title: The prognostic value of mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A, and Ki67, alone and in combinations, in node-negative premenopausal breast cancer.
abstract: Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off ≥10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95%CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95%CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95%CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95%CI: 1.1-6.7), and cyclin A (HR=2.7, 95%CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.
authors: Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden ; Skåne Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors: Marie
authors: M
authors: Klintman
authors: Carina
authors: C
authors: Strand
authors: Cecilia
authors: C
authors: Ahlin
authors: Sanda
authors: S
authors: Beglerbegovic
authors: Marie-Louise
authors: ML
authors: Fjällskog
authors: Dorthe
authors: D
authors: Grabau
authors: Einar
authors: E
authors: Gudlaugsson
authors: Emiel A M
authors: EA
authors: Janssen
authors: Kristina
authors: K
authors: Lövgren
authors: Ivar
authors: I
authors: Skaland
authors: Pär-Ola
authors: PO
authors: Bendahl
authors: Per
authors: P
authors: Malmström
authors: Jan P A
authors: JP
authors: Baak
authors: Mårten
authors: M
authors: Fernö
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology*; D008940:Mitotic Index; D015999:Multivariate Analysis; D010766:Phosphorylation; D017697:Premenopause / Q000378:metabolism*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D019925:Cyclin A; D056744:Cyclin B1; D006657:Histones; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen