Quantitative measurement of soluble cytokeratin fragments in tissue cytosol of 599 node negative breast cancer patients: a prognostic marker possiblyassociated with apoptosis

Apoptosis is associated with caspase-mediated proteolysis of Type I (K18 an d K19) cytokeratins. We previously showed a positive association between th e levels of tissue polypeptide antigen (TPA), that recognizes cytokeratins K8, K18, and K19 fragments, and induced apoptosis in breast cancer cell lin es. The aim of the present study was to evaluate the interrelationships bet ween TPA, steroid receptors, and p53, and their joint prognostic role in no de-negative breast cancer patients not treated with adjuvant therapies. Age and pT were also considered since they are known prognostic factors. Five hundred and ninety-nine cases with N- breast cancer were evaluated (median follow-up: 60 months). TPA was measured by an immunoradiometric assay and p 53 by an immuno-chemiluminescent assay in tumor cytosol. Multiple correspon dence analysis was used to study the associations among variables. Their pr ognostic role (univariate analysis) and their joint effect (multivariate an alysis) on RFS were investigated with Cox regression models. TPA showed a d irect association with ER and PgR. Higher p53 values were weakly associated to low values of ER, PgR, and TPA. Younger age was related to low and inte rmediate values of ER and PgR and to low p53 values, while older age was re lated to high values of ER. Multivariate analysis showed a significant prog nostic impact for pT, age, ER, and TPA. Among the interactions considered c linically relevant, only that between ER and age was found. RFS estimated v alues were poorer in cases with lower than in those with higher TPA values, both in patients expected to have a poor (pT2, young age, low ER) and a be tter prognosis (pT1, older age, high ER). From the findings of the present study we can draw the following conclusions: The relationship of TPA with p rognosis gives an additional contribution to pT, age, and steroid receptors in N- breast cancer; TPA may be considered the first marker of apoptosis m easured with a fully standardized quantitative method in tumor cytosol and could be evaluated in prognostic indexes including markers related to diffe rent biological mechanisms.