Abstract
We aimed to analyze the expression of cell-cycle regulation markers – minichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) − in pre-treatment core-biopsy samples of breast carcinomas in correlation with known predictive and prognostic factors. Totally 52 core biopsy samples obtained prior to neoadjuvant therapy were analyzed. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, the presence of tumor infiltrating lymphocytes (TIL), pathological tumor response rate to the neoadjuvant therapy and patient survival. All investigated markers showed higher expression in high grade and in triple negative tumors (p < 0.01 and p < 0.05, respectively). Hormone receptor negative tumors showed significantly higher expression of Ki-67 (p < 0.01), MCM2 (p < 0.01) and Cyclin A (p < 0.01) than hormone receptor positive ones. Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04). Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher rate of pathological complete remission. Tumors with early relapse (progression-free survival ≤2 years) and shortened overall survival also show a higher rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify tumors with worse prognosis, but with a favorable response to primary systemic therapy. The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to be further substantiated in larger patient cohorts.
Highlights
In breast carcinomas several predictive and prognostic markers have already been defined and used in the daily clinical routine, i.e. TNM stage, tumor grading and biological subtyping [1, 2]
In our current as well as in our earlier published results [21] we proved that besides Ki67, the higher expression of minichromosome maintenance protein 2 (MCM2), Cyclin A and PHH3 accurately predicts the pathologic complete remission (pCR) after primary systemic therapy (PST)
Selecting patients diagnosed with breast cancer for PST is a critical problem in the daily practice
Summary
In breast carcinomas several predictive and prognostic markers have already been defined and used in the daily clinical routine, i.e. TNM stage, tumor grading and biological subtyping [1, 2]. There is still a need to find reliable and reproducible biomarkers, which can predict pathologic complete remission (pCR) and patients’ prognosis, in order to select those who surely benefit from PST. The markers of cell proliferation are promising candidates for this clinical goal [4]. Ki-67 labeling index (Ki-67 LI) is routinely used to assess proliferation activity of breast tumors [1, 2]. It should be highlighted that contradictory data are presented about the reliability of Ki-67 LI to assess tumor proliferation due to its relatively low inter-laboratory reproducibility [5, 6]
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