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HER2 and predicting response to therapy in
breast cancer
Author
Hideko Yamauchi, MD
Daniel F Hayes, MD
Section Editor
Lowell Schnipper, MD
Deputy Editor
Diane MF Savarese, MD
Last literature review for version 16.1: januari 31, 2008 | This topic last
updated: januari 25, 2008
INTRODUCTION — Three options are available for women who require either adjuvant
systemic therapy after local treatment of early stage breast cancer, or treatment for
metastatic disease: hormone therapy, chemotherapy, and the anti-HER2 humanized
monoclonal antibody trastuzumab (Herceptin). The choice of therapy in either situation is
influenced by the following factors.
 Hormone responsiveness — A major determinant is whether an individual breast
cancer is hormonally responsive, as indicated by expression of estrogen (ER)
and/or progesterone (PR) receptors. Both in the adjuvant and metastatic
disease settings, hormone therapy benefits patients with hormone-responsive
breast cancer, but not those with hormone-nonresponsive disease. (See
"Adjuvant systemic therapy for hormone receptor positive early stage breast
cancer in postmenopausal women", see "Adjuvant systemic therapy for
hormone receptor positive early stage breast cancer in premenopausal women"
and see "Endocrine therapy of metastatic breast cancer").
 HER2 overexpression — A second tumor marker that is used to select appropriate
treatment is the HER2 oncogene and its protein products. A variety of
nomenclatures has been used in the literature, including NEU, ERBB-2, HER-2,
HER2, and c-erb-B2. Although ERBB-2 is the official name provided by the
HUGO Gene Nomenclature Committee, HER2 is the most commonly used term,
and will be used throughout this discussion.
In approximately 18 to 20 percent of newly diagnosed breast cancers, HER2 is a useful
marker for therapeutic decision making in patients with breast cancer:
 High levels of HER2 expression serve to identify those patients who are most
likely to benefit from therapy with the anti-HER2 monoclonal antibody
trastuzumab (Herceptin), both in the metastatic and adjuvant therapy settings.
 HER2 overexpression may also select for women who have a better outcome with
anthracycline as compared to nonanthracycline-based adjuvant chemotherapy
regimens.
 At least some data suggest that HER2 overexpression results in a hormoneindependent phenotype in women with ER-positive breast cancer, although the
available studies are conflicting.
 In addition to its value as a marker to predict benefit from certain therapies,
overexpression of HER2 is also associated with a poor prognosis.
Here we will review the relationship between expression of the biologic marker HER2 and
response to hormone therapy, chemotherapy, and trastuzumab, both in the adjuvant
setting and in women with advanced disease.
THE HER2 ONCOGENE — The HER2 oncogene encodes for a 185 KD transmembrane
glycoprotein receptor with intracellular tyrosine kinase activity [1] . The HER2 receptor
belongs to the epidermal growth factor receptor (EGFR) family of receptors, which are
critical in the activation of subcellular signal transduction pathways controlling epithelial
cell growth and differentiation [2,3] and possibly angiogenesis [4,5] . HER2, the
epidermal growth factor receptor 2, was previously called HER2/neu, or ERBB-2.
Amplification of HER2 or overexpression of its protein product is observed in 18 to 20
percent of human breast cancers [6-8] .
Clinical utility of HER2 testing — The American Society of Clinical Oncology Tumor
Marker Guidelines Panel has recommended routine testing of HER2 expression on newly
diagnosed and metastatic breast cancers since 2001 [9] . More recently, a joint
committee representing the American Society of Clinical Oncology (ASCO) and the
College of American Pathologists (CAP) published a separate set of guidelines that
specifically address the technical and analytical aspects of HER2 testing [10] . This
committee recommended strict accreditation for laboratories providing HER2 testing.
(See "Recommendations of the ASCO/CAP consensus panel" below).
Knowledge of HER2 status is useful in the context of clinical care for several reasons.
Prognostic value — HER2 overexpression is associated with high rates of disease
recurrence and death in the absence of adjuvant systemic therapy. In fact, HER2 status
is one of the factors used by the International Consensus Panel on the Treatment of
Primary Breast Cancer in assigning risk status for adjuvant chemotherapy
recommendations [11] . (See "Adjuvant chemotherapy and trastuzumab for early stage
breast cancer", section on Recommendations from major groups and see "Measurement
of prognostic factors in breast cancer", section on HER2 overexpression).
However, the value of this information in clinical practice is questionable. Guidelines from
an ASCO expert panel on tumor markers in breast cancer recommend against using
HER2 as a prognostic factor [9] . Given the substantial benefit of adjuvant trastuzumab
for patients with HER2-overexpressing tumors, it is difficult to separate out the
prognostic versus predictive utility of HER2.
Predictive value — HER2 status predicts response to specific therapies:
 In general, HER-2 positivity is associated with a relative but not absolute
resistance to endocrine therapies in general. Although controversial, at least
some data suggest that this effect may be specific to selective estrogen
modulator (SERM) therapy (eg, tamoxifen) and perhaps not to estrogen
depletion therapies, such as with aromatase inhibitors, although the data are
conflicting [12] . (See "Response to endocrine therapy" below).
 HER2 status also appears to be predictive for resistance or sensitivity to different
types of chemotherapeutic agents. HER2 overexpression correlates with a
response to anthracyclines, although this effect may be secondary to
coamplification of HER2 with topoisomerase II, the direct target of this class of
agents. (See "Response to chemotherapy" below).
 Finally, and perhaps most importantly, high levels of HER2 expression also serve
to identify those women who benefit from treatment with agents that target
HER2 [13] . Trastuzumab, a humanized anti-HER2 monoclonal antibody (MoAb),
is remarkably effective both as a single agent and in combination with cytotoxic
chemotherapy in patients with metastatic disease. Furthermore, multiple
randomized trials indicate a significant survival benefit when this drug is applied
in the adjuvant setting for HER2-overexpressing breast cancer. (See "Adjuvant
chemotherapy and trastuzumab for early stage breast cancer", section on
Trastuzumab).
Controversy regarding the role of trastuzumab for HER2-negative breast cancers is
discussed below. (See "HER2-negative patients" below).
ASSAYS FOR HER2 EXPRESSION — There are many ways to measure the activity of
the HER2 oncogene; the best method, both in terms of the type of assay used, and the
optimal way to perform each type of assay are controversial. The available assays are as
follows:
 HER2 gene amplification — Fluorescence in situ hybridization (FISH),
chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization
(SISH) or differential polymerase chain reaction (PCR).
