Breast Cancer Res Treat (2008) 112:551–556
DOI 10.1007/s10549-008-9893-8
CLINICAL TRIAL
HER2 in well differentiated breast cancer: is testing necessary?
G. Kenneth Haines III Æ Elizabeth Wiley Æ Barbara Susnik Æ Sophia K. Apple Æ
Snjezana Frkovic-Grazio Æ Carolina Reyes Æ Lynn C. Goldstein Æ
Farnaz Dadmanesh Æ Allen M. Gown Æ Mehrdad Nadji Æ Matej Bracko Æ
Fattaneh A. Tavassoli
Received: 29 October 2007 / Accepted: 2 January 2008 / Published online: 18 January 2008
Ó Springer Science+Business Media, LLC. 2008
Abstract Background In addition to providing a timely
and accurate diagnosis, pathologists routinely provide
prognostic and predictive information to assist in the
treatment of patients with invasive breast cancer. As our
understanding of breast cancer at the molecular and genetic
level improves, sophisticated new treatment options have
become available to patients. The demonstrated improve-
ments in disease-free and overall survival with the use of
trastuzumab (Herceptin) has made HER2 testing a standard
of care in the evaluation of patients with breast cancer.
Specialized breast centers have accumulated sufficient
experience to recognize that HER2 positive tumors tend to
G. K. Haines III (&)
F. A. Tavassoli
Department of Pathology, Yale University School of Medicine,
EP2-611 20 York Street, New Haven, CT 06510, USA
e-mail: k.haines@yale.edu
E. Wiley
University of Illinois at Chicago, Chicago, IL, USA
B. Susnik
Feinberg School of Medicine Northwestern University, Chicago,
IL, USA
S. K. Apple
David Geffen School of Medicine, University of California at
Los Angeles, Los Angeles, CA, USA
S. Frkovic-Grazio
M. Bracko
Institute of Oncology, Ljubljana, Slovenia
C. Reyes
M. Nadji
University of Miami Jackson Medical Center, Miami, FL, USA
L. C. Goldstein
A. M. Gown
PhenoPath Laboratories, Seattle, WA, USA
F. Dadmanesh
Cedars-Sinai Medical Center, Los Angeles, CA, USA
be of higher grade and to be estrogen receptor negative,
whereas well-differentiated breast cancers rarely are HER2
positive. Methods To determine whether HER2 testing is
necessary in well-differentiated breast cancer, we analyzed
the frequency of HER2 positivity among 1,162 cases from
7 major breast centers or commercial laboratories in the
United States and Europe. Results Well-differentiated
breast cancers, defined by either nuclear grading or the
Scarff-Bloom-Richardson system, rarely are HER2 positive
(mean 1.6%, range 0–2.8%). Conclusions Given the low
rate of well differentiated HER2 positive tumors, falling
within the range reported for false negative IHC tests for
HER2, and the absence of published data demonstrating a
beneficial effect of trastuzumab therapy in this subset of
patients, HER2 testing should not be considered a standard
of care for all patients with well-differentiated breast
cancer.
Keywords Breast cancer
HER2
Trastuzumab

Immunohistochemistry
FISH
Introduction
Breast cancer is the most common cancer in women in the
United States, with an estimated 180,510 new cases and
40,910 deaths in 2007 and a one in eight lifetime risk [1].
While accurate diagnosis has long been an essential
component of the pathologic evaluation of biopsy and
resection specimens, delineation of prognostic and pre-
dictive features plays an increasingly important role in
directing care of patients with breast cancer.
As we increase our understanding of the molecular
defects driving tumor growth and progression, and thera-
peutic agents targeting these molecular pathways come into
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clinical practice, the need to identify which patients are
most likely to respond to a given treatment becomes more
important. Until molecular profiling of all tumors becomes
practical, cost-effective medical care demands a rational
approach to testing.
Recently, trastuzumab (Herceptin), a humanized
monoclonal antibody directed against the extracellular
domain of HER2, a member of the EGFR family, has
become available for the treatment of breast cancer.
Multiple studies have demonstrated marked improve-
ment in disease-free and overall survival when trastuzumab
is incorporated in therapeutic regimens for HER2 positive
tumors [2, 3]. Only patients whose tumors strongly express
HER2 by immunohistochemistry (IHC) and/or have
amplification of the cerb2 gene by FISH, are likely to
respond to Herceptin treatment [4].
