CA 15-3: a prognostic marker in breast cancer.

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.

Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma.

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.

MDR1 expression is associated with adverse survival in melanoma of the uveal tract.

Metastatic uveal melanoma is profoundly chemoresistant and has a very poor outcome. We have previously shown that the MDR1 gene and its gene product P-glycoprotein (P-gp), which are known to cause drug resistance in cancer cells, are expressed in ocular melanoma. Overexpression of MDR1 has been associated with a poor survival in some tumor types treated by chemotherapy and in some untreated tumours. To assess whether MDR1 expression is of prognostic value in uveal melanoma, we evaluated the expression of MDR1 by immunohistochemistry in 108 cases. Three semiquantitative grades were used to evaluate positive staining. We detected MDR1 expression in 80% of cases; 28% showed grade I staining; 30%, grade II staining; and 22%, grade III staining. There was a statistically significant association (P=.004) between MDR1 expression by tumor cells and shorter survival times (n=96), which was most striking at grade III levels of expression. Multivariate analysis showed that MDR1 expression is an independent prognostic indicator of poor survival. We conclude that (1) MDR1 may be involved in chemoresistance and tumor propagation in primary uveal melanoma, and (2) increasing levels of expression are prognostically significant and may prove a useful marker of tumor invasiveness, independent of established prognostic factors.

Preoperative CA 15-3 concentrations predict outcome of patients with breast carcinoma.

BACKGROUND: CA 15-3 is a breast-associated mucin that is elevated in the majority of breast carcinoma patients with distant metastases. Currently, the main application of this marker is in monitoring and detecting recurrences in patients with diagnosed breast carcinoma. METHODS: Preoperative serum concentrations (prior to excision of the primary tumor) of CA 15-3 were measured in 368 patients undergoing potentially curative surgical treatment for early breast carcinoma. These results were compared with prospectively recorded clinicopathologic characteristics and patient outcome data. RESULTS: A weak but significant positive association was found between CA 15-3 concentrations and both tumor stage and the number of involved axillary lymph nodes but not between CA 15-3 concentrations and estrogen receptor status. Patients with high concentrations of CA 15-3 had a significantly worse prognosis than patients with low concentrations. Using an optimum cutoff value of 30.38 U/mL, the probability of disease free survival at 5 years was 44% in patients with high CA 15-3 levels compared with 65% in patients with low CA 15-3 levels (P = 0.002, Mantel-Cox log rank test). The corresponding probabilities for overall survival were 67% and 83%, respectively (P < 0.001). The association of preoperative CA 15-3 levels with outcome was maintained in multivariate survival analysis and was not explained by the association between CA 15-3 and tumor size or lymph node burden. The relation between CA 15-3 and outcome also was found within some patient subgroups identified by traditional prognostic factors (axillary lymph node positive patients, patients with primary tumors >2 cm in greatest dimension, and patients with estrogen receptor positive tumors). CONCLUSIONS: 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.

High levels of cathepsin B predict poor outcome in patients with breast cancer.

Cathepsin B (CB) is a thiol-stimulated protease implicated in cancer invasion and metastasis. Other proteases involved in cancer spread such as urokinase-type plasminogen activator (uPA) and cathepsin D have previously been shown to be prognostic markers in breast cancer. CB was assayed by ELISA in 193 patients with primary breast cancer. CB levels were significantly higher in both primary and metastatic breast tumors than in fibroadenomas (p = 0.0001). In the primary carcinomas, CB levels showed no significant correlation with either nodal status, tumor size or estrogen receptor (ER) status. Patients with primary breast cancers containing high levels of CB had a significantly shorter disease-free interval (p = 0.01, chi-square = 6.61) and overall survival (p = 0.014, chi-square = 6.08) than patients with low levels of the protease. However, in multivariate analysis, using nodal status, tumor size, ER status and urokinase plasminogen activator (uPA), CB was not an independent prognostic marker. In contrast, nodal status, ER status and uPA were prognostic in multivariate analysis. In conclusion, CB, like certain other proteases implicated in cancer metastasis, correlates with poor outcome in patients with breast cancer. These results thus support the evidence from model systems linking CB to cancer spread. Inhibition of CB expression or activity might therefore be exploited for anti-metastatic therapies.