 Overexpression of the HER2 protein product — Western blotting, enzyme-linked
immunosorbent assay (ELISA), or immunohistochemistry (IHC).
 Overexpression of HER2 RNA — Northern blotting or reverse transcription PCR
(RT-PCR)
Early trials of trastuzumab in metastatic disease enrolled patients after central testing
using an IHC assay and the anti-HER2 antibodies 4D5 (the parent antibody of
trastuzumab) and CB11 on formalin-fixed, paraffin-embedded tissue [14-16] . Staining
patterns were identified as negative (0 or 1+) or positive (2 or 3+), and only patients
with 2 or 3+ staining were enrolled. Subsequent retrospective analyses have suggested
that only patients with IHC 3+ staining benefited from trastuzumab [15-21] , and that
only about one-fourth of IHC 2+ positive tumors had gene amplification when tested by
FISH [7,22-25] .
In contrast, negative (0 to 1+) IHC was highly concordant with a lack of gene
amplification by FISH; the false negative rate for IHC using Herceptest was 2 of 145
cases, or 1.4 percent in one study [23] , and between 4 and 7 percent in a second report
[22] . A preliminary report of the only randomized trial of trastuzumab in patients with
IHC 0-1+ nonamplified HER2 failed to show any statistically significant benefit from
adding trastuzumab to paclitaxel in women with metastatic disease, but the study was
underpowered and limited by the lack of central testing [26] .
For most of the prospective randomized adjuvant trials of trastuzumab, testing
algorithms were somewhat arbitrarily developed consisting of either IHC testing and
reflex FISH if IHC 2+, or reliance on FISH alone to detect gene amplification ratios of 2 or
higher. Individuals with IHC 3+ or FISH positivity were considered suitable for enrollment
[27-29] . For the most part, these algorithms have been adopted into clinical practice,
one of the reasons being that IHC is less expensive and more widely available than FISH.
However, many of these assay methods have not been well standardized, particularly
"home brew assays" that are set up in individual pathology laboratories using FDAapproved analyte-specific reagents [10] . Prospective substudies from two of the
adjuvant trastuzumab trials indicate that at least 20 percent of the HER2 assays
performed locally were incorrect when the same specimen was reevaluated in a highvolume central laboratory [27-29] . In contrast to the discordance between community
and central laboratories, there is a high degree of agreement between central and
reference laboratories [29] . These data underscore the importance of using high-volume,
experienced laboratories for HER2 testing to optimize the selection of patients most likely
to benefit from trastuzumab. (See "Selection of patients for trastuzumab" below).
Recommendations of the ASCO/CAP consensus panel — The optimal testing
algorithm for assessing HER2 status in breast cancer as well as strategies to assure
optimal performance, interpretation, and reporting of individual assays was addressed in
a joint guideline from an expert panel of ASCO and the College of American Pathologists,
summarized in Table 1 (show table 1) [10] .
Recommended algorithms for IHC and FISH testing of breast tumors are provided in
figures 1 and 2 (show figure 1 and show figure 2). In brief:
 A positive result is defined as either uniform intense membrane staining of >30
percent of invasive tumor cells in IHC or a FISH result of amplified HER2 gene
copy number (average of more than six gene copies per nucleus for test
systems without an internal control probe [eg, INFORM HER2/neu probe,
Ventana], or an HER2/CEP 17 ratio of more than 2.2 where CEP is a centromeric
probe for chromosome 17 on which HER2 resides [eg, PathVysion HER2 DNA
probe kit, Abbott]) [10] .
 A negative HER2 result is defined as either a IHC result of 1 or 1+ for cellular
membrane protein expression (no staining or weak, incomplete membrane
staining in any proportion of tumor cells), or a FISH result showing a HER2/CEP
17 ratio of less than 1.8 or an average of fewer than four copies of the HER2
gene per nucleus for systems without an internal control probe.
 An equivocal result on IHC testing is complete membrane staining that is either
nonuniform or weak in intensity but with obvious circumferential distribution in
at least 10 percent of cells, or intense, complete membrane staining of 30
percent or fewer tumor cells. These samples require additional testing to define
the true HER2 status (show figure 1).
An equivocal FISH finding is defined as a HER2/CEP 17 ratio between 1.8 and 2.2, or
average gene copy number between 4 and 6 for those systems without an internal
control probe. However, it is not clear that these patients should be excluded from
receiving trastuzumab. Patients with HER2/CEP 17 FISH ratios between 2 and 2.2 were
previously considered FISH-positive and eligible for the adjuvant trastuzumab trials.
Equivocal samples can be confirmed by counting additional cells or repeating the FISH
result. If the FISH remains equivocal, confirmatory IHC is recommended [10] .
HER2 discordance in primary versus metastases — The level of discordance
between HER2 status in paired primary breast tumors and metastases is thought to be
low (show table 2) [30-32] . However, at least two reports suggest that a substantial
proportion of women with HER2-negative primary tumors acquired protein
overexpression when their tumors recurred [33,34] . In one, nine of 24 initially negative
tumors were HER2-positive at recurrence, and three of four patients had an objective
response to trastuzumab [33] . It seems reasonable to reanalyze HER2 in biopsies
obtained from newly recurrent metastases, especially if the primary tumor was negative
or only weakly positive.
A potentially important new finding is that in some but not all [21] studies, breast tumors
that become resistant to hormone therapy acquire HER2 expression [34] . The
ramifications of this finding on the need to rebiopsy tumor tissue after a patient becomes
refractory to hormone therapy, and its implication for future trastuzumab therapy is
poorly understood, and needs prospective study.
The utility of HER2 in predicting response to hormone therapy is discussed below. (See
"Response to endocrine therapy" below and see "Mechanisms of action of selective
estrogen receptor modulators", section on Tamoxifen resistance in breast cancer).
RESPONSE TO THERAPIES TARGETING HER2 — Trastuzumab (Herceptin®) is a
recombinant humanized monoclonal antibody that binds to a specific epitope of the HER2
protein. This interaction inhibits signal transduction induced by other peptide growth
factors interacting with their own receptors. The net result is cellular growth inhibition,
decreased malignant potential, and possibly reversal of resistance to certain
chemotherapies. The efficacy of trastuzumab for HER2-overexpressing breast cancer has
now been established in patients with metastatic disease as well as in the adjuvant
setting. (See "Chemotherapy for metastatic breast cancer", Section on Trastuzumab and
see "Adjuvant chemotherapy and trastuzumab for early stage breast cancer", section on
Adjuvant trastuzumab).
