Benefits of biomarker selection and clinico-pathological covariate inclusion in breast cancer prognostic models

Introduction: Multi-marker molecular assays have impacted management of early stage breast cancer, facilitating adjuvant chemotherapy decisions. We generated prognostic models that incorporate protein-based molecular markers and clinico-pathological variables to improve survival prediction. Methods: We used a quantitative immunofluorescence method to study protein expression of 14 markers included in the Oncotype DX™ assay on a 638 breast cancer patient cohort with 15-year follow-up. We performed cross-validation analyses to assess performance of multivariate Cox models consisting of these markers and standard clinico-pathological covariates, using an average time-dependent Area Under the Receiver Operating Characteristic curves and compared it to nested Cox models obtained by robust backward selection procedures. Results: A prognostic index derived from of a multivariate Cox regression model incorporating molecular and clinico-pathological covariates (nodal status, tumor size, nuclear grade, and age) is superior to models based on molecular studies alone or clinico-pathological covariates alone. Performance of this composite model can be further improved using feature selection techniques to prune variables. When stratifying patients by Nottingham Prognostic Index (NPI), the most prognostic markers in high and low NPI groups differed. Similarly, for the node-negative, hormone receptor-positive sub-population, we derived a compact model with three clinico-pathological variables and two protein markers that was superior to the full model. Conclusions: Prognostic models that include both molecular and clinico-pathological covariates can be more accurate than models based on either set of features alone. Furthermore, feature selection can decrease the number of molecular variables needed to predict outcome, potentially resulting in less expensive assays.This work was supported by a grant from the Susan G Komen Foundation (to YK)

Centrosomal Chk2 in DNA damage responses and cell cycle progession

Two major control systems regulate early stages of mitosis: activation of Cdk1 and anaphase control through assembly and disassembly of the mitotic spindle. In parallel to cell cycle progression, centrosomal duplication is regulated through proteins including Nek2. Recent studies suggest that centrosome-localized Chk1 forestalls premature activation of centrosomal Cdc25b and Cdk1 for mitotic entry, whereas Chk2 binds centrosomes and arrests mitosis only after activation by ATM and ATR in response to DNA damage. Here, we show that Chk2 centrosomal binding does not require DNA damage, but varies according to cell cycle progression. These and other data suggest a model in which binding of Chk2 to the centrosome at multiple cell cycle junctures controls co-localization of Chk2 with other cell cycle and centrosomal regulators

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer-1

2 and Bcl-2 antanogene-1 (Bag-1). AQUA, automated quantitative analysis.<p><b>Copyright information:</b></p><p>Taken from "Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer"</p><p>http://breast-cancer-research.com/content/10/2/R35</p><p>Breast Cancer Research : BCR 2008;10(2):R35-R35.</p><p>Published online 23 Apr 2008</p><p>PMCID:PMC2397537.</p><p></p

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer-2

Lear Bag-1 staining in a breast cancer histospot – using cytokeratin to the define tumor mask, using 4',6-diamidino-2-phenylindole to define the nuclear compartment, and using Cy5 for identifying the target (Bcl-2 and Bag-1).<p><b>Copyright information:</b></p><p>Taken from "Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer"</p><p>http://breast-cancer-research.com/content/10/2/R35</p><p>Breast Cancer Research : BCR 2008;10(2):R35-R35.</p><p>Published online 23 Apr 2008</p><p>PMCID:PMC2397537.</p><p></p

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer-0

S a loading control in a panel of breast cancer cell lines.<p><b>Copyright information:</b></p><p>Taken from "Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer"</p><p>http://breast-cancer-research.com/content/10/2/R35</p><p>Breast Cancer Research : BCR 2008;10(2):R35-R35.</p><p>Published online 23 Apr 2008</p><p>PMCID:PMC2397537.</p><p></p

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer-3

Ated quantitative analysis scores dichotomized by the median score for the entire cohort of patients, node-negative patients, and node-positive patients.<p><b>Copyright information:</b></p><p>Taken from "Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer"</p><p>http://breast-cancer-research.com/content/10/2/R35</p><p>Breast Cancer Research : BCR 2008;10(2):R35-R35.</p><p>Published online 23 Apr 2008</p><p>PMCID:PMC2397537.</p><p></p

Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer-4

S a loading control in a panel of breast cancer cell lines.<p><b>Copyright information:</b></p><p>Taken from "Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer"</p><p>http://breast-cancer-research.com/content/10/2/R35</p><p>Breast Cancer Research : BCR 2008;10(2):R35-R35.</p><p>Published online 23 Apr 2008</p><p>PMCID:PMC2397537.</p><p></p