Abstract
Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERalpha)-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen. We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors. ERbeta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERalpha-negative patients (P = 0.003; P = 0.04), but not in the ERalpha-positive subgroup (P = 0.49; P = 0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature. Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the United States alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen.
Highlights
Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERa) ^ positive breast carcinoma but are not indicated for persons with ERa-negative cancer
ERa positivity was associated with several clinical variables such as increasing age (P = 0.003), postmenopausal status (P = 0.007), a greater number of lymph nodes with metastases (P = 0.006), progesterone receptor (PgR) positivity (P < 0.001), a low S-phase fraction (P < 0.001), and nonamplified ERBB2 (P < 0.001), ERh expression did not correlate significantly with any of the clinical variables tested (Table 1)
In agreement with the results from the Kaplan-Meier analysis, we found that ERa positivity was a significant independent predictive marker for improved distant disease-free survival only within the ERhÀ group (HR, 0.44; 95% CI, 0.21-0.89; P = 0.02), whereas no significant effect was seen in the other two subgroups (ERh+: hazard ratio (HR), 0.86; 95% CI, 0.45-1.7; P = 0.70; ERh++: HR, 5.2; 95% CI, 0.67-40; P = 0.12)
Summary
Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERa) ^ positive breast carcinoma but are not indicated for persons with ERa-negative cancer. Estrogens play an important role for the development and progression of breast carcinoma Their effects on growth and proliferation are mediated through the two estrogen receptors (ER) a and h (1 – 3), which function as transcription factors and modulate the expression of target genes in response to estrogens. But differ considerably in the NH2-terminal activation function 1 region, where interactions with other proteins in the transcriptional machinery takes place, and to a certain degree in the ligand-binding region [9], indicating that these receptors may share some similar functions but may not be entirely redundant. ERa and ERh can exist as a heterodimer (11 – 13), suggesting a possible role for ERh as a modulator of ERa activity
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