The International Journal of Biological Markers

c-erbB-2 is an oncoprotein which is overexpressed in some breast cancers. Recently it has been established that the extracellular domain of c-erbB-2 is shed into the serum of patients with breast cancer. There appears to be no association between tumor stage and extracellular domain of c-erbB-2 (c-erbB-2/ECD): c-erbB-2/ECD seems to correlate with patient prognosis whatever the stage of disease. The data also suggest that c-erbB-2/ECD may be useful in monitoring for tumor recurrence and in predicting resistance to hormonal therapy, but not as useful in predicting response to chemotherapy. This may relate to the power of this marker to reflect disease burden, which has an overwhelmingly negative impact on outcome.

c-erbB-2 is an oncoprotein which is overexpressed in up to 40% of primary breast cancers. c-erbB-2 overexpression is a bad prognostic factor in patients with lymph node-positive disease. Unfortunately, there has been no agreement to date on whether c-erbB-2 overexpression is of prognostic significance in patients with lymph node-negative disease. c-erbB-2 overexpression is correlated with the absence of estrogen receptor expression in a number of publications. Correlation between c-erbB-2 overexpression and hormone sensitivity in the clinical setting is less well established and is the focus of ongoing studies. Both preclinical and clinical studies support an association between c-erbB-2 receptor overexpression and resistance to alkylating agents. In contrast, the data for c-erbB-2 and anthracyclines should be viewed in a slightly different manner. Anthracyclines appear to have a greater therapeutic effect in c-erbB-2-positive disease which may be dose sensitive. In c-erbB-2-negative disease not only is the therapeutic effect reduced but there does not appear to be any improved response to higher doses of anthracyclines. The data for c-erbB-2 and the taxanes is still not clear enough to provide any definite conclusions. If there is a correlation it would at present appear to be between paclitaxel and response rates, but this needs to be confirmed in larger studies. Few studies have looked at changes in c-erbB-2 on therapy. Those that have seem to show no significant change on either tamoxifen or chemotherapy.

Several circulating mucinous markers, including CA 15.3, MCA, CA 459, CASA, and Truquant BR, are secreted products of the polymorphic MUC1 gene, and are used as diagnostic tools in patients with breast cancer. In clinical practice the measurement of the levels of these markers in the blood can give important information on the tumor's response to treatment and its biological behavior during disease monitoring. Since the marker levels reflect the activity of the tumor, it is important to know all factors influencing the production/secretion and the blood concentrations of MUC1 mucin. Recent findings suggest that MUC1 gene expression is regulated by steroid hormones and other substances present in the serum. Such observations are very important not only because of their biological significance but also for their clinical implications, as one approach to breast cancer therapy is based on chemical hormone manipulation. Nevertheless, we have preliminarily demonstrated that endocrine treatment in breast cancer patients does not influence the circulating CA 15.3 serum levels, so changes in marker levels are related only to the clinical evolution of the tumor.

A critical review of CA 27.29 and CA 15-3 is performed in this paper. A review of the literature is undertaken. A review of the FDA submissions for 27.29 for both early stage and monitoring metastatic breast cancer patients is reviewed.

TPA and CA 15.3 concentrations were routinely determined in serum of patients treated for breast cancer during a 15-month period. ROC curves did not show differences in the ability to differentiate between NED and PD on the basis of matching tumor marker values. During monitoring of patients with NED, TPA levels showed fluctuations of more than 25% that were not disease related. We concluded that CA 15.3 is a more slowly reacting marker of tumor burden than TPA, which is an immediate indicator of cell turnover.

The management of metastatic breast cancer patients reflects the heterogeneous nature of the disease. While patients may benefit from hormonal treatment, in most cases more toxic chemotherapy is applied in the advanced stages. The pretreatment levels of TPS in patients with metastatic breast cancer are correlated with prognosis. Decreasing TPS levels (>50%) during treatment are indicative of response. The fastest decrease in TPS levels is obtained in patients with a favorable prognosis. Increasing TPS levels (>25%) predict disease progression with a considerable lead time (median 8 months). The clinical impact of these observations is discussed in this paper.

In this prospective study the correlation of pathological with biological prognostic factors and serum tumor markers has been investigated in 574 patients with primary invasive breast cancer. The p53 protein and Bax level correlated positively with tumor size, lymph node status and histological grade. The serum levels of CEA, CA 15.3, TPA-M and TK correlated with tumor extent. There was a significant difference between pre- and postmenopausal breast cancer patients in serum levels of TPA-M and cytosol levels of Bax. Whether these correlations can help in predicting the prognosis of breast cancer by providing additional information with respect to the conventional factors, will have to be investigated by several years of careful clinical follow-up.