n engl j med 366;14 nejm.

org april 5, 2012

1348
The new engl and journal o f medicine
correspondence
Pertuzumab plus Trastuzumab in Metastatic Breast Cancer
To the Editor: Baselga and colleagues (Jan. 12
issue)
1
report that in the Clinical Evaluation of
Pertuzumab and Trastuzumab (CLEOPATRA;
ClinicalTrials.gov number, NCT00567190) trial
involving patients with human epidermal growth
factor receptor 2 (HER2)positive metastatic breast
cancer receiving first-line therapy, the addition of
pertuzumab to docetaxel plus trastuzu mab was
associated with a 6-month increase in progression-
free survival. Pertuzumab, a recombinant human-
ized monoclonal antibody binding to the HER2
dimerization domain, prevents dimerization of
HER2 with other HER receptors (HER3, HER1,
and HER4), especially with HER3.
2
Chiu et al. re-
ported that HER3 overexpression was identified
in 10.0% of tumors in patients with breast cancer
in one randomized study and can be a clinically
significant marker of reduced survival in such
patients.
3
In another randomized, phase 2 study,
Makhija et al. found that low HER3 levels corre-
sponded with the positive response to pertuzu-
mab in patients with platinum-resistant ovarian
cancer.
4
On these grounds, it would be interesting
to know the distribution of HER3 overexpression
among the groups in the CLEOPATRA trial, since
this variable might have influenced the outcomes
of this study. HER3 overexpression may be a use-
ful marker for predicting which patients are most
likely to benefit from pertuzumab.
Mehmet A.N. endur, M.D.
Sercan Aksoy, M.D.
Nurullah Zengin, M.D.
Ankara Numune Education and Research Hospital
Ankara, Turkey
masendur@yahoo.com.tr
No potential conflict of interest relevant to this letter was re-
ported.
1. Baselga J, Corts J, Kim S-B, et al. Pertuzumab plus trastuz-
umab plus docetaxel for metastatic breast cancer. N Engl J Med
2012;366:109-19.
2. Adams CW, Allison DE, Flagella K, et al. Humanization of a
recombinant monoclonal antibody to produce a therapeutic HER
dimerization inhibitor, pertuzumab. Cancer Immunol Immuno-
ther 2006;55:717-27.
3. Chiu CG, Masoudi H, Leung S, et al. HER-3 overexpression
is prognostic of reduced breast cancer survival: a study of 4046
patients. Ann Surg 2010;251:1107-16.
4. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gem-
citabine plus pertuzumab in platinum-resistant ovarian cancer,
fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol
2010;28:1215-23.
To the Editor: In the study by Baselga et al., the
incidence of severe febrile neutropenia in patients
from Asia was 26% in the pertuzumab group and
12% in the control group. In patients from other
areas, the incidence was approximately 10% in
both groups. This suggests ethnic factors asso-
ciated with the risk of neutropenia. To untangle
this discordance, we would again plead
1
for bet-
ter definitions of Asian and ethnicity. The
interpretation of the results for Asian subgroups
is unclear, since genomic predictors of efficacy
and adverse effects may not cosegregate. The
HLA-B*1502 allele, a predictor of carbamazepine
hypersensitivity, is common (>5.0%) in Han Chi-
nese persons from Taiwan and Thais but relatively
rare in Japanese persons, with a prevalence that
this weeks letters
1348 Pertuzumab plus Trastuzumab in Metastatic
Breast Cancer
1350 Subclinical Atrial Fibrillation and the Risk of Stroke
1353 Low-Dose Interleukin-2 and HCV-Induced Vasculitis
1354 Defense Costs of Medical Malpractice Claims
The New England Journal of Medicine
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correspondence
n engl j med 366;14 nejm.org april 5, 2012
1349
is 50 times as low as the rate among these other
Asian groups and closer to that of whites
(<0.1%).
2
The CLEOPATRA study included phar-
macogenetically diverse Hispanics
3
who were
classified as white. We are beginning to better
dissect the elements of ethnicity that are predic-
tive of drug response, including each persons
ethnicity-associated intestinal microbiome.
4
In-
fection was the most common cause of death in
the CLEOPATRA trial. Can the authors of this
study help by detailing the frequency of severe
neutropenia in each Asian ethnic subgroup?
Alain Li-Wan-Po, Ph.D.
