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

Balázs Ács, Veronika Zámbó, Laura Vízkeleti, A. Marcell Szász, Lilla Madaras, Gyöngyvér Szentmártoni, Tímea Tokés, B. Molnár, István Artúr Molnár, Stefan Vári-Kakas, J. Kulka, A. Tőkés

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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.

Original languageEnglish
Article number20
JournalDiagnostic Pathology
Volume12
Issue number1
DOIs
Publication statusPublished - Feb 21 2017

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Breast Neoplasms
Drug Therapy
Survival
ROC Curve
Neoplasms
Multivariate Analysis
Regression Analysis
Neoplasm Metastasis
Therapeutics

Keywords

  • Breast
  • Ki-67
  • Neoadjuvant chemotherapy
  • Predictive and prognostic markers

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

Cite this

Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy. / Ács, Balázs; Zámbó, Veronika; Vízkeleti, Laura; Szász, A. Marcell; Madaras, Lilla; Szentmártoni, Gyöngyvér; Tokés, Tímea; Molnár, B.; Molnár, István Artúr; Vári-Kakas, Stefan; Kulka, J.; Tőkés, A.

In: Diagnostic Pathology, Vol. 12, No. 1, 20, 21.02.2017.

Research output: Contribution to journalArticle

Ács, B, Zámbó, V, Vízkeleti, L, Szász, AM, Madaras, L, Szentmártoni, G, Tokés, T, Molnár, B, Molnár, IA, Vári-Kakas, S, Kulka, J & Tőkés, A 2017, 'Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy', Diagnostic Pathology, vol. 12, no. 1, 20. https://doi.org/10.1186/s13000-017-0608-5
Ács, Balázs ; Zámbó, Veronika ; Vízkeleti, Laura ; Szász, A. Marcell ; Madaras, Lilla ; Szentmártoni, Gyöngyvér ; Tokés, Tímea ; Molnár, B. ; Molnár, István Artúr ; Vári-Kakas, Stefan ; Kulka, J. ; Tőkés, A. / Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy. In: Diagnostic Pathology. 2017 ; Vol. 12, No. 1.
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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.",
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T1 - Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

AU - Ács, Balázs

AU - Zámbó, Veronika

AU - Vízkeleti, Laura

AU - Szász, A. Marcell

AU - Madaras, Lilla

AU - Szentmártoni, Gyöngyvér

AU - Tokés, Tímea

AU - Molnár, B.

AU - Molnár, István Artúr

AU - Vári-Kakas, Stefan

AU - Kulka, J.

AU - Tőkés, A.

PY - 2017/2/21

Y1 - 2017/2/21

N2 - 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.

AB - 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.

KW - Breast

KW - Ki-67

KW - Neoadjuvant chemotherapy

KW - Predictive and prognostic markers

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