Testing invasive breast carcinomas for HER2 expres-
sion/gene amplification has become a standard of practice
[5]. Much of the recent literature has focused on the best
method for documenting HER2 overexpression (IHC vs.
FISH), technical limitations of each method, and the need
for consistency and QA in test performance [2, 6–8]. The
National Comprehensive Cancer Network HER2 Testing in
Breast Cancer Task Force concluded that where adequate
quality control / quality assurance procedures are followed,
either IHC or FISH are acceptable methods [9]. To address
the quality assurance concerns, the American Society of
Clinical Oncology (ASCO) and College of American
Pathologists (CAP) have recently proposed guidelines for
the performance of HER2 testing in clinical laboratories
[10].
Whether a laboratory uses IHC with FISH for equivocal
cases, or uses FISH as the initial HER2 screen, these tests
are expensive to perform. Yaziji et al. place mean direct
reagent costs at $10 for IHC and $140 for FISH [6]. While
these costs per test are modest, there have already been
reports of patient’s health insurance status influencing
HER2 testing patterns [11]. Development of a rational
approach to selecting cases for HER2 testing would pro-
mote cost effectiveness in the health care system.
We observed that in routine practice, well-differentiated
breast cancers rarely show HER2 protein overexpression or
gene amplification. We hypothesized that such overex-
pression is sufficiently rare that HER2 testing can be
avoided.
Materials and methods
After receiving approval from the Human Investigation
Committee or Institutional Review Board of the local
institution, the pathology database of each center was
searched for cases of well differentiated invasive breast
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Breast Cancer Res Treat (2008) 112:551–556
carcinoma with HER2 test results. Each institution reported
the tumor grading system used (nuclear, overall or both),
and methods used for HER2 assessment (immunohisto-
chemistry (IHC), fluorescence in situ hybridization (FISH),
or both). For each case, the histological grade, ER and
HER2 status was recorded. In cases where both IHC and
FISH analysis for HER2 was performed, a positive result
by either method was considered ‘positive’ for study
purposes. In order for the study to realistically reflect the
actual practices in each center, no attempt was made to
review the cases to standardize specimen preparation,
tumor grading or the interpretation of HER2 testing. In all
centers, the current criteria for a positive IHC test for
HER2 was 3+ staining (strong, complete membrane
staining in more than 30% of tumor cells). FISH was
considered positive when the HER2:Cep17 ratio was equal
to or greater than 2.
Statistical analysis was performed using the GraphPad
InStatÒ statistical software package (GraphPad Software,
Inc. San Diego, CA). A P value of 0.05 was considered to
be statistically significant.
Results
Two centers utilized a nuclear grading system, four centers
reported data using the modified Scarf-Bloom-Richardson
(SBR) system that incorporates architecture, nuclear fea-
tures and mitotic activity, and one center provided data for
both systems.
Overall, only 19 of 1,164 (1.6%) cases of invasive well
differentiated breast carcinomas showed HER2 overex-
pression by immunohistochemistry and/or gene
amplification by FISH (Table 1). No significant difference
in the frequency of HER2 positivity was seen between
individual institutions (Chi-Squared, Fisher’s exact test),
with an absolute rate ranging from 0 to 2.8%.
Comparison of HER2 positivity in well differentiated
breast cancer by time period
Standardization of procedures and interpretation has been
emphasized by a number of groups in recent years. To
determine whether this has had an impact on the incidence
of HER2 positivity over time, historic data from one
institution was compared with more recent data from the
same center. A dramatic decrease in HER2 positivity was
noted for well-differentiated breast cancer in the recent
data (currently 2.5%, down from 7.1%) (Table 2). This
may reflect differences in interpretive criteria (inclusion of
2+ HER2 IHC results as positive), inclusion of cases where
HER2 was performed at the referring institution (often
Breast Cancer Res Treat (2008) 112:551–556 553

Table 1 HER2 status in well differentiated breast carcinoma by Table 3 Comparison of IHC and FISH for HER2 in well-differen-
institution tiated breast cancer
Institution Grading Total HER-2 % HER-2 IHC-/ IHC+/ IHC+/ IHC-/
system cases positive positive FISH- FISH+ FISH- FISH+

Yale SBR 160 4 2.5 Yale 126 1 2 0

N (83) (1) (1.2) Ljubljana 322 0 2 1
UCLA N 124 2 1.6 UCLA 108 1 1 0
NMH SBR 161 4 2.5 Total 556 2 5 1
PhenoPath SBR 141 4 2.8 The overall concordance rate between IHC and FISH was 98.9%
Ljubljana SBR 334 3 0.9
U Miami N 144 0 0 Comparison SBR grade vs. nuclear grade
Cedar SBR 100 2 2.0
Total 1,164 19 1.6 Grading of invasive breast carcinoma is not globally
No statistical difference is seen in rate of HER2 positive cases among standardized. While data was requested using the grading
institutions (P = 0.38, Chi-squared test) Data in parentheses ‘‘( )’’ not system in routine use in each center, data for both SBR and
included in total
nuclear grading systems were provided from several cen-
ters. At Yale, none of the four HER2 positive SBR grade 1
Table 2 Comparison of HER2 positivity rate by time period tumors was of nuclear grade 1. Conversely, only 1 of 83
nuclear grade 1 tumors was HER2 positive. Interestingly,
NMH Total cases HER-2 positive % HER-2 positive
this case showed 3+ staining by immunohistochemistry,
2006–2007 161 4 2.5 but was negative for HER2 amplification by FISH analysis.
