does er-βcx really have no clinical importance in tamoxifen-treated breast cancer patients? Does ER-βcx Really Have No Clinical Importance in Tamoxifen-Treated Breast Cancer Patients?

Does ER-βcx Really Have No Clinical Importance in Tamoxifen-Treated Breast Cancer Patients?

  1. Carlo Palmieri
  1. Department of Cancer Medicine, Imperial College London, Cancer Research UK Laboratories, London, United Kingdom
  1. Ondrej Gojis
  1. Department of Pathology, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic
  1. Susan Cleator
  1. Department of Cancer Medicine, Imperial College London, Cancer Research UK Laboratories, London, United Kingdom

To the Editor:

We read with interest the article by Honma et al1 on the utility of estrogen receptor β (ER-β) in breast cancer patients treated with adjuvant tamoxifen, but there are a number of issues we wish to raise with regard to the ER-βcx data that call into question the authors’ conclusion regarding its use. First, a 10% cutoff was used to determine positivity for ER-βcx; however this cutoff, although based on published data for ER-β1, is not the case for ER-βcx, and no evidence or data were provided to support or validate its use. Previous immunohistochemical studies of ER-βcx in breast cancer have used either (1) the Allred scoring system, in which samples were defined as being either negative (Allred score 0 to 1) or positive (Allred score 2 to 8)2 or has having low (Allred score 0 to 5) or high ER-βcx (Allred score 6 to 8) expression,3 or (2) a method in which the exact percentage of cells with nuclear staining was recorded, with staining of 30% or more taken as positive.4 Only one of these studies3 used the same antibody used by Honma et al,1 and within this study, the cutoff for ER-βcx was defined in a nonarbitrary manner, using a receiver operator curve analysis. It therefore appears that the decision to use a 10% cutoff was arbitrary and not based on any validated data. Given this, the subsequent results and interpretation with regard to ER-βcx have to be questioned, as others have clearly shown that determination of what constitutes positive or negative within the context of ERβ staining requires a well validated scoring system alongside correlation with defined clinical outcomes.5

Furthermore, given what is known about the molecular biology and function of ER-βcx, it is likely that a more detailed analysis of outcome in ERα-positive tamoxifen-treated patients would have been appropriate. It is known that ER-βcx preferentially forms heterodimers with ERα and ERS; whereas ERα is inhibited by ER-Scx, ER-S1 is unaffected. Therefore, ER-Scx dimerization with ERα negatively modulates its ligand-binding activity and acts as a dominant-negative inhibitor of ERα.6 It is therefore possible that the expression of ER-Scx could block estrogen-dependent signaling via ERα and potentially synergize with antiestrogens, such as tamoxifen, thus making endocrine therapy more effective. If this hypothesis is correct, expression of ERScx could be a useful biomarker in predicting benefit to tamoxifen. To date, all studies that have specifically investigated the possible role of ER-Scx in modulating response to tamoxifen have been small, and the results have been inconsistent. A study of 50 patients with tamoxifen-resistant tumors (n = 16) or tamoxifen-sensitive tumors (n = 34) reported the tamoxifen-sensitive group to have a higher positivity for ER-Scx.4 A study of 23 patients with assessable disease found ER-Scx expression to be significantly associated with a response to endocrine therapy and with longer survival.7 In 56 patients given adjuvant tamoxifen alone, high ER-Scx mRNA levels were significantly associated with an improvement in overall survival.8 High ER-Scx mRNA levels, but not protein levels, were independently predictive of outcome in 85 patients treated with adjuvant tamoxifen,3 and a neoadjuvant study of 18 women found ER-Scx to be associated with a poor clinical response to tamoxifen.2 Therefore, further work is needed to determine the potential role, if any, of ER-Scx as a biomarker in endocrine therapy.

In light of these issues, it would appear essential that the ERScx immunostaining in the ERα-positive patients exposed to tamoxifen be rescored using the Allred method and that a receiver operator characteristic curve analysis be performed to select a clinically relevant cutoff.9 The data could then be used to address the utility of ER-Scx in determining sensitivity or resistance to tamoxifen therapy.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

Footnotes

  • published online ahead of print at www.jco.org on November 10, 2008.

REFERENCES

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