PROGNOSTIC IMPLICATIONS OF DIFFERENT CELL-CYCLE ANALYSIS MODELS OF FLOW CYTOMETRIC DNA HISTOGRAMS OF 1,301 BREAST-CANCER PATIENTS - RESULTSFROM THE MULTICENTER MORPHOMETRIC MAMMARY-CARCINOMA PROJECT (MMMCP)

Conflicting prognostic results with regard to DNA flow cytometric cell cycle variables have been reported for breast cancer patients, An imp ortant reason for this may be related to differences in the interpreta tion of DNA histograms. Several computer programs based on different c ell cycle fitting models are available resulting in significant variat ions in percent: S-phase and other cell cycle variables, Our present s tudy evaluated the prognostic value of percent S-phase cells obtained using 5 different cell cycle analysis models, Flow cytometric DNA hist ograms obtained from 1,301 fresh frozen breast cancer samples were int erpreted with 5 different cell cycle analysis models using a commercia lly available computer program. Model I used the zero order S-phase ca lculation and ''sliced nuclei'' debris correction, model 2 added fixed G(2)/M- to G(0)/G(1)-phase ratio, and model 3 added correction for ag gregates. Model 4 applied the first-order S-phase calculation and slic ed debris correction. Model 5 fixed the coefficients of variation CVs of the G(0)/G(1)- and G(2)/M-phases in addition to applying the sliced nuclei debris correction and zero order S-phase calculation. The diff erent models yielded clearly different prognostic results, The average percent S-phase cells of the aggregate correction model (model 3) pro vided the best prognostic value in all cases for overall survival (OS) as well as disease-free survival (DFS) (OS: p < 0.0001; DFS: p < 0.00 01), in lymph node-positive cases (OS: p < 0.000 1; DFS: p = 0.004) an d in DNA-diploid subgroups (OS: p = 0.004; DFS: p = 0.001), For the ly mph node negative and DNA-non-diploid subgroups, the percent S-phase o f the second cell cycle reached slightly better prognostic significanc e than the average percent S-phase cells, In multivariate analysis, th e average percent S-phase of the aggregate correction model had the be st additional prognostic value to tumor size and lymph node status. In conclusion, different cell cycle analysis models yield clearly differ ent prognostic results for invasive breast cancer patients, The most i mportant prognostic percent S-phase variable was the average percent S -phase cells when aggregate correction was included in cell cycle anal ysis. (C) 1997 Wiley-Liss, Inc.