Selection of patients for trastuzumab
Overexpression of HER2 by IHC and FISH — High levels of HER2 overexpression, as
determined by either 3+ IHC staining or FISH positivity are used to select patients for
trastuzumab therapy, both in the adjuvant and metastatic disease settings [9,13] . Thus
practice is based upon retrospective subgroup analysis of early trastuzumab trials in
metastatic disease, which suggested that only patients with high levels of HER2 receptor
overexpression (IHC 3+ staining) or high copy number of the gene (>2 by FISH)
benefited from trastuzumab [15-21] . It was subsequently recognized that about 24
percent of IHC 2+ positive tumors had gene amplification when tested by FISH [7,2225,35] .
While FISH seems to represent a more accurate means of selecting patients for
trastuzumab, it is more expensive and less widely available than IHC. As recommended
in guidelines issued by a joint ASCO/CAP consensus panel, patients whose tumors are 2+
by IHC staining should undergo confirmatory FISH testing prior to receiving trastuzumab
(show figure 1) [10] . (See "Assays for HER2 expression" above).
Not all women with high levels of HER2 overexpression respond to trastuzumab. Several
potential mechanisms to explain trastuzumab resistance have been proposed [36-39] .
One possibility is that a subgroup of HER2-positive tumors also express p95HER2, a
truncated form of the HER2 receptor that has kinase activity but lacks the extracellular
trastuzumab-binding domain [36,37] . In a study of 46 patients with metastatic disease,
only one of nine patients expressing p95HER2 responded to trastuzumab, compared to
19 of 37 of those expressing full-length HER2 [37] .
Preclinical data from this study also suggested that tumors expressing the truncated
receptor remain sensitive to other therapies targeting HER2 (eg, lapatinib, see "Selection
of patients for lapatinib" below). Although intriguing, until further information becomes
available, analysis of tumors for p95HER2 expression as a means of selecting patients for
trastuzumab or lapatinib is not warranted.
Another possibility is that trastuzumab activity is inhibited by excessive signaling through
the insulin like growth factor-I receptor (IGF-IR) [38] . Therapeutic strategies that target
IGF-IR signaling may circumvent trastuzumab resistance.
HER2-negative patients — While trastuzumab is thought to benefit only patients with
HER2-overexpressing tumors, the possibility that some women with HER2-negative
tumors might respond has been raised [40-43] .
Retrospective, unplanned subgroup analysis of highly selected data from the adjuvant
trastuzumab trials conducted by the US Intergroup and NSABP have produced
speculation that at least some women whose tumors were HER2-negative on central
testing benefited from the drug [41,42] :
 Preliminary data on central HER2 confirmatory testing from two trials testing the
benefit of trastuzumab also provide support for the concept that trastuzumab
provides benefit for at least some women with HER2-negative tumors. In both
trials, HER2 positivity by IHC or FISH was required for enrollment.
- In NSABP B31, 10 percent of the 1662 tumor blocks tested by FISH and IHC were
HER2-negative on central testing [41] . The relapse rate in the 87 doubly-negative
patients treated with chemotherapy alone was two- to three-fold higher than the rate of
relapse in the 74 doubly-negative patients who received chemotherapy plus trastuzumab
(21 versus 8 percent).
- Similar results were noted when 1842 tumor blocks from a second NCCTG trial
were retested [42] . The relapse rate in the 44 doubly-negative women treated with
chemotherapy alone was twice that of the 59 doubly-negative women who also received
trastuzumab.
 Additional findings come from an analysis of data from CALGB 9840, in which
women with metastatic disease thought to be HER2-negative (not IHC 3+ or
FISH ≥2.0) were randomly assigned to paclitaxel with or without trastuzumab
[26] . The authors examined the tumor tissue blocks for polysomy of
chromosome 17, the location of the HER2 gene, postulating that this finding
might increase the copy number of HER2 below the threshold set for FISH
positivity (ie, HER2 FISH ratios <2.0) and be predictive of trastuzumab benefit.
In data presented at the 2007 ASCO meeting, 25 of the 129 cases (19 percent) that were
locally HER2 negative and centrally FISH negative had polysomy 17 [40] . When all 38
centrally-tested FISH-negative cases with polysomy 17 were analyzed, response rates
were significantly higher in those who received trastuzumab in addition to paclitaxel (63
versus 26 percent), although DFS and overall survival were similar.
There are several possible explanations for these observations, including chance alone,
given the retrospective nature of the studies from which they were generated. Second, in
the adjuvant trials, tumors were designated as positive locally, and the data represent
the results of central retesting. While central testing is generally considered superior, this
is not necessarily so, and some patients may truly have had HER2-positive tumors.
However, there are also intriguing biologically plausible explanations as well. For example,
neuregulin, a transmembrane growth factor that is frequently expressed in breast cancer,
appears to modulate the clinical response to trastuzumab [43] . In a small series of 11
patients with metastatic disease, neuregulin overexpression correlated with significantly
longer event-free and overall survival in patients with low or normal HER2 expression
who received trastuzumab but not in HER2 overexpressors.
These findings require confirmation and further study. Until more information is available,
a change in standard practice (restricting trastuzumab use to patients with IHC 3+ or
FISH+ tumors) is not warranted.
Selection of patients for lapatinib — A second drug that targets HER2 is available for
women with advanced, HER2-overexpressing breast cancer who have failed trastuzumab.
Lapatinib is an orally active tyrosine kinase inhibitor that blocks HER2 (also called
epidermal growth factor receptor [EGFR]-2) as well as other members of the EGFR family.
The precise role of HER2 testing in selecting patients for lapatinib therapy remains to be
defined. As noted above, tumors expressing the truncated form of HER2 might
preferentially respond to lapatinib rather than trastuzumab [37] , but clinical validation of
this hypothesis in prospective studies is needed. (See "Chemotherapy for metastatic
breast cancer", section on Lapatinib).
Serum circulating ECD levels — Multiple studies have addressed whether circulating
HER2 protein ECD levels can predict response to trastuzumab [15,44,45] . In a
preliminary report of a pooled analysis of seven trials of first-line trastuzumab with or
without chemotherapy, patients with a 20 percent or greater decline in serum ECD levels
over baseline had significantly higher response rates to trastuzumab (57 versus 28
percent) as well as significantly longer TTP and overall survival compared to those with a
lesser degree of decline [45] . However it is not clear whether this observation relates to
response to any therapy, or if it is specific to trastuzumab.
