CA 15-3 (also known as MUC1) is the most widely used serum marker in breast cancer. MUC1 is a large transmembrane glycoprotein which is frequently overexpressed and aberrantly glycosylated in cancer. Physiologically, MUC1 appears to play a role in cell adhesion and the high levels present in cancer may be causally involved in metastasis. At present the main uses of CA 15-3 are in preclinically detecting recurrent breast cancer and monitoring the treatment of patients with advanced breast cancer. In a prospective study of 368 patients we show that patients with high preoperative levels of CA 15-3 (>30.4 U/mL) had a worse outcome than patients with low levels of the marker. In multivariate analysis CA 15-3 as a prognostic marker was independent of both tumor size and nodal status. Furthermore, in multivariate analysis the prognostic impact of CA 15-3 was stronger than that of tumor size and at least as strong as nodal status. CA 15-3 may thus be the first independent prognostic serum marker in breast cancer.

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The process of cancer invasion and metastasis is associated with tissue remodeling (Aznavoorian et al., 1993). It is now widely believed that this process is controlled by different proteases released from the primary cancer. The proteases implicated in cancer progression include urokinase-plasminogen activator (uPA), cathepsins B, D and L and various matrix metalloproteases (MMPs) (for review, see DufFy, 1992;Birkedal-Hansen, 1995). One MMP that may be involved in cancer progression is stromelysin-3 (ST3). ST3 was originally identified using subtractive hybridization of a cDNA library prepared from a human breast cancer (Basset et a/., 1990). In breast and other cancers, ST3 is specifically expressed in fibroblast-like cells immediately surrounding cancer cells (for review, see Basset et al., 1993;Rouyer et al., 1994). While almost all invasive breast carcinomas express mRNA for ST3, expression of this gene was found in only 5% of 21 fibroadenomas, 31% of in situ ductal carcinomas of the non-comedo type and in 61% of in situ ductal carcinomas of the comedo type (Wolf et al., 1993). The latter are the most aggressive sub-type of in situ ductal carcinoma and are characterized by high nuclear grade and necrosis. Furthermore, ST3 expression has been shown to promote the tumor take of breast-cancer cells in nude mice . These findings taken together suggest that ST3 may contribute to breast-cancer progression.

Preoperative serum concentrations of CA 15-3 appear to have a significant relation to outcome in patients with early breast carcinoma and may have a role in the rational selection of patients for appropriate adjuvant treatments. To the authors' knowledge, CA 15-3 thus is one of the first circulating markers shown to be an independent prognostic indicator in patients with breast carcinoma.

The process of cancer invasion and metastasis is associated with tissue remodeling (Aznavoorian et al., 1993). It is now widely believed that this process is controlled by different proteases released from the primary cancer. The proteases implicated in cancer progression include urokinase-plasminogen activator (uPA), cathepsins B, D and L and various matrix metalloproteases (MMPs) (for review, see DufFy, 1992;Birkedal-Hansen, 1995). One MMP that may be involved in cancer progression is stromelysin-3 (ST3). ST3 was originally identified using subtractive hybridization of a cDNA library prepared from a human breast cancer (Basset et a/., 1990). In breast and other cancers, ST3 is specifically expressed in fibroblast-like cells immediately surrounding cancer cells (for review, see Basset et al., 1993;Rouyer et al., 1994). While almost all invasive breast carcinomas express mRNA for ST3, expression of this gene was found in only 5% of 21 fibroadenomas, 31% of in situ ductal carcinomas of the non-comedo type and in 61% of in situ ductal carcinomas of the comedo type (Wolf et al., 1993). The latter are the most aggressive sub-type of in situ ductal carcinoma and are characterized by high nuclear grade and necrosis. Furthermore, ST3 expression has been shown to promote the tumor take of breast-cancer cells in nude mice . These findings taken together suggest that ST3 may contribute to breast-cancer progression.

The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma, compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease, compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast carcinoma demonstrated that TPO.Ab titres > or = 0.3 U/mL were associated with a significantly better disease-free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid volumes within the intermediate range (10.1-18.8 mL) and did not further enhance the good outcome recorded when volumes were < or = 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a biological link between breast carcinoma and thyroid disease.

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