title: The prognostic value of apoptotic and proliferative markers in breast cancer.
abstract: Increasing ability of early breast cancer (BC) diagnosis leading to more early stage detection, better survival, and low relapse marks one of the milestones achieved over the decades. Foregoing poses a challenge for clinicians regarding optimal treatment, in which over- and under-treatment should be avoided. Classical prognostic and predictive factors fall short for individualized adjuvant therapy selection in this patient group. The key to better characterization may be found in the biology underlying individual tumors. We hypothesized that markers related to cellular proliferation and apoptosis and the balance between these two processes in tumor development will be predictive for clinical outcome. Our study population (N = 822) consisted of all early stage BC patients primarily treated with surgery in our center between 1985 and 1996. Sections of available tumor tissue (87 %, 714/822) were immunohistochemically stained for expression of p53, active-caspase-3, and Ki67. In 43 % (304/714) and 18 % (126/714) of this cohort, respectively, a biochemical C2P(®) risk prediction and caspase-3 assay were performed. Expression data of the mentioned markers, single, or combined, were analyzed. Results showed that both the single and combined markers, whether of apoptotic or proliferative origin had associations with clinical outcome. An additive effect was seen for the hazard ratios when data on p53, active caspase-3, and Ki67 status were combined. The assembled prognostic apoptotic-proliferative subtype showed significant association for both the overall survival (p = 0.024) and relapse-free period (p = 0.001) in the multivariate analyses of grade I breast tumors. Combined markers of tumor cell apoptosis and proliferation represent tumor aggressiveness. The apoptotic-proliferative subtypes that we present in this study represent a clinical prognostic profile with solid underlying biological rationale and pose a promising method for accurate identification of grade I BC patients in need of an aggressive therapeutic approach, thus contributing to precision medicine in BC disease.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.
authors.forename: Charla C
authors.initials: CC
authors.lastname: Engels
authors.forename: Francesca
authors.initials: F
authors.lastname: Ruberta
authors.forename: Esther M
authors.initials: EM
authors.lastname: de Kruijf
authors.forename: Gabi W
authors.initials: GW
authors.lastname: van Pelt
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsushima
authors.forename: Masaki
authors.initials: M
authors.lastname: Shibayama
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishihara
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000601:surgery*; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D049109:Cell Proliferation; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3