National Genetics Education and Development Centre
Birmingham, United Kingdom
a.liwanpo@talk21.com
No potential conflict of interest relevant to this letter was re-
ported.
1. Li-Wan-Po A. Personalised medicine: who is an Asian? Lancet
2007;369:1770-1.
2. Ozeki T, Mushiroda T, Yowang A, et al. Genome-wide asso-
ciation study identifies HLA-A*3101 allele as a genetic risk factor
for carbamazepine-induced cutaneous adverse drug reactions in
Japanese population. Hum Mol Genet 2011;20:1034-41.
3. Choudhry S, Ung N, Avila PC, et al. Pharmacogenetic differ-
ences in response to albuterol between Puerto Ricans and Mexi-
cans with asthma. Am J Respir Crit Care Med 2005;171:563-70.
4. Li-Wan-Po A, Farndon P. Barking up the wrong genome
we are not alone. J Clin Pharm Ther 2011;36:125-7.
To the Editor: The heart is an ever acting, never
resting tissue that needs a constant background
mechanism of repair. Myocardial maintenance is
the responsibility of the ill-defined neuregulin-
ErbB signaling pathways, comprising neuregulin
interactions with the epidermal growth factor re-
ceptor 1 (EGFR1) and ErbB2, ErbB3, and ErbB4.
1
A rational theoretical hypothesis would hint
toward greater cardiac toxicity with dual blockade
of ErbB2 and ErbB3 than with the use of ErbB2
blockade alone. However, in the CLEOPATRA
trial, it was surprising that lower rates of systolic
dysfunction were noted among patients receiv-
ing pertuzumab in addition to trastuzumab than
among those receiving trastuzumab alone, in
spite of the fact that the doses of trastuzumab
were the same in the two groups.
Though the CLEOPATRA trial stratified pa-
tients according to the use or nonuse of prior
chemotherapy, no attempt was made to stratify
the patients according to the prior use or nonuse
of radiotherapy. This could be an overlooked
source of bias, since radiotherapy is known to
affect cardiac function more so in patients
who have received radiotherapy for cancer in the
left breast.
2
Swaroop Revannasiddaiah, M.D.
Rajeev Seam, M.D.
Manoj Gupta, M.D.
Regional Cancer Centre
Shimla, India
swarooptheone@gmail.com
No potential conflict of interest relevant to this letter was re-
ported.
1. Britsch S. The neuregulin-I/ErbB signaling system in devel-
opment and disease. Adv Anat Embryol Cell Biol 2007;190:1-65.
2. Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris
EE. Coronary artery findings after left-sided compared with right-
sided radiation treatment for early-stage breast cancer. J Clin
Oncol 2007;25:3031-7.
The Authors Reply: We agree with endur et al.
that HER3 is one of several molecules that are
important to explore as potential markers for
treatment benefit with pertuzumab plus trastuz-
umab plus docetaxel in HER2-positive metastatic
breast cancer. Gianni et al. recently presented re-
sults of analyses of exploratory biomarkers
(which included HER3 protein and messenger
RNA [mRNA]) in the Neoadjuvant Study of Pertuz-
umab and Herceptin in an Early Regimen Evalu-
ation (NEOSPHERE; NCT00545688), a study of
pertuzumab plus trastuzumab-based neoadjuvant
therapy in HER2-positive early breast cancer.
1
In
their study, the level of HER3 protein and mRNA
did not correlate with treatment outcome. Re-
sults from the predefined HER3 biomarker analy-
ses in the CLEOPATRA trial are consistent with
the findings in NEOSPHERE indicating that pa-
tients derive benefit from the combination of
pertuzumab plus trastuzumab plus docetaxel, re-
gardless of the level of HER3 protein or mRNA
expression. However, we and others have recently
reported that HER3 expression and activation is
modulated in response to HER2, HER3, or phos-
phatidylinositol 3 kinase pathway inhibition,
2-4
which may not be reflected by the analysis of
primary tumors.
HER signaling pathways are involved in myo-
cardial homeostasis, and trastuzumab has been
associated with cardiac dysfunction, especially in
patients with exposure to anthracyclines.
5
Be-
cause two anti-HER2 antibodies were combined
in the CLEOPATRA trial, cardiac adverse events
were closely monitored, but no difference in their
The New England Journal of Medicine
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Copyright 2012 Massachusetts Medical Society. All rights reserved.
