THE FUNCTIONAL-RELATIONSHIP BETWEEN IN-VIVO BROMODEOXYURIDINE LABELING INDEX AND KI-67 PROLIFERATION INDEX IN HUMAN BREAST-CANCER

Proliferation indices are used, along with other parameters, to estima te the risk of recurrence of breast cancer for individual patients. Be cause it is unlikely one index will be practical for all patients, it is important to understand the relationship between various indices of proliferation. For this reason, we compared a proliferation index bas ed on in vivo labeling of S-phase tumor cells with the thymidine analo g bromodeoxyuridine (BrdUrd), to a proliferation index based on an est imate of the growth fraction with the MIB-1 antibody to the Ki-67 anti gen. With informed consent, we gave 145 patients 200 mg/m(2) BrdUrd in travenously just prior to surgical removal of breast cancer. On histol ogy sections, we visually counted S-phase cells which had incorporated BrdUrd using the Br-3 antibody which is specific to DNA-incorporated BrdUrd, and we counted cells in the growth fraction using the MIB-1 an tibody to the Ki-67 antigen. We found that both indices were positivel y correlated with tumor size, number of positive nodes, and tumor grad e, and both were negatively correlated with age and estrogen-progester one receptor positivity. Using a linear functional relationship model, we found that the best (i.e. the maximal) fit between the two indices (correlation coefficient 0.79; p < 0.0001) occurred when each index w as square root transformed, as is appropriate when counts follow a Poi sson distribution. When we used the median as a cutpoint for each inde x, the classification of 19 percent of data pairs changed depending up on which index was used. We also estimated that the Ki-67 intercept (1 .02 +/- 0.25) was significantly greater than zero. We conclude that th e BrdUrd index of DNA synthesis in S-phase correlates highly with the MIB-1 index of the growth fraction, and both indices correlate well wi th other parameters of tumor aggressiveness. Because this correlation is driven by concordance of the extremes of high and low counts, clini cal comparison will be necessary to determine which is the better prog nostic marker for human breast cancer.