Research article

Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy

Silvia Darb-Esfahani¹ , Sibylle Loibl² , Berit M Müller¹ , Marc Roller² , Carsten Denkert¹ , Martina Komor² , Karsten Schlüns¹ , Jens Uwe Blohmer³ , Jan Budczies¹ , Bernd Gerber⁴ , Aurelia Noske¹ , Andreas du Bois⁵ , Wilko Weichert¹ , Christian Jackisch⁶ , Manfred Dietel¹ , Klaus Richter⁷ , Manfred Kaufmann⁸ and Gunter von Minckwitz²

¹  Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

²  GBG Forschungs GmbH, Schleussnerstrasse 42, Neu-Isenburg, 63263, Germany

³  Department of Obstetrics and Gynecology, St. Gertrauden Hospital, Paretzer Str. 12, Berlin, 10713, Germany

⁴  Department of Obstetrics and Gynecology, Klinikum Südstadt, Südring 81, Rostock, 18059, Germany

⁵  Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Hospital (HSK), Ludwig-Erhard-Str. 100, Wiesbaden, 65199, Germany

⁶  Department of Obstetrics and Gynecology, Klinikum Offenbach, Starkenburgring 66, Offenbach am Main, 63069, Germany

⁷  Institute of Pathology, Berliner Allee 48, Hannover, 30175, Germany

⁸  Department of Obstetrics and Gynecology, Klinikum der Johann Wolofgang Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, Germany

author email corresponding author email

Breast Cancer Research 2009, 11:R69doi:10.1186/bcr2363

Published:	16 September 2009

Abstract

Introduction

Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.

Methods

Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.

Results

pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).

Conclusions

Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.

Trial registration

ClinicalTrials.gov identifier: NCT00793377