors examined hundreds of indicators of quality,
developed according to complex but well-estab-
lished methods from RAND and UCLA, empha-
sizing the most common reasons for which
children use the health care system. They inten-
tionally studied a full spectrum of ambulatory
services at least within the traditional health
care domains of preventive care, care for acute
conditions, and care for chronic conditions
for children of all ages.
Their observations are shocking: the right ser-
vices appear to be carried out less than half the
time. Services are not delivered when they should
be, or they are delivered when they should not
1549