Thus, the clinical utility of following serum circulating ECD levels during trastuzumab
therapy is not yet established. The ASCO expert panel on tumor markers in breast cancer
recommended against the use of serum ECD in any clinical setting [9] .
RESPONSE TO CHEMOTHERAPY — A possible link between HER2 overexpression and
chemotherapeutic responsiveness was suggested by the observation of enhanced clinical
activity with the addition of certain chemotherapeutic agents to trastuzumab in women
with metastatic disease. (See "Chemotherapy for metastatic breast cancer").
In vitro, drugs that target HER2 enhance the cytotoxic effect of several antineoplastics
[46-50] . However, drug sensitivity assays that attempt to correlate HER2
overexpression with relative chemotherapy resistance have provided conflicting data [5154] . These disparate results can be explained by a number of factors, including:
 The different mechanism of action of unrelated chemotherapy drugs [55]
 Variability of human breast cancer cell lines with regard to growth factor
receptors, coamplification of other genes, and acquired drug resistance
phenotypes
 Interaction between HER2 and a drug like doxorubicin may not be direct but
instead, receptor overexpression may simply be a marker or surrogate for a
related coamplified gene, such as topoisomerase II, the true target gene for
anthracycline sensitivity.
Anthracycline-based therapy
Adjuvant setting — Most [56-62] but not all [63] studies report a correlation of HER2
overexpression with better outcomes from adjuvant anthracycline-containing as
compared to CMF-type (cyclophosphamide, methotrexate, fluorouracil) chemotherapy.
Two of the largest series are described below:
 Analysis of HER2 was performed in 992 women with node-positive disease who
were randomly assigned to one of three dose levels of adjuvant CAF
(cyclophosphamide, doxorubicin, 5-FU) in a CALGB trial [56,64] . The highest
dose level of CAF was associated with significantly better disease-free survival
(DFS) and overall survival, and the effect appeared confined to those women
with overexpressed HER2.
 Formalin-fixed tumor specimens were obtained from 639 women with nodepositive breast cancer enrolled on a National Cancer Institute of Canada trial
comparing CEF (cyclophosphamide, epirubicin, fluorouracil) versus CMF [62] .
For women with amplified HER2 tumors, CEF was significantly superior to CMF
in terms of relapse-free survival (hazard ratio [HR] 0.52, 95% CI 0.34 to 0.80)
and there was a trend toward better overall survival (HR 0.65, 95% CI 0.42 to
1.02, p = 0.06). CEF did not improve outcomes in women whose tumors did not
overexpress HER2.
A meta-analysis of eight trials comparing anthracycline versus nonanthracycline-based
chemotherapy and reported efficacy data according to HER2 status also concluded that
the benefits of adjuvant anthracycline use were confined to women with HER2overexpressing tumors [65] . For HER2-positive disease, anthracyclines were superior in
terms of DFS (HR for relapse 0.71) and overall survival (pooled HR for death 0.73). In
HER2-negative disease, anthracyclines did not improve either DFS or overall survival.
The reason for the relationship is uncertain. One hypothesis is that HER2 expression
simply represents a marker or surrogate for the real anthracycline target, the enzyme
topoisomerase II alpha [66-73] . The TOP2A gene is adjacent to the HER2 gene on
chromosome 17q12-q21. However, expression of the two genes is not necessarily linked;
HER2 and TOP2A often have different copy numbers within the same tumor [74] , and
the two genes are not always coamplified/coexpressed [75] . This is an area of active
study.
Taken together, the data linking HER2 overexpression with anthracycline sensitivity are
sufficiently compelling that ASCO guidelines recommend that an anthracycline-based
regimen be strongly considered in women with HER2-overexpressing early breast cancer
[9] . However, whether the use of anthracyclines should be abandoned in patients with
HER2-negative breast cancer remains unsettled [76] .
Metastatic disease — The association of HER2 positivity with enhanced response to
anthracyclines is less certain in metastatic disease [77-79] . One study showed a higher
probability of response to a doxorubicin-based regimen compared to CMF in patients with
metastatic disease and elevated HER2 protein ECD, while patients with normal levels
responded equally [77] . However, in a second report, the response rates from FEC
(fluorouracil, epirubicin, cyclophosphamide) chemotherapy were not significantly different
with HER2-positive and negative tumors [78] . In a third series, women with HER2-
overexpressing tumors had a slightly lower response rate to mitoxantrone monotherapy
(50 versus 58 percent), a shorter response duration (median 17 versus 29 weeks), and
significantly worse survival compared to those with HER2-negative disease [79] .
CMF-type regimens
Adjuvant CMF — In contrast to the data on anthracyclines, women whose tumors
overexpress HER2 may derive less benefit from adjuvant CMF as compared to
nonoverexpressors [80-82] :
 One study evaluated HER2 status in 206 women who participated in a United
States Intergroup trial for node-negative early stage breast cancer (INT-0011)
[80] . Patients were randomly assigned to postoperative adjuvant CMFp (CMF
plus prednisone) or no systemic therapy. Women with HER2-negative tumors
who were treated with CMFp had a significantly better five year DFS compared
to the control group (80 versus 58 percent), while there was no significant
benefit for CMFp treatment in women with HER2-overexpressing tumors (fiveyear DFS, 78 versus 68 percent).
 In a second trial, the International (Ludwig) Breast Cancer Study Group Trial V,
1229 women with node-positive breast cancer were randomly assigned to six
postoperative cycles of CMF (plus tamoxifen if postmenopausal) versus one
perioperative cycle of CMF [83,84] . Tissue specimens for HER2 analysis (by
IHC) were available in 746 (61 percent) of the women [81] . Patients with
HER2-negative tumors who received six cycles of CMF had significantly better
six year DFS (52 versus 36 percent) and overall survival (71 versus 61 percent)
than did those who received a single perioperative cycle of chemotherapy. In
contrast, the differences with longer versus shorter CMF therapy in women with
HER2-overexpressing tumors were not statistically significant (six-year DFS, 38
versus 29 percent; overall survival, 46 versus 40 percent).
