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Other Guidelines
Guidelines on endocrine therapy of breast cancer
1. Rationale
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Many endocrine agents have been designed to interfere with oestrogen action, an
event that is critically dependent upon the presence of ER. Not surprisingly,
therefore, pre-clinical studies overwhelmingly show that the major growth
inhibitory effects of such agents occur specifically within ER-positive breast
cancer cell lines in both in vitro and in vivo model systems.
Moreover, clinical studies in advanced disease demonstrate that the benefits
associated with many forms of endocrine therapy are primarily restricted to
ER-positive patients, with only 5-10% of women with ER-negative disease being
responsive. Similarly, in the adjuvant setting, only ER-positive patients
benefited, with no significant effect in ER-poor or -negative disease
[1].
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With regard to the most appropriate lower cut-off point to define ER status for
each of the assay types, values of 10 an 20 fmol/mg protein are generally
recommended for the ligand binding- and enzyme immuno-assays, respectively
[2]. In reporting the results of immunohistochemistry,simple scoring
systems have been shown to work best
[3]
[4]
[5]. These are based on either a direct count of the proportion of
epithelial nuclei that take up the stain or a simple combination of the
proportion of cells staining plus a measure of intensity of stain (H-score).
Lower cut-off points to define ER status by immunohistochemistry, equivalent to
approximately 10% of cells positive, have been widely used.
Upper cut-off values (higher ER values enrich for endocrine response predicting
response rates of 75% or more) are generally set at ER values of >100
fmol/mg protein for the ligand binding- and enzyme immuno-assays and 30-100%
ER-positive epithelial nuclei with intense immuno-staining for the
immuno-histochemical assay or an H-score of 100 out of 300.
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Although ER status is the single best predictor of endocrine responsive and
unresponsive tumours, high Progesterone Receptor (PgR) levels in an ER-negative
tumour may indicate a chance of endocrine response. However, a negative PgR
measurement alone is not informative, approximately 30% of
ER-positive-PgR-negative tumours will respond to first-line endocrine
therapy
[6].
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ER negativity is highly predictive of endocrine non-responsiveness. However,
the relationship between ER-positivity and response is not perfect and even
high ER-positive tumours fail to respond in approximately 25% of cases.
Several other biological factors have been suggested to be associated with
endocrine response, e. g. protein expression may be induced by oestrogens, such
as pS2
[7][8]
or correlation with endocrine failure; e.g. positive growth factor receptors
epidermal growth factor (EGF)-receptor, c-erbB-2
[9]
[10]
[11]. None has found its way into routine clinical practice since
their predictive value does not add to ER in multivariate analysis. Thus
EGF-receptor and c-erbB-2-positive tumours are mainly ER-negative and
pS2-positive tumours are invariably ER-positive. Additionally,
well-differentiated tumours, which are also more likely to be ER-positive, are
associated with increased response to endocrine therapies, as are those with
low proliferative indices. These additional factors are not routinely employed
to select patients for endocrine measures.
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Any assay that is used in a clinical setting must have a good quality assurance
(QA) programme associate with it.
Excellent QA schemes for the ER and PgR ligand binding- and enzyme
immuno-assays were set up in the 1980s in Europe
[12] and are still running today. For immunohistochemical methods, the
UK-based NEQAS-ICC (Scheme organisers, K. Miller and T. Rhodes, Department of
Histopathology, University College London Medical School, London WC2E
6JJ, UK) has over 150 participating laboratories and is designed to provide
unstained breast cancer sections of known ER content that are then assayed by
the participating laboratories. Such slides are subject to review by an expert
panel to ensure acceptable staining of ER
[3]. EUSOMA recommends the adoption of this QA scheme in those
European laboratories undertaking the routine assessment of steroid hormone
receptors in breast cancer specimens.
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In advanced disease, the primary tumour is usually the sole source of material
for the assessment of the ER status.
At least 80% of tumours retain their receptor status from primary to metastatic
disease
[13]. However, if metastatic tissue is easily available and of suitable
quality, additional assay should be performed before commencing endocrine
therapy
[14].
| Quality objective |
Outcome measure
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To identify those patients who are likely to benefit/fail to benefit from
endocrine therapy. |
An ER assay must be performed in every case on the primary tumour
tissue, prior to decisions regarding systemic therapy.
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Whilst all the above assays are amenable to routine use, immunohistochemical
assays allow direct correlation with routine histology to be made.
| Quality objective |
Outcome measure
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To standardise the assessment of ER across Europe and facilitate QA.
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Laboratories that are newly-establishing ER assays should use an
immunohistochemistry method.
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To provide the best information for clinical use.
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1. All primary breast cancers must be assaye for ER using a ligand binding
procedure, an enzyme immunoassay or an immunohistochemical assay (see above).
2. Upper an lower cut-off points must be assigned to each of the ER assays that
will allow sub-groups of patients to be identified at high and low probability
of obtaining a response to endocrine therapy (see below).
3. Additional PgR assays should be performed in order to identify those
tumours, which are ER-low or negative, yet may be responsive to endocrine
measures.
4. ER and PgR assays must only be performed by laboratories working within
internal and external quality assessment schemes, in which the consistency and
quality of receptor measurements is assured.
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