title: Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial.
abstract: BACKGROUND
  The proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort.
  
  
  METHODS
  We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs).
  
  
  RESULTS
  A wide range of Ki67 cut points between 3%-94% (for pCR), 6%-46% (for DFS) and 4%-58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%-35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors.
  
  
  CONCLUSIONS
  Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.
authors: Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin.
authors: C
authors: C
authors: Denkert
authors: S
authors: S
authors: Loibl
authors: B M
authors: BM
authors: Müller
authors: H
authors: H
authors: Eidtmann
authors: W D
authors: WD
authors: Schmitt
authors: W
authors: W
authors: Eiermann
authors: B
authors: B
authors: Gerber
authors: H
authors: H
authors: Tesch
authors: J
authors: J
authors: Hilfrich
authors: J
authors: J
authors: Huober
authors: T
authors: T
authors: Fehm
authors: J
authors: J
authors: Barinoff
authors: C
authors: C
authors: Jackisch
authors: J
authors: J
authors: Prinzler
authors: T
authors: T
authors: Rüdiger
authors: E
authors: E
authors: Erbstösser
authors: J U
authors: JU
authors: Blohmer
authors: J
authors: J
authors: Budczies
authors: K M
authors: KM
authors: Mehta
authors: G
authors: G
authors: von Minckwitz
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human
keywords: Ki67; breast cancer; immunohistochemistry; neoadjuvant; prediction; prognosis