Cervical exploration for primary hyperparathyroidism--A 25 year experience.

Parathyroidectomy should be considered in every patient with hypercalcaemia and primary hyperparathyroidism even if the symptoms are vague. Cervical exploration is a safe operation with very satisfactory results. Our experience in 214 patients over 25 years shows permanent postoperative normocalcaemia in 95% of cases with a complication rate of 2.8%. All patients with primary HPT, regardless of age or the severity of symptoms should be candidates for cervical exploration.

Assay of E-cadherin by ELISA in human breast cancers.

E-cadherin is a membrane-bound adhesion glycoprotein. Loss of E-cadherin has been correlated with invasion and metastasis in model systems. Using a new ELISA, we found higher levels of E-cadherin in fibroadenomas than in primary breast cancers. Levels in primary cancers showed no significant relationship with either tumour size, nodal status or oestrogen receptor levels. Patients with breast cancers containing low levels of the adhesion protein had a significantly shorter disease-free interval than patients with high levels (P = 0.041). The prognostic value of E-cadherin, for disease-free interval, was also found in node-negative patients as well as in patients presenting with small tumors (< or = 2 cm). In conclusion, loss of E-cadherin expression in human breast cancers is associated with increased metastatic potential as has previously been found in model systems. Loss of E-cadherin is thus likely to contribute to breast cancer progression.

A 25 year review of parotid surgery.

At a single institution over 25 years, 110 patients were operated upon for a mixture of parotid disease. The mean duration of symptoms for benign disease was 40.8 months compared with 15.6 months for malignant disease. Pain was a significant feature of malignant parotid disorders (46.1% compared with 17.8% for benign conditions). The pathology of these masses was diverse, with pleomorphic adenoma being the commonest (44%). Superficial parotidectomy was the commonest procedure employed (69/110) with local excision being performed only prior to 1984 (15/110). There were five cases of permanent facial palsy, all following radical resection for malignancy. One patient developed Frey's syndrome. Recurrence rate for pleomorphic adenomas was 7/48 (15%), three following enucleations prior to 1984. In primary malignancy of the parotid, 3/21 (14%) developed recurrences. Parotid tumours have a low incidence. Surgery for these tumours can be safely performed by those with a special interest in parotid surgery.

High levels of stromelysin-3 correlate with poor prognosis in patients with breast carcinoma.

Stromelysin 3 (ST3) is a matrix metalloprotease (MMP) expressed in fibroblast-like cells of most human invasive carcinomas. In this investigation, ST3 was measured by semiquantitative immunohistochemistry in 111 primary breast cancers. ST3 levels showed no correlation with tumor size, axillary-node status or tumor grade (Scarff-Bloom-Richardson system; SBR) but were significantly associated with higher nuclear grade (modified SBR). In addition, ST3 levels were significantly higher in ductal than in lobular cancers. Patients with high scores of ST3 staining had a shorter disease-free interval and shorter overall survival than patients with low scores. ST3 is thus one of the first MMPs to correlate with patient outcome in breast cancer. These findings are consistent with earlier clinical and experimental observations suggesting that ST3 contributes to breast-cancer progression.

Thyroid disorders and breast cancer.

We have investigated the controversial association between diseases of the thyroid gland and breast carcinoma using methodology which allows positive exclusion of cases of breast disease from control groups and the detection of subclinical alterations in thyroid volume using high resolution ultrasonography, thus addressing the deficiencies of earlier studies. Whereas the prevalence of hyperthyroidism and hypothyroidism in patients with breast carcinoma and in healthy controls without clinical evidence of breast disease was similar, non-toxic goitre was more than twice as common in the breast carcinoma patients. Thyroid volumes were also significantly higher in breast carcinoma patients than in controls; using World Health Organisation criteria, 45.5% of breast carcinoma patients had thyroid enlargement compared with only 10.5% of controls. Finally, antithyroid peroxidase autoantibodies were twice as common in breast cancer patients than in controls. These findings provide clear evidence of a relationship between thyroid disease and breast carcinoma, although the mechanisms underlying this relationship require further study, future studies of breast cancer risk factors should therefore include assessment of thyroid function, antibody status and volume.