1997–2001 652 46 7.1 Similarly, both HER2 positive SBR grade 1 tumors from
Cedar-Sinai were nuclear grade 2. From Ljubljana, only
The rate of positive HER2 cases is significantly lower in the recent
data. (P = 0.0280, Fisher’s exact test) one of the three SBR grade 1 HER2 positive cases was of
low nuclear grade. Nuclear grade was available on 131 of
the recent SBR grade 1 tumors from NMH. None of the 83
community hospitals), procedural or technical differences SBR grade 1, nuclear grade 1 tumors were HER2 positive.
(type and duration of fixation). In the historic data from NMH, Eighteen of 382 (4.7%)
nuclear grade 1 tumors were HER2 positive, compared to
46 of 652 (7.1%) SBR grade 1 cases. Although suggestive,
Comparison IHC vs. FISH in well differentiated breast
direct comparison of HER2 positivity rates between
cancer
nuclear and SBR grading systems within individual insti-
tutions did not reach statistical significance (Table 5).
Three of the study centers routinely performed HER2
Further, the rate of HER2 positive tumors did not statisti-
analysis by both immunohistochemistry and fluorescence
cally differ between those centers using a nuclear grading
in situ hybridization. Overall, 556/564 (98.6%) cases were
system (0.8%, 3 of 351) and those using the SBR system
HER2 negative by both methods. Of the remaining eight
(1.9%, 17 of 896, P = 0.2202, Fisher’s exact test).
cases, 2 were positive by both methods, five were positive
by immunohistochemistry only and one was positive only
by FISH. The overall concordance rate between IHC and
Discussion
FISH was 98.9% (Table 3).
Therapeutic advances, based on improved understanding of
Comparison % HER2+ by grade the molecular mechanisms underlying carcinogenesis and
tumor progression are revolutionizing the treatment of
Data for all tumor grades was available from four of the cancer. HER2 is a tyrosine kinase member of the epidermal
study centers (Table 4). Among this group, 11 of 779 growth factor family. HER2 expression in breast cancer is
(1.4%) of well-differentiated breast cancers were HER2 associated with a worse prognosis, higher histological
positive. This increased to 13.5% (312 of 2,317 cases) for grade, absence of hormone receptors and resistance to
moderately differentiated cancers, and 28.3% (314/1110) tamoxifen [12]. The introduction of trastuzumab, a
for poorly differentiated breast carcinomas. This finding is humanized monoclonal antibody targeting the extracellular
consistent with previous reports correlating HER2 with domain of HER2, into clinical practice has produced dra-
higher-grade breast cancers. matic reductions in the rate of breast cancer recurrence for

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Table 4 HER2 positivity by

Grade 1 Grade 2 Grade 3 Overall
grade
Yale 4/160 (2.5%) 39/275 (14.2%) 42/138 (30.4%) 85/573 (14.8%)
Ljubljana 3/334 (0.9%) 91/761 (12.0%) 152/588 (25.9%) 246/1683 (14.6%)
PhenoPath 4/141 (2.8%) 86/629 (13.7%) 63/230 (27.4%) 153/1000 (15.3%)
HER2 positivity correlates with U Miami 0/144 (0%) 96/652 (14.7%) 57/154 (37.0%) 153/950 (16.1%)
increasing tumor grade. Overall 11/779 (1.4%) 312/2317 (13.5%) 314/1110 (28.3%) 637/4206 (15.1%)
(P \ 0.0001, Chi-squared test)

Table 5 HER2 status by tumor grade
SBR grade Nuclear grade Fisher’s exact test
Yale
1 4/160 (2.5%) 1/83 (1.2%) P = 0.6635
2 35/270 (13.0%) 29/300 (9.7%) P = 0.2331
3 37/133 (27.8%) 56/190 (29.5%) P = 0.8033
NMH ’97-01
1 46/652 (7.1%) 18/382 (4.7%) P = 0.1428
2 125/707 (17.7%) 72/527 (13.7%) P = 0.0596
3 209/740 (28.2%) 154/537 (28.7%) P = 0.9000
Comparison of Scarf-Bloom-Richardson (SBR) and nuclear grading
systems. HER2 positivity increases with tumor grade, independent of
grading system. Differences in HER2 frequency based on grading
system do not reach statistical significance and diminish with
increasing grade
patients with HER2 positive tumors [2]. Therapy with
Herceptin is expensive, with a projected lifetime cost of
$26,417 per quality-adjusted life year gained [13]. In
addition to the cost, Herceptin therapy has been associated
with life-threatening side effects including cardiotoxicity in
a subset of patients [14]. Thus, it is important to correctly
identify not only those patients most likely to respond to
Herceptin, but also those patients unlikely to benefit from
this form of therapy.
