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Clinical Chemistry 50: 559-563, 2004. First published January 15, 2004; 10.1373/clinchem.2003.025288
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(Clinical Chemistry. 2004;50:559-563.)
© 2004 American Association for Clinical Chemistry, Inc.

Cancer Diagnostics

High Preoperative CA 15-3 Concentrations Predict Adverse Outcome in Node-Negative and Node-Positive Breast Cancer: Study of 600 Patients with Histologically Confirmed Breast Cancer

Michael J. Duffy1,3,4,a, Catherine Duggan5, Rachel Keane3,4, Arnold D.K. Hill3,4, Enda McDermott3,4, John Crown2 and Niall O’Higgins3,4

Departments of1 Nuclear Medicine and 2 Medical Oncology, St. Vincent’s University Hospital, Dublin, Ireland.3 Department of Surgery, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.4 Dublin Institute of Molecular Medicine, Dublin, Ireland.5 Department of Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, UK.

aAddress correspondence to this author at: Department of Nuclear Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Fax 353-1-2696018; e-mail Michael.J.Duffy{at}ucd.ie.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: CA 15-3 is the most widely used serum marker in breast cancer. Currently, its main uses are in the surveillance of patients with diagnosed disease and monitoring the treatment of patients with advanced disease.

Methods: Preoperative CA 15-3 concentrations were measured prospectively in 600 patients with histologically confirmed breast cancer. Marker concentrations were related to patient outcome by both univariate and multivariate analysis.

Results: After a median follow-up of 6.27 years, patients with high preoperative concentrations of CA 15-3 (>30 units/L) had a significantly shorter overall survival pattern than those with low concentrations. As a prognostic factor, CA 15-3 was independent of tumor size, axillary node status, and patient age. As well as being prognostic in the total population of patients, CA 15-3 also predicted outcome in different subgroups of patients, including those with both node-negative and node-positive disease, those who were both estrogen receptor (ER)-negative and ER-positive, and those younger and older that 50 years of age. CA 15-3 was also predictive of outcome irrespective of the type of adjuvant therapy administered, i.e., whether adjuvant hormone therapy, adjuvant chemotherapy, or radiotherapy was administered.

Conclusion: Assay of CA 15-3 is a relatively inexpensive, convenient, and noninvasive method for evaluating prognosis in newly diagnosed breast cancer patients.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The CA 15-3 assay measures the protein product of the MUC1 gene. MUC1 protein is a large transmembrane glycosylated molecule containing three main domains, a large extracellular region, a membrane-spanning sequence, and a cytoplasmic domain [for reviews, see Refs. (1),(2)]. Although the physiologic function of MUC1 is unclear, the glycoprotein has been implicated in cell adhesion, immunity, and metastasis (1)(2). Compared with healthy breast tissue, MUC1 is present in higher concentrations but less glycosylated in breast carcinoma (2).

Currently, CA 15-3 is the most widely used serum marker for breast cancer (3). Its main applications include the surveillance of patients with diagnosed breast cancer and monitoring therapy in advanced disease (1). In the follow-up of patients with diagnosed breast cancer, increased CA 15-3 was found either before or at the time of recurrence in ~70% of cases (4). For monitoring the treatment of advanced disease, CA 15-3 concentrations were found to decrease in almost 70% of patients with chemotherapy-induced disease regression and to increase in 80% of patients with progressive disease (4).

Existing histologic (tumor size, tumor grade, and axillary node status) (5) and biological [e.g., urokinase plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), 1 cathepsin D, and HER-2] (6)(7) prognostic factors for breast cancer all require tumor tissue. Clearly, the availability of a circulating prognostic factor, especially if it provided independent data and was prognostic within subgroups defined by traditional criteria, would be of value in breast cancer.

Previously, both we (8) and others(9)(10)(11)(12)(13)(14) reported that patients with increased preoperative concentrations of CA 15-3 had a worse prognosis than those with low concentrations. The aim of this investigation was to confirm and extend our original findings, using both a larger number of patients (n = 600) and longer follow-up (median, 6.27 years). In this study, we also investigated the prognostic impact of CA 15-3 in different subgroups of patients with breast cancer.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
A total of 647 patients with a histologic diagnosis of breast cancer and attending the Breast Clinic at St. Vincent’s University Hospital Dublin over the period July 1981 through November 1999 had preoperative CA 15-3 concentrations measured. Patients were excluded if they had a previous diagnosis of breast cancer or if CA 15-3 was not determined in the 6 weeks before surgery. Of these, 47 had incomplete data on either tumor size or nodal status and were excluded from the study. All patients underwent either modified radical mastectomy or local excision combined with external beam radiotherapy. Data relating to tumor size, axillary node involvement, estrogen receptor (ER) status, and patient age are summarized in Table 1 .


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  		Table 1. Pathologic, biochemical, and clinical characteristics of cancers investigated.

A summary of the adjuvant treatments administered is shown in Table 2 . The median follow-up time was 6.27 years. Of the 600 patients investigated, 368 were also included in our previous study (8). However, these patients were subjected to additional follow-up, whereas 232 new patients were included.