 Similarly, 274 women with node positive breast cancer were randomly assigned
to 12 cycles of adjuvant CMF versus no therapy [82,85] . Compared to
observation only, chemotherapy was associated with a significantly better
median survival in women with HER2-negative disease (median survival, 12.7
versus 7.3 years), but the difference in those with HER2-positive disease (6.1
versus 4.4 years) was not statistically significant. Untreated HER2-positive
patients had significantly worse DFS and overall survival than the control HER2negative patients independent of therapy.
 Conflicting results have been noted by others. In a study from Milan, 386 women
were randomly assigned to 12 cycles of CMF (n=207) or no treatment (n=179)
[86,87] . Compared to observation, the use of CMF was associated with
significantly improved DFS and overall survival in all patients, regardless of
HER2 status. If anything, HER2-positive women were more likely to benefit from
CMF than those who were HER2-negative.
Metastatic setting — Data regarding HER2 expression and response to CMF-type
regimens in women with metastatic disease are currently limited, and contradictory to
the results in the adjuvant setting. In one study, women with HER2-positive tumors (by
gene amplification and/or overexpression) had an improved response rate (75 versus 45
percent), and a longer progression-free survival (287 versus 90 days) compared to those
whose tumors did not amplify and/or overexpress HER2 [88] .
Response to taxanes — Preclinical data suggest that overexpression of HER2 may
correlate with taxane resistance [52] . Subsequent clinical investigations conducted in
women with locally advanced or metastatic breast cancer and in those receiving
neoadjuvant or adjuvant therapy for operable disease have been small, often confounded
by other concomitant therapies, and the results inconsistent and contradictory.
The following represents the range of findings:
 In a series of 297 women with metastatic breast cancer who received either
paclitaxel or cyclophosphamide plus epirubicin, women whose tumors were
HER2-positive had a significantly longer progression-free survival and overall
survival with a taxane-containing regimen, while there were no differences
between the two regimens in those whose tumors were HER2-negative [89] .
These results have been confirmed by some [90,91] but not all studies [92] .
 In the adjuvant setting, the interaction between HER2 status and benefit from
taxanes was evaluated in a subset of 1322 women who were treated on CALGB
9344 (which showed that four cycles of adjuvant paclitaxel after AC significantly
improved disease-free survival and overall survival compared to four cycles of
AC alone in women with node-positive breast cancer), and who had tissue
blocks available for analysis [93] . In a prespecified analysis, there was a
significant benefit from the addition of paclitaxel after AC in women with HER2positive cancers, regardless of ER status, and in ER-negative tumors regardless
of HER2 status, while there was no evidence of benefit in the subgroup with ERpositive, HER2-negative tumors. (See "Adjuvant chemotherapy and
trastuzumab for early stage breast cancer", section on Benefit of taxanes).
 Reports of preoperative (neoadjuvant) taxane therapy have come to disparate
conclusions, with one suggesting a better response rate for HER2-positive
tumors [94] , two a worse response rate [95,96] , and two others, no
association between HER2 gene amplification or overexpression and response
[97,98] .
An ASCO expert panel on tumor markers in breast cancer recommended against the use
of HER2 to guide the use of taxanes, at least in the adjuvant setting [9] .
Summary
Adjuvant setting — Although the available data are far from conclusive, women whose
tumors overexpress HER2 appear to derive greater benefit from anthracycline-based
adjuvant therapy than from adjuvant therapy that is alkylating agent-based, such as CMF.
The ASCO expert panel on tumor markers in breast cancer recommended that
anthracycline-based adjuvant therapy be strongly considered in patients whose tumors
had high levels of HER2 expression, as determined by 3+ immunohistochemistry or a
FISH ratio >2 by gene amplification, in the absence of a contraindication to use of this
class of drugs [9] .
However, patients with high-risk HER2-positive tumors also benefit from trastuzumab,
which dramatically decreases the risk of recurrence and mortality by 50 and 30 percent,
respectively [99,100] . At least one study, reported at several meetings but not yet
published, suggests that patients with HER2-positive breast cancer who receive a
nonanthracycline-containing adjuvant chemotherapy regimen coupled with trastuzumab
have similar outcomes as do those treated with doxorubicin, cyclophosphamide, and
docetaxel plus trastuzumab [101] . While these intriguing preliminary data have not yet
led to a change in clinical practice, they suggest that the addition of trastuzumab to a
nonanthracycline-containing regimen might provide a comparable degree of benefit for
HER2-overexpressing tumors while avoiding the risk of heart failure and treatmentrelated leukemia associated with anthracyclines. (See "Adjuvant chemotherapy and
trastuzumab for early stage breast cancer", section on Trastuzumab).
Until further data become available, we preferentially recommend anthracycline-based
therapy to patients with HER2-overexpressing breast cancer in the adjuvant setting,
unless such therapy is contraindicated (eg, in women with underlying heart disease, or
women who received prior anthracycline therapy for a previous breast cancer). However,
it is reasonable to offer CMF to patients with HER2-positive tumors if they have a
contraindication to anthracycline, since, if resistance exists, it is relative and not absolute.
For patients with HER2-negative tumors, either CMF or an anthracycline-based regimen
is appropriate, based on the physician's discretion and patient's choice. (See "Adjuvant
chemotherapy and trastuzumab for early stage breast cancer", section on Anthracyclinecontaining versus CMF-type regimens).
Whether HER2 overexpression should be used to select patients for taxane therapy
remains uncertain. Although the data from CALGB 9344 suggest that the sequential use
of four 21-day cycles of adjuvant paclitaxel following AC provides little if any benefit for
women with HER2-negative, ER-positive tumors, these results require validation.
Furthermore, it is not clear that the results can be extrapolated to regimens that contain
dose-dense therapy or docetaxel rather than paclitaxel. ASCO guidelines recommended
against the use of HER2 to guide decisions about the use of adjuvant taxanes [9] . (See
"Adjuvant chemotherapy and trastuzumab for early stage breast cancer", section on
Benefit of taxanes).
Metastatic disease — There is no conclusive evidence to suggest that women with
metastatic breast cancer whose tumors overexpress HER2 are likely to derive greater
benefit from anthracycline-containing or taxane-containing combinations as compared to
CMF-like regimens. The data are insufficient at this time to draw clinically meaningful
conclusions as to optimal treatment choice. The ASCO expert panel did not recommend
that HER2 overexpression be used to make treatment decisions in this setting [9] .
