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-Esfahani, Sibylle Loibl, Berit M Müller, Marc Roller, Carsten Denkert, Martina Komor, Karsten Schlüns, Jens Uwe Blohmer, Jan Budczies, Bernd Gerber, Aurelia Noske, Andreas du Bois, Wilko Weichert, Christian Jackisch, Manfred Dietel, Klaus Richter, Manfred Kaufmann, Gunter von Minckwitz, Silvia Darb-Esfahani, Sibylle Loibl, Berit M Müller, Marc Roller, Carsten Denkert, Martina Komor, Karsten Schlüns, Jens Uwe Blohmer, Jan Budczies, Bernd Gerber, Aurelia Noske, Andreas du Bois, Wilko Weichert, Christian Jackisch, Manfred Dietel, Klaus Richter, Manfred Kaufmann, Gunter von Minckwitz

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 NCT00793377.

Figures

Figure 1
Figure 1
(a) Strong expression of ER in a ductal-invasive breast carcinoma. (b) Strong expression of PgR in a moderately differentiated breast carcinoma. (c) Complete membranous expression of HER2 in a high-grade breast carcinoma (3+). (d) Silver-enhanced in situ hybridization (SISH): multiple Her2 gene copies (black dots) in tumor cell nuclei of a Her2-amplified breast carcinoma. (e) Nuclear expression of Ki67 in a poorly differentiated breast carcinoma. (f) Focal perimembranous expression of CK5/6 in a high grade tumor. (g) Moderate cytoplasmic expression of COX-2 in a ductal-invasive breast carcinoma. (h) Diffuse cytoplasmic expression of YB-1 in invasive breast cancer nests.
Figure 2
Figure 2
Rate of patients achieving a pCR in dependence of biology-based tumor type (p: likelihood ratio test), Ki67 labeling index, CK5/6 expression, grading, and pre-operative chemotherapy. p: logistic regression.
Figure 3
Figure 3
(a) Kaplan-Meier curve indicating disease-free survival times of patients in dependence of breast cancer subclassification. (b) Disease-free survival of patients who did not achieve a pCR in dependence of biology-based tumor type. p: Cox regression.

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