Multiple centers participated in this study, reflecting
both academic and commercial institutions from geo-
graphically diverse regions of the United States, as well as
Europe.
Criteria for grading invasive breast carcinoma, per-
forming and interpreting HER2 testing were according to
the established procedures of each individual institution.
No attempt to standardize criteria, or re-evaluate tumor
grading or FISH interpretation for the study was under-
taken. The current ASCO recommendation for FISH
interpretation sets a threshold HER2:Cep17 ratio of 2.2 for
a positive test [10]. We did not reclassify FISH results
according to this new criterion. This approach was taken to
insure the broadest applicability of the study findings to
actual practice conditions throughout the world.
Overall, less than 2% of well-differentiated breast car-
cinomas were categorized as HER2 positive (Table 1).
This rate varied from 0% to 2.8% (mean 1.6%). No
significant difference in the rate of HER2 positivity was
seen among the participating institutions (chi-square test,
P = 0.038).
Considerable attention has been given to the need for
standardization of HER2 testing [10, 15–18]. To determine
if such efforts have altered rates of positive HER2 tests, we
compared HER2 testing at one institution (NMH) in two
time periods (1997–2001 and 2006–2007) (Table 2). The
rate of HER2 positive well-differentiated carcinomas fell
from 7.1% (46 of 652 cases) to 2.5% (4 of 161 cases). A
number of factors may have been involved in this reduc-
tion. During the earlier period, HER2 scoring by
immunohistochemical staining had not been standardized.
Cases that would be considered 2+ staining may have been
recorded as ‘‘positive’’, without confirmation by FISH.
Some of the cases in the historic data set had HER2 testing
performed at the referring institution (usually a community
hospital). Other studies have noted a high rate of discordant
results between smaller community hospital laboratories
and larger referral centers [6, 19]. Differences in fixation
(alcoholic formalin vs. 10% neutral buffered formalin) may
also contribute to the higher than expected frequency of
HER2 overexpression [6]. This finding emphasizes the
importance of standardization of procedures emphasized in
the recent ASCO/CAP guidelines [10].
The ideal methodology (immunohistochemistry vs.
FISH) for screening breast cancers for HER2 remains
controversial. No significant difference in percentage of
HER2 positive cases was seen between institutions that
perform FISH analysis on all tumors (Ljubljana, UCLA,
Yale), and others that use FISH only on select or equivocal
cases (Cedar-Sinai, NMH, PhenoPath, U Miami). While
the current study does not favor one approach over another,
centers that use both will occasionally generate discordant
results. In the current study, five of the six cases with
discordant results were HER2 positive only by immuno-
histochemistry. A variety of explanations have been
offered for discordant results, including amplification of
the centromere on chromosome 17 (IHC+/FISH-) and
shedding of the protein (IHC-/FISH+) [20]. Baselga
reported HER2 amplification in 7 of 214 (3%) and 2 of 30
(7%) of cases reported as 0 or 1+ by immunohistochem-
istry, respectively [21]. Yaziji reported a false negative
rate of immunohistochemistry of 2.8% [6]. In contrast,

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Vera-Román reported no cases of HER2 amplification by
FISH for cases with an immunohistochemical score of 0,
1+ or 2+, and no 3+ IHC cases without gene amplification
[7]. Recently, Gown reported a false negative rate for
HER2 IHC of 1.6% in a series of 6,720 cases [22].
