Estrogen receptor measurement in dcis – current status and future directions
OESTROGEN RECEPTOR ASSESSMENT IN DUCTAL CARCINOMA IN SITU Introduction
The response of invasive breast cancer to endocrine therapy is well recognised as being
related to the hormone receptor status of the tumour. 1 It is therefore logical to investigate
the role of hormone receptors in determining the role of endocrine therapy in the
management of ductal carcinoma in situ (DCIS). However, to date, there remain issues
with regard to the latter and with the assessment of hormone receptors. Evidence from Clinical Trials
The value of tamoxifen in the management of DCIS has been reported in two randomized
1. The NSABP B-24 trial of the use of tamoxifen and radiotherapy in DCIS showed a
benefit from endocrine therapy, primarily due to a reduction of ipsilateral recurrent
invasive carcinomaThe 7-year risk of local recurrence in the treated breast after
lumpectomy plus radiation was reduced from 11·1% without tamoxifen to 7·7% with
tamoxifen (P= 0·02). The risk of all breast cancer events (ipsilateral plus contralateral)
was reduced from 16·9% to 10·0% (P = 0·0003). Allred and colleagues retrospectively
reviewed 628 cases from this trial and demonstrated that the benefit was confined to
those patients whose tumours were Oestrogen Receptor (ER) positive; this was defined as
10% or more cells staini However, it is not clear whether there was a difference in
ipsilateral and /or contralateral recurrence with regard to ER status of the primary disease
process, as the data are available in abstract form only. It is also not clear how this 10%
figure was reached and in particular whether modelling was carried out to determine a
cut-off value or range that best correlated with therapeutic benefit. The review included a
mixture of both locally reported ER and central assays and concern was raised about
possible false negative results from laboratories using diverse non-standardised assays.
With the exception of the abstract referred to above the study has not been published.
2. The UK/ANZ (UKCCCR) Triacomparing radiotherapy and tamoxifen in the
treatment of DCIS showed after 53 months follow up a non-significant reduction of all
breast events with the addition of tamoxifen but a relative risk reduction of 22%. It
should be noted that the follow up period in the UK/ANZ trial at the time of reporting
was shorter than NSABP B-24 (4·4 years v 6·9 years) and receptor status of the DCIS
was not measured prospectively in this trial. In addition, a high proportion of cases were
of high cytonuclear grade; a relatively high proportion are therefore likely to be ER
negative which will have influenced the affect of hormone treatment in this series (SE
A further study, the NSABP-P1 trial of Tamoxifen for prevention of breast cancer,
studied 13,000 “at risk” wome This cohort did not include patients with DCIS but
illustrates the potential benefit of endocrine therapy in the prevention of breast cancer
events. Invasive and non-invasive carcinomas were reduced by 50% at 69 months follow
up. There was a three fold increase in thrombo-embolic events, a marginal increase of
cataracts and a non-significant increase of strokes.
Current guidance and options
A cut off point for positive versus negative for ER in DCIS was set at <5% cells staining
as an entry criterion for two UK clinical trials of endocrine therapy in DCIS (IBISII and
DCISII, the latter discontinued). The UK breast screening guidelines 6 recommend the
use <5% cells staining for DCIS, and the use of the Allred score for invasive cancers. A
cut-off of Allred score 3 has been used in a large study of pure DCIS examining the
distribution of various different phenotypeand is the same as is applied to invasive
It would be illogical to adopt a different scoring system from those already in use for
invasive disease unless sound evidence to the contrary emerged. Furthermore, there is
strong evidence that the ER status of invasive breast cancer parallels that of associated
DCIS in individual casesIndividual practitioners benefit from a familiarity with a
particular scoring technique and clinical colleagues require consistency in approach to
reporting. The three scoring methods currently in use worldwide are: 1) a simple
percentage of cells staining without reference to intensity; 2) the Histochemical “H”
“score” which is the sum of the percentage of cells with three levels of staining, giving a
range of 0-300 3) Allred scoring (replacing previous “Quick Score”) which is the sum
of an intensity score of 1 -3 and the percentage of cells staining banded in a non-linear
fashion using a score of 1 -5 giving a final score between 2 a
Allred scoring and the histochemical score provide similar information about receptor
status as both include an assessment of intensity as well as percentage of cell nuclei
staining. Simple percentage scoring gives no information about staining intensity
although low proportion scores tend to go hand in hand with low intensity scoring with
ER scoring, as opposed to progesterone receptor (PGR) immunoreactivity.
There is no evidence base to support a preference for a particular scoring technique.
