- © 2008 by American Society of Clinical Oncology
Does ER-βcx Really Have No Clinical Importance in Tamoxifen-Treated Breast Cancer Patients?
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
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published online ahead of print at www.jco.org on November 10, 2008.