A number of studies have correlated HER2 overex-
pression/gene amplification with adverse histopathologic
features, including high tumor grade and negative hormone
receptor status [12, 23, 24]. Three of our study centers
reported HER2 test data for breast cancers of all grades
(Table 4). The mean rate of HER2 positive tumors
increased from 1.8% in grade 1 tumors, 15.2% in grade 2
tumors, to 30.2% in grade 3 carcinomas. The overall rate of
HER2 positive tumors was 15.8%, consistent with the
range reported in the literature. As expected, over 99% of
the well-differentiated carcinomas in the current study
were ER positive (data not shown).
Previous reports have correlated HER2 with high
nuclear grade [12, 23]. Invasive breast cancers may be
graded based solely on nuclear characteristics (nuclear
grade) or on a combination of architectural features,
nuclear characteristics and mitotic activity (modified
Scarff-Bloom-Richardson) [25]. Centers participating in
this study routinely reported nuclear grade (UCLA and U
Miami), SBR grade (Cedar-Sinai, Ljubljana, NMH-current,
PhenoPath) or both (Yale, NMH-historic). Data from two
centers was available to compare nuclear grade to the
modified Scarff-Bloom-Richardson (SBR) system for all
tumor grades (Table 5). The rate of HER2 positivity pro-
gressed from grade 1 to grade 3 in either system. While a
lower absolute percentage of nuclear grade 1 tumors were
HER2 positive, compared to SBR grade 1, that difference
never reached statistical significance. Further, centers using
a nuclear grading system did not statistically differ from
centers using the SBR system in rates of HER2 positivity.
Pooling data there was no statistical difference in rate of
HER2 positivity between those centers using a nuclear
grading system (0.8%, 3 of 351) and those using the SBR
system (1.9%, 17 of 896, P = 0.2202, Fisher’s exact test).
While overall grading schemes may provide additional
useful prognostic information, for the purpose of predicting
which tumors will be HER2 negative, there appears to be
no difference between SBR and nuclear grading schemes.
While the rarity of HER2 positive tumors in nuclear
grade 1 breast cancers may justify exclusion from routine
testing, certain caveats must be kept in mind. Stark et al.
reported that whereas the risk of a positive HER2 status
increased linearly with nuclear grade in Caucasian women,
no correlation was seen among African American women
[26]. HER2 expression may be dissociated from tumor
grade in other patient groups as well. Choi et al. reported a
positive HER2 status in 47.5% of Korean women, com-
pared to 15.8% of Caucasian women [8]. Maru reported a
555
higher frequency of HER2 positive breast cancers in
women 30 years of age or younger. However, there were
no grade 1 tumors in that cohort of patients [27].
Ultimately, data assessing Herceptin response rates in
the small subset of HER2 positive, well differentiated
breast carcinomas would be useful in assessing the absolute
risk: benefit ratio for this group of patients. Just as stan-
dardization of methods and adherence to quality assurance
guidelines are improving the reliability of HER2 testing,
reports of prognostic or predictive markers should follow
similar rigorous quality standards. The National Cancer
Institute-European Organization for Research and Treat-
ment of Cancer (NCI-EORTC) has proposed a set of
guidelines for tumor marker prognostic/predictive studies
[28]. Publications containing more detailed information
about patient and tumor characteristics could allow insights
into clinically significant subgroups that may not be
apparent when grouped in larger categories. Until such data
concerning HER2 in this group of patients becomes
available, centers that choose to continue testing well-dif-
ferentiated breast cancers for HER2 overexpression, may
consider employing alternative strategies to improve cost-
effectiveness, such as creating tissue microarrays to be run
on a weekly basis [17].
Conclusion
This multi-institutional study from the United States and
Europe demonstrates that the risk of a well differentiated
breast cancer being HER2 positive is extremely low (mean
1.6%, range 0–2.8%), and falls within the range of reported
false negative rates for standard immunohistochemical and
FISH protocols. Elimination of HER2 testing as a ‘‘stan-
dard of care’’ should be considered in this subset of
patients. Because of the possibility of unique patient groups
with an altered HER2: nuclear grade relationship, each
center should examine its own data before deciding if such
testing is necessary for optimal cost-effective patient care.
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