The new engl and journal o f medicine
n engl j med 366;14 nejm.org april 5, 2012
1350
incidence was observed between the groups.
Revannasiddaiah et al. highlight the potential
for an imbalance between the groups with re-
gard to the use or nonuse of prior radiotherapy,
which could have an effect on the cardiac events
observed in our trial. A total of 43% of the pa-
tients in each group had received radiotherapy
before study entry. Therefore, although prior
radiotherapy was not a stratification factor in our
trial, this variable did not result in an imbalance
between the groups.
Li-Wan-Pos point regarding ethnic differences
and patient responses to treatment is an impor-
tant and complex issue. Although detailed eth-
nicity data were not collected in the CLEOPATRA
trial, we agree that obtaining more comprehen-
sive data on ethnicity is an important consider-
ation for future global studies. As Li-Wan-Po also
points out, the incidence of febrile neutropenia
of grade 3 or more was higher in patients from
Asia, and in the overall study population, infec-
tion was the most common cause of death due
to an adverse event. In our trial, the incidence of
grade 3 or higher infections and infestations
was similar between the control and the pertu-
zumab groups (10.1% vs. 11.1%); the incidence
of deaths due to infections, sepsis, or febrile
neutropenia was low (1.0% overall) and similar
between the two groups within the overall study
population and in patients from Asia.
Jos Baselga, M.D., Ph.D.
Massachusetts General Hospital Cancer Center
Boston, MA
jbaselga@partners.org
Mark C. Benyunes, M.D.
Genentech
South San Francisco, CA
Sandra M. Swain, M.D.
MedStar Washington Hospital Center
Washington, DC
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Gianni L, Bianchini G, Kiermaier A, et al. Neoadjuvant per-
tuzumab (P) and trastuzumab (H): biomarker analyses of a 4-arm
randomized Phase II study (NeoSphere) in patients (pts) with
HER2-positive breast cancer (BC). Presented at the 34th Annual
San Antonio Breast Cancer Symposium, San Antonio, TX, Decem-
ber 610, 2011. abstract.
2. Makhija S, Amler LC, Glenn D, et al. Clinical activity of gem-
citabine plus pertuzumab in platinum-resistant ovarian cancer,
fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol
2010;28:1215-23.
3. Serra V, Scaltriti M, Prudkin L, et al. PI3K inhibition results
in enhanced HER signaling and acquired ERK dependency in
HER2-overexpressing breast cancer. Oncogene 2011;30:2547-57.
4. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition
relieves feedback suppression of receptor tyrosine kinase ex-
pression and activity. Cancer Cell 2011;19:58-71.
5. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in
the trastuzumab clinical trials experience. J Clin Oncol 2002;20:
1215-21.
Subclinical Atrial Fibrillation and the Risk of Stroke
To the Editor: In their article on the results of
the Asymptomatic Atrial Fibrillation and Stroke
Evaluation in Pacemaker Patients and the Atrial
Fibrillation Reduction Atrial Pacing Trial (ASSERT;
ClinicalTrials.gov number, NCT00256152), Healey
et al. (Jan. 12 issue)
1
note that subclinical atrial
fibrillation is believed to be a major cause of stroke
of unknown cause, and their article supports this
idea. We recently performed 7-day Holter monitor-
ing in an unselected population of patients with
stroke and found paroxysmal atrial fibrillation in
12.5% of all patients, but only 18% of strokes in
patients with paroxysmal atrial fibrillation had
been classified as stroke of unknown cause.
2
In
many cases, patients with paroxysmal atrial fi-
brillation have competing risks such as athero-
sclerotic disease, but paroxysmal atrial fibrilla-
tion may not be detected in these patients because
of selection bias (i.e., deferred further diagnostic
testing after findings that provide support for the
competing cause). Other studies on diagnostic
approaches for paroxysmal atrial fibrillation have
been limited to strokes of unknown cause.
3
We
therefore ask the authors to provide some infor-
mation on the classification of ischemic stroke
(e.g., with the use of the Trial of Org 10172 in
Acute Stroke Treatment [TOAST] criteria)
4
in the
patients in the ASSERT study who had strokes.
Rolf Wachter, M.D.
Raoul Stahrenberg, M.D.
University of Gttingen
Gttingen, Germany
wachter@med.uni-goettingen.de
Klaus Grschel, M.D.
University of Mainz
Mainz, Germany
The New England Journal of Medicine
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