title: RANK expression as a prognostic and predictive marker in breast cancer.
abstract: RANK ligand (RANKL) is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mammary epithelium via its receptor RANK and has a role in expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. Primary breast carcinoma samples from the neoadjuvant GeparTrio study were analyzed to correlate the expression of human RANK and RANKL with pathological complete response (pCR), disease-free (DFS), and overall (OS) survival. Pre-treatment FFPE core biopsies (n = 601) were analyzed for percentage and intensity of immunohistochemical RANK and RANKL expression. Antibodies against human RANK (N-1H8; Amgen) and human RANKL (M366; Amgen) were used. RANK protein was expressed in 160 (27 %) patients. Increased RANK expression was observed in 14.5 % of patients and correlated with high tumor grade (p < 0.023) and negative hormone receptor (HR) status (p < 0.001). Patients with high RANK expression showed a higher pCR rate (23.0 % vs. 12.6 %, p = 0.010), shorter DFS (p = 0.038), and OS (p = 0.011). However, prognostic and predictive information was not an independent parameter. Only 6 % of samples expressed RANKL, which was not correlated with any clinical features. Higher RANK expression in the primary tumor is associated with a higher sensitivity to chemotherapy, but also a higher risk of relapse and death. Our study provides a basis for further exploration of the antitumor activity of clinical antibodies against RANKL.
authors.affiliation: Institute of Pathology, Campus Mitte, Charité University Hospital Berlin, Charitéplatz 1, 10117, Berlin, Germany, berit.pfitzner@charite.de.
authors.forename: Berit Maria
authors.initials: BM
authors.lastname: Pfitzner
authors.forename: Daniel
authors.initials: D
authors.lastname: Branstetter
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.forename: Bianca
authors.initials: B
authors.lastname: Lederer
authors.forename: Wolfgang Daniel
authors.initials: WD
authors.lastname: Schmitt
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011237:Predictive Value of Tests; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human