RESPONSE TO ENDOCRINE THERAPY — Amplification and/or overexpression of HER2
may be associated with primary resistance to endocrine therapy. Preclinical studies
suggest physiologic "cross-talk" between the HER2 and ER signal transduction pathways.
HER2 expression in human breast cancer cells is downregulated by estrogens [102] .
Conversely, transfection and overexpression of HER2 in vitro promotes estrogenindependent growth and tamoxifen resistance in ER-positive (estrogen dependent)
human breast cancer cells [51,103,104] . Among the hypothesized mechanisms whereby
overexpression of HER2 renders cells hormonally independent are phosphorylation of the
ER, ligand-independent ER activation, and regulation of hormone receptor expression
[104,105] . (See "Mechanisms of action of selective estrogen receptor modulators",
section on Modulation of ER expression through second messengers).
Although these data provide a rational explanation for the lower response of HER2overexpressing tumors to endocrine therapy seen in several clinical studies, most were
retrospective and nonrandomized. Randomized trials have not provided consistent and
confirmatory evidence of a lower response to endocrine therapy in HER2-overexpressing
tumors, either in the adjuvant or metastatic disease setting.
Adjuvant therapy — Although several trials have concluded that patients with HER2overexpressing tumors are relatively resistant to adjuvant hormone therapy [106-110] ,
a similar number have failed to demonstrate such a relationship [111-117] , and others
even suggest a positive influence of HER2 overexpression on treatment response.
Trials showing a negative impact on response
 In the largest series derived from the Gruppo Universitario Napoletano 1 (GUN-1)
cooperative trial, HER2 expression (by IHC) was evaluated in 145 of 308 (47
percent) patients with node-negative breast cancer who were randomly
assigned to two years of tamoxifen (n = 59) or observation (n = 86) [108] .
Compared to untreated controls, adjuvant tamoxifen was associated with a
better 10-year disease-free survival (DFS, 54 versus 82 percent, p = 0.03) and
overall survival (68 versus 86 percent, p = 0.09) in women with HER2-negative
tumors. In contrast, the use of tamoxifen was associated with a worse 10 year
DFS (63 versus 51 percent, p = 0.3) and overall survival (82 versus 57 percent,
p = 0.003) in women with HER2-positive tumors.
Similar findings were noted in women with node-positive breast cancer who were
enrolled on the same trial [109] . Premenopausal women all received CMF
(cyclophosphamide, methotrexate and fluorouracil) with or without tamoxifen (for two
years) while postmenopausal women were randomly assigned to two years of tamoxifen
alone or no treatment. As in the earlier analysis, compared to no endocrine therapy, the
beneficial effect of tamoxifen in improving relapse-free and overall survival was only
evident in those with HER2-negative tumors, while a statistically insignificant trend
toward a worse outcome was evident in those with HER2-positive tumors. Expression of
HER2 had no predictive effect in women who received concurrent CMF. When
premenopausal women treated with CMF were excluded, the hazard ratio (HR) for death
in the tamoxifen-treated versus no tamoxifen group was 2.23 in the HER2-positive
patients, compared with 0.54 in the HER2-negative group.
 It has been hypothesized that the adverse influence of HER2 overexpression is
limited to therapies that are based upon a ligand binding agent (eg, selective
estrogen receptor modulators [SERMs] such as tamoxifen) as opposed to
ligand-depleting therapy (eg, ovarian ablation, aromatase inhibitors). This
hypothesis was based on an analysis of a trial in which 250 postmenopausal
women with ER-positive breast cancer who were ineligible for breast conserving
treatment were randomly assigned to four months of preoperative letrozole (2.5
mg daily) or tamoxifen (20 mg daily) [110] . Women with HER2-positive tumors
had significantly lower response rates to neoadjuvant tamoxifen when compared
to those who were HER2-negative (17 versus 40 percent). In contrast, no
difference was noted in the response to letrozole (69 versus 53 percent for
HER2 positive and negative tumors, respectively).
However, contradictory results have also been reported in two other trials conducted in
the adjuvant setting (the ATAC and BIG 1-98 trials [12,118] ) as well as in women
receiving endocrine therapy for metastatic disease. In both adjuvant trials, the benefits
of an aromatase inhibitor (anastrozole or letrozole) over tamoxifen were seen regardless
of HER2 status. (See "Metastatic breast cancer" below) and see "Adjuvant systemic
therapy for hormone receptor positive early stage breast cancer in postmenopausal
women", section on Aromatase inhibitors).
Furthermore, others have shown continued proliferation despite ongoing letrozole in close
to 90 percent of HER2-positive tumors, suggesting that therapeutic resistance might
become manifest later in the course of the disease [119] .
As a result of all of these issues, the available data are not considered sufficiently robust
to use HER2 status as a factor in selecting an aromatase inhibitor over tamoxifen
[9,120] . This topic is discussed further elsewhere. (See "Adjuvant systemic therapy for
hormone receptor positive early stage breast cancer in postmenopausal women", section
on AIs versus tamoxifen).
Trials showing no impact on response — Many other trials have failed to
demonstrate a predictive impact of HER2 expression on response to adjuvant hormone
therapy [111-118] . The two largest are described in detail:
 In a prospective trial, the Danish Breast Cancer Cooperative Group assigned 1716
high-risk postmenopausal women with early stage breast cancer to tamoxifen
(30 mg daily for one year only) or observation [111] . Both hormone receptor
content and HER2 status were determined by IHC on fixed, paraffin-embedded
tissues. Among women treated with tamoxifen, HER2 positivity was not
associated with an increased risk of recurrence. The influence of HER2 status on
benefit from adjuvant tamoxifen compared to observation could not be
discerned because there were too few women who were highly positive for HER2
(n = 52).
 A Cancer and Leukemia Group B (CALGB) study assessed the interaction between
HER2 overexpression and tamoxifen use among women with ER and/or PRpositive breast cancer who were included in CALGB trial 8541, which was
designed to compare low, moderate, and high doses of adjuvant CAF
(cyclophosphamide, doxorubicin and fluorouracil) [112] . Tamoxifen was given
to some women with hormone receptor-positive tumors at the discretion of the
treating physician [113,114] . Of 741 patients for whom blocks were available
for IHC, tamoxifen had been given to 263 of 555 (47 percent), and 68 of 186
(37 percent) of women with HER2-negative and HER2-positive breast cancer,
respectively.
