Originally published as JCO Early Release 10.1200/JCO.2008.19.5529 on November 10 2008

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Palmieri, C. Articles by Cleator, S. Search for Related Content PubMed PubMed Citation Articles by Palmieri, C. Articles by Cleator, S. Social Bookmarking                            What's this?

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

Carlo Palmieri

Department of Cancer Medicine, Imperial College London, Cancer Research UK Laboratories, London, United Kingdom

Ondrej Gojis

Department of Pathology, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic

Bharath Rudraraju, Susan Cleator

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 ER-positive tamoxifen-treated patients would have been appropriate. It is known that ER-βcx preferentially forms heterodimers with ER and ERS; whereas ER is inhibited by ER-Scx, ER-S1 is unaffected. Therefore, ER-Scx dimerization with ER negatively modulates its ligand-binding activity and acts as a dominant-negative inhibitor of ER.⁶ It is therefore possible that the expression of ER-Scx could block estrogen-dependent signaling via ER 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 ER-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.

NOTES

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

REFERENCES

1. Honma N, Horii R, Iwase T, et al: Clinical importance of estrogen receptor-β evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol 28:3727-3734, 2008

2. Saji S, Omoto Y, Shimizu C, et al: Expression of estrogen receptor (ER) betacx protein in ERalpha-positive breast cancer: Specific correlation with progesterone receptor. Cancer Res 62:4849-4853, 2002[Abstract/Free Full Text]

3. Vinayagam R, Sibson DR, Holcombe C, et al: Association of oestrogen receptor beta 2 (ER beta 2/ER beta cx) with outcome of adjuvant endocrine treatment for primary breast cancer: A retrospective study. BMC Cancer 7:131, 2007[CrossRef][Medline]

4. Esslimani-Sahla M, Simony-Lafontaine J, Kramar A, et al: Estrogen receptor beta (ERbeta) level but not its ERbetacx variant helps to predict tamoxifen resistance in breast cancer. Clin Cancer Res 10:5769-5776, 2004[Abstract/Free Full Text]

5. Carder PJ, Murphy PJ, Dervan P, et al: A multi-centre investigation towards reaching a consensus on the immunohistochemical detection of ERbeta in archival formalin-fixed paraffin embedded human breast tissue. Breast Cancer Res Treat 92:287-293, 2005[CrossRef][Medline]

6. Ogawa S, Inoue S, Watanabe T, et al: Molecular cloning and characterization of human estrogen receptor betacx: A potential inhibitor of oestrogen action in human. Nucleic Acids Res 26:3505-3512, 1998[Abstract/Free Full Text]

7. Palmieri C, Lam EW, Mansi J, et al: The expression of ER beta cx in human breast cancer and the relationship to endocrine therapy and survival. Clin Cancer Res 10:2421-2428, 2004[Abstract/Free Full Text]

8. Davies MP, O’Neill PA, Innes H, et al: Correlation of mRNA for oestrogen receptor beta splice variants ERbeta1, ERbeta2/ERbetacx and ERbeta5 with outcome in endocrine-treated breast cancer. J Mol Endocrinol 33:773-782, 2004[Abstract/Free Full Text]

9. Hanley J: Receiver operating characteristic (ROC) methodology: The state of the art. Critical Rev Diagn Imagin 29:307-337, 1989

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Palmieri, C. Articles by Cleator, S. Search for Related Content PubMed PubMed Citation Articles by Palmieri, C. Articles by Cleator, S. Social Bookmarking                            What's this?