However, there is evidence for assessment of proportion and intensity staining in invasive
breast cancer, and as such evaluation is routine practice, it would be logical to mirror this
practice in the reporting of DCIS. Evidence from the Sloane Project, a UK audit of
screen-detected DCIS and atypical hyperplasias of the breast, points to considerable
confusion in this area amongst pathologists in their reporting practice of ER status in
DCIS. A wide variation is seen between and within laboratories not only of the scoring
method used but also of the cut off point for positive versus negative results. In that audit
40% of reporting laboratories used one method and the same cut off criterion throughout,
19% used one method but different cut off criteria for different cases. However 15% of
laboratories used two methods for different cases with equivalent cut off points for each
method while 25% of laboratories used two methods and non-equivalent cut off points
Because there is such uncertainty about what cut off is therapeutically relevant (if any) in
the pharmacological management of DCIS and possibly as a more general prognostic
marker for this disease process, it would be sensible to record the percentage of cells
staining and the average intensity in the duct profiles available and correlate this
Patterns of ER expression in DCIS
From the data gathered by the Sloane Project, intermediate and low grade DCIS are
almost invariably ER positive whereas high grade DCIS is positive in 69% of cases
Baqai and Shousha reviewed 60 cases of DCIS, 56 pure and 4 with associated
microinvasion. DCIS was assessed in terms of grade, architecture and, amongst other
things, ER positivity was defined as disease with >10% of cells showing dark brown
nuclear staining (Allred score >4, Histoscore >20). The grade distribution seen was 52%
high, 38% intermediate and 10% low, which is very similar to the distribution among the
Sloane Project cases. 12 There was a strong association between ER negativity and high
nuclear grade. The number of cases in this study was small and the cut off point was set
relatively high. It is a pity that the opportunity to model different cut off points against
Ottesen et al 13 in a series of 133 cases of DCIS showed that one third displayed 5% or
less staining for ER the overwhelming majority of which were of large nuclear size. In
this series, perhaps unusually, most cases were either strongly positive or negative.
Basal phenotype DCIS, seen in approximately 6% of high grade lesions, is commonly
It is likely that the IBIS II trial will give invaluable information about the validity of
setting a positive/negative cut off point at 5 or 10% for ER. Obviously there will be
limited information about the relevance of staining intensity unless Allred scores are used
and these are not obligatory. The Sloane Project, given its long term goals of prolonged
follow up of DCIS patients, will also provide information about a range of cut off points
because of the variability that has already been demonstrated in the first cohort of patients
reviewed.11 Because data are not available to give guidance on the clinical relevance of
different proportion and intensity scores it is recommended as a minimum to record both
when reporting the hormone receptor status of DCIS. This will enable Histoscores and/or
Allred scores to be derived without loss of the original scoring information.
There remains considerable scope for modeling ER cut off points in DCIS against clinical
outcomes in large cohorts of patients but until such time as that is possible seems
reasonable to apply the limited evidence available at the present time and use the
currently accepted cut off points to guide the endocrine management of patients with
DCIS as for reporting ER status in invasive breast cancer
Key points and Recommendations
• > 80% of DCIS is ER positive and there is a body of evidence indicating a
therapeutic benefit for endocrine treatment in selected ER positive patients.
• Previously a cut off point of 5% of cells staining has been recommended to define
positive and negative. It is recommended that both proportion of cells staining and
Fisher B, Dignam J, Wolmark, N et al. Tamoxifen in treatment of intraductal breast cancer:
National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999, 353:1993-2000.
2 Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: An update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol28:400-418, 2001 3 Allred DC, Bryant J, Land S et al. Estrogen receptor expression as a predictive marker of the
effectiveness of tamoxifen in the treatment of DCIS: Findings from the NSABP Protocol B-24. (Abstract 30) Breast Can Res Treat 2002; 76: S36.
4 Houghton J, George WD, Cusick J, Duggan C, Fentiman IS, Spittle M. Radiotherapy and
tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia and New Zealand: randomised controlled trial. Lancet 2003; 362:95-192.
5 Fisher B, Constantino JP, Wickerham L et al. Tamoxifen for prevention of breast cancer: report
of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998, 90: 1371-1388.
6 Pathology Reporting of Breast Disease. NHS Breast Screening Programme Publication No 58.
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7 Livasy CA, Perou CM, Karaca G et al. Identification of a basal-like subtype of breast ductal carcinoma in situ. Human Pathology. 2007; 38: 197-204 8 Leong A S-Y, Sormunen RT, Vinyuvat S, Hamdani RW, Suthipintawong C. Biologic markers
in ductal carcinoma in situ and concurrent infiltrating carcinoma. A comparison of eight contemporary grading systems. Am J Clin Pathol. 2001; 115:709-18
9 McCarty KS Jr, Szabo E, Flowers JL et al. Use of a monoclonal anti-estrogen receptor antibody
in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46 (8 Suppl):4244s-4248s.
10 Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by
immunohistochemistry is superior to the ligand binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474-1481.
11 Thomas JSJ, Hanby AM, Pinder SE, Ellis IO, Macartney JC, Clements K, Lawrence GM and
Bishop HM on behalf of the Sloane Project Steering Group. Implications of inconsistent measurement of ER status in non-invasive breast cancer: a study of 1684 cases from the Sloane Project. The Breast Journal. 2008; 14: 31-36
12 Baqai T, Sousha S. Oestrogen receptor negativity as a marker for high grade ductal carcinoma
in situ of the breast. Histopathology 2003; 42: 440-447.
13 Otteson GL, Christesen IJ, Larsen JK et al. Carcinoma in situ of the breast: correlation of
hstopathology to immunohstochemical markers and DNA ploidy. Br Can Res Treat. 2000; 60: 219–226.
14 Bryan BB, Schnitt SJ, Collins LC. Ductal carcinoma in situ with basal-like phenotype: a
possible precursor to invasive basal-like breast cancer. Mod Pathol. 2006;19:617-21.
15 Dabbs DJ, Chivukula M, Carter G, Bhargava R. Basal phenotype of ductal carcinoma in situ:
recognition and immunohistologic profile. Mod Pathol. 2006;19:1506-11. Grade of DCIS and ER status – Sloane Project data based on 1684 cases
High (%) Intermediate (%) Low (%) Unknown (%) (%)
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