title: Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy.
abstract: BACKGROUND
  Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain.
  
  
  METHODS
  One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival).
  
  
  RESULTS
  Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS.
  
  
  CONCLUSIONS
  NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker.
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Ács
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.
authors.forename: Veronika
authors.initials: V
authors.lastname: Zámbó
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.|MTA-SE-NAP Brain Metastasis Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Vízkeleti
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.|MTA-TTK Lendület Cancer Biomarker Research Group, 1091, Budapest, Üllői út 93, Hungary.
authors.forename: A Marcell
authors.initials: AM
authors.lastname: Szász
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Madaras
authors.affiliation: Department of Clinical Oncology, Semmelweis University, 1083, Budapest, Tömő uta 25-29, Hungary.
authors.forename: Gyöngyvér
authors.initials: G
authors.lastname: Szentmártoni
authors.affiliation: Department of Clinical Oncology, Semmelweis University, 1083, Budapest, Tömő uta 25-29, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Tőkés
authors.affiliation: 1st Department of Surgery, Semmelweis University, 1082, Budapest Üllői út 78, Hungary.
authors.forename: Béla Á
authors.initials: BÁ
authors.lastname: Molnár
authors.affiliation: 1st Department of Surgery, Semmelweis University, 1082, Budapest Üllői út 78, Hungary.
authors.forename: István Artúr
authors.initials: IA
authors.lastname: Molnár
authors.affiliation: University of Oradea, Romania, Faculty of Electrical Engineering and Information Technology, Str. Universitatii nr. 1, Oradea, Romania.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vári-Kakas
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary.
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.affiliation: 2nd Department of Pathology, Semmelweis University, 1091, Budapest, Üllői út 93, Hungary. tokesa1972@yahoo.co.uk.|MTA-SE Tumor Progression Research Group, Semmelweis University, 2nd Department of Pathology, 1091 Budapest, Üllői út 93, Hungary. tokesa1972@yahoo.co.uk.
authors.forename: Anna-Mária
authors.initials: AM
authors.lastname: Tőkés
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen
keywords: Breast; Ki-67; Neoadjuvant chemotherapy; Predictive and prognostic markers