Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

• Published in: Diagnostic pathology Vol. 12; no. 1; p. 20
• Main Authors: Ács, Balázs, Zámbó, Veronika, Vízkeleti, Laura, Szász, A. Marcell, Madaras, Lilla, Szentmártoni, Gyöngyvér, Tőkés, Tímea, Molnár, Béla Á., Molnár, István Artúr, Vári-Kakas, Stefan, Kulka, Janina, Tőkés, Anna-Mária
• Format: Journal Article
• Language: English
• Published: London BioMed Central 21.02.2017; BioMed Central Ltd
• Subjects: Adjuvant treatment; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Biomarkers, Tumor - analysis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Care and treatment; Chemotherapy, Adjuvant; Cohort Studies; Cross-Sectional Studies; Disease-Free Survival; Female; Genetic aspects; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Ki-67 Antigen - analysis; Medicine; Medicine & Public Health; Middle Aged; Neoadjuvant Therapy; Pathology; Prognosis; Proportional Hazards Models; Retrospective Studies; ROC Curve; Neoadjuvant chemotherapy; Breast; Ki-67; Predictive and prognostic markers
• ISSN: 1746-1596; 1746-1596
• DOI: 10.1186/s13000-017-0608-5

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.