With a median follow-up of 8.7 years, the five-year relapse-free survival (RFS) rate was
better in patients who received tamoxifen compared to those who did not, irrespective of
HER2 status. Furthermore, the risk of relapse was similar among tamoxifen-treated
patients who were HER2-negative or HER2-positive (42 versus 44 percent). Thus,
negative HER2 status did not appear to predict for a more favorable response to
tamoxifen. These results may have been confounded by the use of doxorubicin-based
chemotherapy prior to tamoxifen in all women, since overexpression of HER2 may predict
for improved outcome after doxorubicin (see "Response to chemotherapy" above).
 The duration of tamoxifen may also influence the predictive value of HER2
overexpression on outcomes. This was illustrated in a study in which 405
postmenopausal women with ER-positive tumors were randomly assigned to
adjuvant tamoxifen for either two or five years [115] . Overall, HER2 positivity
was associated with a significantly lower recurrence-free probability and survival
(ie, it was of prognostic value). When the benefit of five versus two years of
tamoxifen was analyzed in relation to HER2 status for patients still disease-free
two years after surgery, patients with HER2-negative tumors benefited
significantly from longer treatment (relative risk [RR] for recurrence 0.62, 95%
confidence interval (95% CI 0.42-0.93), while benefit was not evident in the
subset with HER2-positive disease (RR = 1.1, 95% CI 0.41-3.2).
Trials showing positive impact on response — In contrast to these results, a
potentially positive impact of HER2 overexpression on benefit from adjuvant hormone
therapy was suggested in a series of 282 premenopausal women with ER-positive disease
(50 percent node-positive) who were randomly assigned to adjuvant oophorectomy plus
tamoxifen or observation [116] . HER2 overexpression was a negative prognostic factor
for overall survival in multivariate analysis. It was also associated with a significantly
greater benefit from adjuvant endocrine therapy (three-year DFS 81 versus 52 percent
for patients with HER2-positive tumors receiving hormone therapy versus observation)
while DFS was not significantly better in the treated group for those with HER2-negative
disease (three-year DFS 85 versus 73 percent, respectively).
Thus, although some studies suggest that HER2 overexpression is associated with
relative resistance to adjuvant hormone therapy, particularly with tamoxifen, the data
are conflicting. Guidelines from an expert panel on tumor markers in breast cancer
convened by ASCO recommended that HER2 status not be used to withhold endocrine
therapy for a patient with a hormone receptor-positive breast cancer, nor to select one
specific type of endocrine therapy over another [9] . (See "Measurement of prognostic
factors in breast cancer", section on HER2 overexpression).
Metastatic breast cancer — In contrast to the adjuvant studies, trials examining the
predictive value of HER2 status in women receiving hormone therapy for metastatic
breast cancer have not compared treated versus untreated patients due to ethical
concerns. Instead, multiple studies have assessed response rates to endocrine therapy
among women with HER2-positive versus negative tumors. Although the results are
mixed (show table 3), the bulk of evidence favors an adverse influence of HER2
overexpression on response to treatment with tamoxifen [88,121-131] . The following
illustrates the range of findings in women with hormone receptor-positive tumors:
Immunohistochemistry
 In one study, overexpression of HER2 (by IHC) was studied in 65 available
specimens collected from 221 women with advanced breast cancer participating
in several hormone therapy trials [121] . Postmenopausal women received
tamoxifen as first-line therapy, while premenopausal women underwent initial
ovarian ablation followed by second-line tamoxifen. Only 1 of 14 women (7
percent) with HER2-positive disease responded to endocrine therapy compared
to 19 of 51 (37 percent) women with HER2-negative tumors (p<0.05). Among
patients with ER-positive tumors, only one of five patients whose tumor
expressed HER2 had an objective response to hormone therapy, compared to
almost one-half of those with HER2-negative tumors.
 Findings were similar in a second report that correlated HER2 overexpression (by
IHC) with response rate in 241 women with advanced breast cancer receiving
either tamoxifen (n = 211) or ovarian ablation (n = 30) at first recurrence
[125] . Women with HER2-positive tumors had significantly lower response
rates to both hormone therapies (38 versus 56 percent, p = 0.02), and a
shorter time to progression (TTP) (4.1 versus 8.7 months, p<0.001). In the
subgroup of 189 women with ER-positive disease, the detrimental effect of
HER2 positivity was more impressive, both in terms of reduced response rate
(24 versus 64 percent, p = 0.05) and shorter TTP (6 versus 11 months,
p<0.001).
 Others have failed to show any significant correlation between tissue HER2
overexpression (by IHC) and response to tamoxifen. As an example, in
Southwest Oncology Group (SWOG) companion trial 8228, 205 specimens were
available from 349 tumors in women with ER-positive metastatic breast cancer
who received tamoxifen as first-line therapy [124] . When patients with HER2positive versus negative tumors were compared, there was no difference in
response rate (54 versus 57 percent, p = 0.67), DFS (6 versus 8 months, p =
0.15), or overall survival (29 versus 31 months, p = 0.36).
A meta-analysis of 12 studies (n = 2379 patients) was performed to address the question
of interaction between HER2 expression and response to hormone treatment for
advanced breast cancer [117] . The relative risk for treatment failure for HER2-positive
tumors was significantly higher than for HER2-negative tumors among women treated
with tamoxifen (relative risk [RR] 1.33, 95% CI 1.2 to 1.48) as well as other hormone
therapies (RR 1.49, 95% CI 1.36 to 1.64).
Serum levels of circulating HER2 ECD — Other researchers have studied the
relationship between pretreatment serum levels of circulating HER2 ECD and response to
hormone therapy in women with metastatic breast cancer [122,123,130,132-134] . The
data are conflicting:
An inverse relationship was reported between circulating HER2 ECD and outcomes from
first-line droloxifene [123] . Compared to patients with elevated circulating ECD levels,
those with normal or undetectable levels had significantly higher response rates (56
versus 9 percent, p = 0.00001), and longer time to tumor progression (HR for
progression 0.36, 95 percent Cl 0.21-0.63) and overall survival (HR for death 0.35, 95
percent Cl 0.17-0.70).
At least three series note significantly poorer response rates, time to progression and
overall survival among women receiving aromatase inhibitors who have elevated serum
levels of HER2 ECD as compared to those with normal or undetectable levels
[130,132,134] . The largest report included 562 women with previously untreated
hormone receptor-positive metastatic breast cancer who were randomly assigned to
tamoxifen or letrozole [130] . The overall response rate with letrozole was significantly
higher among patients with a normal as compared to elevated serum level of ECD (39
versus 17 percent), as was the time to tumor progression (12.2 versus 6.1 months).
