Estrogen Receptor and Progesterone Receptor As Predictive Biomarkers of Response to Endocrine Therapy: A Prospectively Powered Pathology Study in the Tamoxifen and Exemestane Adjuvant Multinational Trial

Abstract

A B S T R A C T PurposeThe Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. Patients and MethodsPathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. ResultsOf 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred Ͻ 4) and 77% were PgRrich (Allred Ն 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P ϭ .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P Ͻ .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P ϭ .002), and multivariate analyses (P Ͻ .001 and P ϭ .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. ConclusionPreferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment. Oncol 29:1531Oncol 29: -1538 J Clin

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

“…Most studies analyzing predictive or prognostic factors in ER-positive breast cancer have been performed in postmenopausal women, mainly using patients and samples in adjuvant aromatase inhibitor trials [3,4,23]. In premenopausal women, however, even the clinical role of PgR has been little analyzed so far.…”

“…Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer [1][2][3][4]. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine [5].…”

“…It was reported that quantitative analysis of ER and PgR expression provided highly significant information on risk of early relapse in postmenopausal patients in the Tamoxifen and Exemestane Adjuvant Multinational trial [4]. It has been demonstrated that ER-positive, PgR-negative tumors are a distinct subset of breast cancers characterized by aggressive behavior and tamoxifen resistance [6].…”

Prognostic impact of progesterone receptor status combined with body mass index in breast cancer patients treated with adjuvant aromatase inhibitor

“…A number of studies have investigated tumor biomarkers that indicated differential benefit from aromatase inhibitors versus tamoxifen in patients with early breast cancer (4)(5)(6). Such biomarkers included the conventional factors, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2) and Ki-67, and did not identify patients who derived a differential relative benefit from aromatase inhibitors over tamoxifen.…”

Reply to ‘Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance'

“…We agree that different treatment may account for different outcome, as shown in the study by Bartlett et al 5 For survival analysis, they used TEAM (Tamoxifen vs Exemestane adjuvant Multicentre) pathology study composed of estrogen receptor-positive early breast cancers, treated with adjuvant endocrine therapy (exemestane versus tamoxifen), but not with chemotherapy. 6 However, tumors with heterogeneous HER2 amplification cannot be equated with those with borderline/low HER2 amplification. Although HER2 genetic and regional heterogeneity was more common in tumors with equivocal/low-grade amplification, they were found in 23 and 38% of tumors with equivocal/lowgrade amplification in our study.…”