A high level of estrogen-stimulated proteins selects breast cancer patients treated with adjuvant endocrine therapy with good prognosis

Abstract

Background: Adjuvant endocrine therapy has significantly improved survival of estrogen receptor α (ER)-positive breast cancer patients, but around 20% relapse within 10 years. High expression of ER-stimulated proteins like progesterone receptor (PR), Bcl-2 and insulin-like growth factor receptor I (IGF-IR) is a marker for estrogen-driven cell growth. Therefore, patients with high tumor levels of these proteins may have particularly good prognosis following adjuvant endocrine therapy.

Patients and methods: Archival tumor tissue was available from 1323 of 1396 Danish breast cancer patients enrolled in BIG 1-98, a randomized phase-III clinical trial comparing adjuvant letrozole, tamoxifen or a sequence of the two drugs. Immunohistochemical staining for ER, HER-2, PR, Bcl-2 and IGF-IR was performed and determined by Allred scoring (ER, PR and Bcl-2) or HercepTest (HER-2 and IGF-IR).

Results: Data on all five markers were available from 969 patients with ER-positive, HER-2-negative tumors. These patients were classified in ER activity groups based on the level of PR, Bcl-2 and IGF-IR. High ER activity profile was found in 102 patients (10.5%) and compared with the remaining patients, univariate and multivariate analysis revealed HR (95% CI) and p values for disease-free survival (DFS) of 2.00 (1.20–3.22), 0.008 and 1.70 (1.01–2.84), 0.04 and for the overall survival (OS) of 2.33 (1.19–4.57), 0.01 and 1.90 (0.97–3.79), 0.06, respectively. The high ER activity profile did not disclose difference in DFS or OS according to treatment with tamoxifen or letrozole (p = .06 and .09, respectively).

Conclusions: Stratifying endocrine-treated patients in ER activity profile groups disclosed that patient with high ER activity profile (10.5%) had significantly longer DFS and OS, and the profile was an independent marker for DFS. High ER activity is a marker for estrogen-driven tumor growth. We suggest further analyses to disclose whether the ER activity profile or other markers associated with estrogen-driven growth may be used to identify ER-positive high-risk breast cancer patients who can be spared adjuvant chemotherapy.

Acknowledgments

Annegrethe Schaadt and Vinni Bredahl are acknowledged for technical assistance. We kindly acknowledge the participating Danish Pathology Departments for supplying paraffin-embedded tumor material: Aalborg Syghus, Aarhus Hospital, Bispebjerg Hospital, Esbjerg Sygehus, Gentofte Hospital, Herlev Hospital, Hillerød Hospital, Hjørring Sygehus, Holstebro Sygehus, Hvidovre Hospital, Nykøbing Falster sygehus, Næstved Sygehus, Odense Hospital, Randers Sygehus, Rigshospitalet, Roskilde Sygehus, Skive Sygehus, Slagelse Sygehus, Svendborg Sygehus, Sønderborg Sygehus, Vejle Sygehus and Viborg Sygehus. We thank the International Breast Cancer Study Group for providing data on the Danish patients enrolled in the BIG 1-98 trial.

Disclosure statement

No potential conflict of interest was reported by the authors.