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

Purpose: The 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 methods: Pathology 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.

Results: Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred < 4) and 77% were PgR- rich (Allred ≥ 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 = .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 < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed.

Conclusion: Preferential 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.

Fig 1.

Progesterone receptor (PgR) as a prognostic marker of disease-free survival by (A) Allred score (≤ 4 v ≥ 5) and (B) quantitative PgR expression plotted versus log hazard ratios (HRs); gray line represents PgR histoscore versus hazad ratio; blue lines represent 95% CI of estimate. T, tamoxifen; E, exemestane. (*) Per 50-unit increase in PgR.

Fig 2.

Progesterone receptor (PgR) is not predictive of exemestane (E) versus tamoxifen (T) benefit. (A) Hazard ratio (HR) by Allred score (≤ 4 [PgR poor] v ≥ 5 [PgR rich]); (B) exemestane versus tamoxifen in PgR-poor, and (C) PgR-rich tumors. (*) Test for interaction by PgR staining.

Fig 3.

Estrogen receptor (ER) as a prognostic disease-free survival marker by (A) Allred score (≤ 6 v ≥ 7) and (B) quantitative ER expression plotted against log hazard ratios (HRs); gray line represents ER histoscore versus hazard ratio; blue lines represent 95% CI of estimate. T, tamoxifen; E, exemestane. (*) Per 50-unit increase in ER.

Fig 4.

Estrogen receptor (ER) as a predictive marker for exemestane (E) versus tamoxifen (T) treatment. (A) Hazard ratio (HR) by histoscore (≤ 190 [ER-poor tumors] v > 190 [ER-rich tumors]); (B) exemestane versus tamoxifen in ER-poor and (C) ER-rich tumors. (*) Test for interaction by ER staining.

Fig 5.

Risk score is prognostic for disease-free survival and predicts greater benefit from exemestane in patients with a higher risk score. NNT, number needed to treat.