Originally published as JCO Early Release 10.1200/JCO.2008.19.6212 on November 10 2008

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In Reply

Naoko Honma

Research Team for Geriatric Diseases, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan and Department of Breast Pathology, Cancer Institute, Tokyo, Japan

Shigehira Saji

Division of Clinical Trials and Research, Department of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

Mamoun Younes

Department of Pathology, Baylor College of Medicine, Houston, TX

We thank Dr. Palmieri, Dr. Speirs, and their colleagues for their interest in our recent article¹ and for the thoughtful comments, which we are happy to address.

We have already scored all of our immunostaining according to the Allred method, but we elected to use 10% as the cutoff in the final analysis because this is the most commonly used cutoff value for both estrogen receptor- (ER-; classic ER) and ER-β.¹ In response to the comments by Palmieri et al, we have reanalyzed our data as suggested. Receiver operating characteristics analysis identified an Allred score of 5 or more as the most suitable cutoff value for ER-βcx (or ER-β2) positivity in the present study setting. According to this new cutoff value, the log-rank test for survival difference by ER-βcx status was P = .025 and P = .113 for disease-free survival (DFS) and overall survival (OS), respectively. This is similar to our results with the 10% cutoff (P = .030 and P = .038 for DFS and OS, respectively).¹ ER-βcx positivity seemed to be associated with a favorable clinical outcome when ER-βcx was the only factor examined; however, when ER-β1 status and ER-βN status were also taken into consideration, Bonferroni adjustment had to be performed, and the difference in clinical outcome according to ER-βcx status became nonsignificant. When multivariate analysis for recurrence or mortality was performed, taking into consideration the status of ER-βcx, ER-β1, and ER-βN, ER-β1 emerged as the only independent predictor of clinical outcome, suggesting that ER-β1 has the most predictive power. In addition, unlike ER-β1, ER-βcx was not an independent predictor of clinical outcome (P = .100 and P = .367 for recurrence and mortality, respectively) in multivariate analysis that included tumor size, nodal status, grade, human epidermal growth factor 2 status, ER- status, and progesterone receptor status.

On the basis of the comments by Palmieri et al, we have repeated survival analysis according to ER-βcx status, using the new cutoff value for patients with ER-–positive tumors who received adjuvant tamoxifen monotherapy. The clinical outcome of these patients did not differ by ER-βcx status (P = .226 and P = .516 for DFS and OS, respectively). Because both tamoxifen and ER-βcx inhibit the function of ER-,² the effect of ER-βcx on clinical outcome may have been obscured by tamoxifen. The dominant negative effect of ER-βcx against ER- suggested by a molecular biology study² may be clearly demonstrated in patients who did not receive adjuvant tamoxifen. A similar study restricted to tamoxifen-untreated patients will help to reveal the role of ER-βcx in clinical breast cancers.

Contrary to the results of the study by Shaaban et al,³ ER-β1 nuclear positivity by itself was significantly associated with a favorable clinical outcome irrespective of the cutoff value (Allred score 3, 4, 5, and 6) in our study setting. Using appropriate statistical methods, we did not find the predictive value of ER-βcx for clinical outcome in tamoxifen-treated patients suggested by Shaaban et al,³ as shown above. We were also interested in the cytoplasmic staining of ER-βs and have already evaluated it according to the Allred method, although the data were not included in our article. Unlike Shaaban et al,³ we found that cytoplasmic staining of ER-βcx was not associated with clinical outcome, irrespective of the cutoff value.

It is difficult to properly compare our results with those of Shaaban et al,³ because of the different study settings. First, regarding patient treatment, all patients in our study received adjuvant tamoxifen monotherapy, whereas the patients in the study by Shaaban et al.³ were "unselected" and probably included hormone receptor-positive patients who did or did not receive adjuvant endocrine treatment and patients who received adjuvant chemotherapy. Second, there are many methodological differences in immunohistochemistry: sections examined (tissue microarrays in the Shaaban et al study ³ v representative slides in ours¹), concentration of the primary antibody, incubation time and temperature, cutoff value, and so on. Given these important differences, it is not surprising that Shaaban et al reached a different conclusion. We agree that ethnic differences may influence which ER-β isotypes are frequently expressed in breast cancers, leading to different patient survival.

In conclusion, the finding of our study regarding the clinical significance of ER-βcx expression did not change, even after we used a new cutoff value, as recommended by Palmieri et al, or after we took cytoplasmic staining into consideration, as recommended by Speirs et al. ER-βcx nuclear status had no significant difference on clinical outcome in patients with ER--positive tumors treated with adjuvant tamoxifen monotherapy. A large systematic study using archival material and uniform immunostaining and evaluation methods for patients from different ethnic groups with predefined adjuvant treatments is needed to confirm the clinical importance of ER-β expression in breast cancer.

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 26:3727-3734, 2008[Abstract/Free Full Text]

2. 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]

3. Shaaban AM, Green AR, Karthik S, et al: Nuclear and cytoplasmic expression of ERβ1, ERβ2, and ERβ5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 14:5228-5235, 2008[Abstract/Free Full Text]

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