title: Expression of cell cycle markers is predictive of the response to primary systemic therapy of locally advanced breast cancer.
abstract: We aimed to analyze to what extent expression of four cell cycle regulation markers-minichromosome maintenance protein (MCM2), Ki-67, cyclin A, and phosphohistone-H3 (PHH3)-predict response to primary systemic therapy in terms of pathological complete remission (pCR). In search of an accurate and reproducible scoring method, we compared computer-assisted (CA) and routine visual assessment (VA) of immunoreactivity. We included 57 patients with breast cancer in the study. The cell cycle markers were detected using immunohistochemistry on pre-therapy core biopsy samples. Parallel CA (validated by manual labeling) and standard VA were performed and compared for diagnostic agreement and predictive value for pCR. CA and VA results were dichotomized based on receiver operating characteristic analysis defined optimal cut-off values. "High" was defined by staining scores above the optimal cut-off, while "low" had staining scores below the optimal cut-off. The CA method resulted in significantly lower values for Ki-67 and MCM2 compared to VA (mean difference, -3.939 and -4.323). Diagnostic agreement was highest for cyclin A and PHH3 (-0.586 and -0.666, respectively). Regardless of the method (CA/VA) used, all tested markers were predictive of pCR. Optimal cut-off-based dichotomization improved diagnostic agreement between the CA and VA methods for every marker, in particular for MCM2 (κ = 1, p < 0.000). Cyclin A displayed excellent agreement (κ = 0.925; p < 0.000), while Ki-67 and PHH3 showed good agreement (κ = 0.789, p < 0.000 and κ = 0.794, p < 0.000, respectively). We found all cell cycle markers (Ki-67, MCM2, cyclin A, and PHH3) predictive of pCR. Diagnostic agreement between CA and VA was better at lower staining scores but improved after optimal cut-off-based dichotomization.
authors.affiliation: 1st Department of Internal Medicine, Oncological Division, Semmelweis University, Tömő utca 25-29, 4th floor, Budapest, 1083, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Tőkés
authors.affiliation: MTA-SE Tumor Progression Research Group, 2nd Department of Pahtology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary.|2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary.
authors.forename: Anna-Mária
authors.initials: AM
authors.lastname: Tőkés
authors.affiliation: 1st Department of Internal Medicine, Oncological Division, Semmelweis University, Tömő utca 25-29, 4th floor, Budapest, 1083, Hungary.
authors.forename: Gyöngyvér
authors.initials: G
authors.lastname: Szentmártoni
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary.
authors.forename: Gergő
authors.initials: G
authors.lastname: Kiszner
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Madaras
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary.
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.affiliation: MTA-SE Tumor Progression Research Group, 2nd Department of Pahtology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary.|1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenács
authors.affiliation: 1st Department of Internal Medicine, Oncological Division, Semmelweis University, Tömő utca 25-29, 4th floor, Budapest, 1083, Hungary. phd.se.oncology@gmail.com.
authors.forename: Magdolna
authors.initials: M
authors.lastname: Dank
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen
keywords: Breast cancer; Cell cycle; Digital pathology; Primary systemic therapy; Proliferation