Among patients with elevated serum HER2, there was no significant difference between
letrozole and tamoxifen in objective response rate, although there was a strong trend
favoring longer time to tumor progression with letrozole.
On the other hand, investigators from CALGB reported no difference in outcome among
women receiving megestrol acetate for metastatic breast cancer who were either ECDpositive or negative [133] . These data, which represent long term follow-up, are in
contrast to earlier reports of the same population, which suggested that women treated
with megestrol acetate who had elevated pretreatment serum HER2 levels had shorter
DFS and overall survival [135] .
Similarly, in serum collected from 77 women with stage III or IV breast cancer, no
correlation was observed between elevated pretreatment ECD levels and the response to
first-line tamoxifen (70 versus 62 percent, p = 0.71) [131] .
Guidelines from an ASCO expert panel on tumor markers in breast cancer concluded that
the measurement of circulating HER2 ECD was not recommended in any clinical setting
[9] .
Summary — Although the data are conflicting, the available clinical evidence does not
support the hypothesis that HER2 amplification and/or overexpression results in a
hormone-independent phenotype in women with ER-positive breast cancer. Although the
relative benefit from antiestrogens is probably lower for patients with HER2-positive
tumors, the effect is incomplete, and some patients with HER2-overexpressing, hormone
receptor-positive breast cancer will have a meaningful response to hormone therapy. The
data are insufficient to routinely recommend using HER2 status to identify patients with
ER-positive breast cancer who are likely to be resistant to hormone therapy, or to specific
types of hormone therapy, such as tamoxifen.
An expert panel convened by ASCO recommended that neither primary tumor HER2
expression nor circulating HER2 ECD levels be used to make decisions regarding hormone
therapy in either the adjuvant or metastatic disease setting [9] . The selection of
endocrine therapy should be based only upon established markers such as ER and PR.
Larger, more definitive studies are underway to further explore the relationship between
HER2 status and the selection of a SERM or aromatase inhibitor therapy.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for
patients. (See "Patient information: Breast cancer guide to diagnosis and treatment").
We encourage you to print or e-mail this topic review, or to refer patients to our public
web site, www.uptodate.com/patients, which includes this and other topics.
SUMMARY AND RECOMMENDATIONS — Approximately 18 to 20 percent of breast
cancers have amplification and/or overexpression of the gene encoding the cell surface
receptor HER2. Assay for this molecular marker is warranted as a routine part of the
diagnostic work-up on all breast cancers, since HER2 overexpression is of major value in
treatment selection in these patients. (See "The HER2 oncogene" above).
Prognostic significance — The bulk of available evidence supports the view that HER2
overexpression is associated with a poor prognosis. (See "Prognostic value" above). It is
one of the factors used by the International Consensus Panel on the Treatment of
Primary Breast Cancer in assigning risk status for adjuvant chemotherapy
recommendations [136] . (See "Adjuvant chemotherapy and trastuzumab for early stage
breast cancer", section on Recommendations from major groups and see "Measurement
of prognostic factors in breast cancer", section on HER2 overexpression).
The value of this information in clinical practice is questionable, and guidelines from an
expert panel on tumor markers in breast cancer convened by the American Society of
Clinical Oncology (ASCO) recommended against the use of HER2 in assessing prognosis
[9] . Given the substantial benefit of adjuvant trastuzumab for patients with HER2overexpressing tumors, it is difficult to separate out the prognostic versus predictive
utility of HER2.
Identifying patients for trastuzumab
 For patients with metastatic breast cancer, as well as those with earlier stage
disease treated in the adjuvant setting, high levels of HER2 overexpression
serve to identify those patients who are most likely to benefit from therapy with
the anti-HER2 monoclonal antibody trastuzumab (Herceptin®). (See "Response
to therapies targeting HER2" above).
 The best method to select women for trastuzumab therapy is not clearly
established. Guidelines for HER2 testing from a joint consensus panel of ASCO
and the College of American Pathologists (CAP) are provided in table 1 (show
table 1) [10] .
Regardless of the method chosen, we recommend that the use of trastuzumab be
restricted to patients with high levels of HER2 protein overexpression (as determined by
3+ immunohistochemical staining [IHC]), or gene amplification (as determined by
positive fluorescence in situ hybridization [FISH]) (Grade 1A). (See "Selection of
patients for trastuzumab" above).
In keeping with joint ASCO/CAP guidelines, confirmatory FISH testing is recommended
for patients whose tumors are 2+ by IHC (show figure 1).
Choice of adjuvant chemotherapy
Patients whose tumors overexpress high levels of HER2 (as determined by 3+ IHC,
or positive FISH) appear to derive greater benefit from anthracycline-based
chemotherapy than from alkylating agent-based regimens such as CMF. In keeping
with ASCO guidelines, we preferentially recommend anthracycline-based therapy to
patients with HER2-overexpressing breast cancer in the adjuvant setting, unless
such therapy is contraindicated (eg, in women with underlying heart disease, or
women who received prior anthracycline therapy for a previous breast cancer)
(Grade 1B) [9] . However, it is reasonable to offer CMF to patients with HER2positive tumors if they have a contraindication to anthracycline, since, if resistance
exists, it is relative and not absolute.
We suggest that low levels or absent HER2 expression not be used to exclude patients
from anthracycline treatment (Grade 2B). (See "Anthracycline-based therapy" above).
 Whether HER2 overexpression is linked to taxane responsiveness is unclear. The
observation that women with node-positive, ER-positive, HER2-negative tumors
may not derive benefit from the addition of taxanes requires validation. Until
then, and in keeping with ASCO guidelines, we suggest that decisions regarding
the use of adjuvant taxanes be made without regard to HER2 overexpression
(Grade 2C) [9] . (See "Response to taxanes" above).
Choice of endocrine therapy
 Whether amplification and/or overexpression of HER2 is associated with a worse
response to endocrine therapy in general, or to any one type of endocrine
therapy is unclear; the clinical data are conflicting and inconclusive. Even if real,
the effect is incomplete. In keeping with ASCO guidelines, we recommend that
decisions regarding endocrine treatment in either the adjuvant or metastatic
setting be made without regard to HER2 status (Grade 1B) [9] . (See
"Response to endocrine therapy" above).