Estrogen receptor measurement in dcis – current status and future directions

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 Future directions
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 References
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Grade of DCIS and ER status – Sloane Project data based on 1684 cases
High (%) Intermediate (%) Low (%) Unknown (%) (%)


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