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  		Table 2. List of adjuvant treatments administered

assays
Serum CA 15-3 was measured by ELISA (ES300/Elecsys 2010; Roche Diagnostics). Between-assay variation was <6% for commercial control sera (Preci Controls; Roche Diagnostics). CA 15-3 concentrations were stratified using a cutoff value of 30 units/L because we had previously shown that this is the optimum cutoff point (8). Tumor concentrations of ER were also determined by ELISA (Abbott Diagnostics). The cutoff point for ER was 200 fmol/g of tumor tissue. All of these assays were carried out by either qualified clinical chemists or laboratory technicians.

statistics
Nonparametric analysis was performed because CA 15-3 did not follow a gaussian distribution. The Kruskal–Wallis test was used for relating CA 15-3 concentrations to both tumor size and nodal involvement, whereas the Mann–Whitney U-test was used for relating CA 15-3 concentrations to both ER status and patient age. Cuzick’s (9) test for trend was used to determine whether there was a statistically significant trend of increasing CA 15-3 values across groups (tumor size and increasing nodal involvement).

Analysis of events (death as endpoint) was performed by Cox regression analysis (10). Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to convey the effects. All P values were two-sided. Multivariate analysis was performed with Cox proportional hazard regression (10). All factors that were significant at the 0.05 level in the univariate analysis were included in the multivariate proportional hazard model. Stepwise and backward regressions were used to obtain the final model.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
relationship between ca 15-3 and tumor and patient characteristics
CA 15-3 concentrations were significantly higher in patients with larger tumors (P = 0.002) and in patients with increasing nodal burden (P = 0.004). Cuzick’s test for trend demonstrated a significant increase in CA 15-3 across these groups for tumor size (P <0.0001) and for nodal burden (P <0.0001). There was no difference in CA 15-3 concentrations in patients who were ER positive or negative, but concentrations were significantly higher in patients 50 years or older compared with those younger than 50 (P = 0.03). Concentrations were also higher in patients who were axillary node positive compared with those who were axillary node negative (P = 0.004). A detailed breakdown on the distribution of CA 15-3 concentrations in relation to tumor size, patient age, axillary nodal status, and ER status is shown in Table 3 .


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  		Table 3. Median and mean CA 15-3 concentrations in different subgroups.

relationship between ca 15-3 and overall survival
As shown in Fig. 1 and Table 4 , patients with high CA 15-3 (>30 units/L) had a worse overall survival pattern than those with low concentrations of the marker. This prognostic impact of CA 15-3 was clearly seen by both univariate and multivariate analysis (Table 4 ). In multivariate analysis, the prognostic benefit of CA 15-3 was independent of tumor size, axillary node status, and patient age. When used as a continuous variable, CA 15-3 concentrations also predicted adverse outcome (P <0.0001).



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  		Figure 1. Overall survival according to serum CA 15-3 concentrations in 600 patients with breast cancer.

Thin line, CA 15-3 <=30 units/L (n = 489); thick line, CA 15-3 >30 units/L (n = 111). HR = 2.16 (CI, 1.55–3.03); P <0.0001.


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  		Table 4. Comparative prognostic value of CA 15-3, nodal status, tumor size, patient age, and ER status.

The prognostic value of CA 15-3 in different subgroups of patients with breast cancer is summarized in Table 5 . Of particular significance was the finding that CA 15-3 predicted outcome in patients without histologic evidence of metastasis to axillary nodes (Fig. 2 ). However, CA 15-3 was also prognostic in other subgroups, including node-positive patients, in those who had both ER-positive and -negative tumors, in those with tumors between 2 and 5 cm in size, and in those who were both younger and older than 50 years. In contrast, CA 15-3 failed to correlate with outcome in patients with small tumors, i.e., <2 cm in diameter.


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  		Table 5. Prognostic value of CA 15-3 in different subgroups of patients with breast cancer.



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  		Figure 2. Overall survival according to serum CA 15-3 concentrations in 290 patients with axillary node-negative breast cancer.

Thin line, CA 15-3 <=30 units/L (n = 252); thick line, CA 15-3 >30 units/L (n = 38). HR = 2.42 (CI, 1.35–4.34); P = 0.003.

As shown in Table 6 , CA 15-3 was also prognostic irrespective of the type of adjuvant therapy administered, i.e., whether patients received adjuvant hormone therapy, adjuvant chemotherapy, or radiotherapy. Although the number of patients not given any therapy postsurgery was small (n = 42), high CA 15-3 concentrations also appeared to be associated with shortened overall survival in this untreated group.


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  		Table 6. Prognostic value of CA 15-3 in different subgroups of patients with breast cancer based on adjuvant therapy administered.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
As mentioned above, existing histologic and biological prognostic factors for breast cancer all require tumor tissue. In this study, we both confirm and extend our previous findings on the prognostic value of serum CA 15-3 in breast cancer (8). Our previous report included 368 patients with a median follow-up of 3.28 years (8). In contrast, this study includes 600 patients with a median follow-up of 6.27 years. Among the most significant differences between this and our previous report are the inclusion of more patients and longer follow-up, CA 15-3 was prognostic in the node-negative subgroup of patients. Another difference is that in the present study, CA 15-3 predicted outcome in ER-negative patients, whereas in the earlier investigation it failed to do so (8). Furthermore, we report for the first time that preoperative CA 15-3 concentrations predict outcome irrespective of the type of adjuvant therapy administered.

Other groups have also found that high preoperative CA 15-3 predicts adverse outcome in patients with breast cancer (11)(12)(13)(14)(15)(16). In two of these studies, only small numbers of patients were investigated (<100) and multivariate analysis was not used (11)(12). Ebeling et al.(14), however, studied 1046 patients and found that preoperative concentrations of both CA 15-3 and carcinoembryonic antigen (CEA) were prognostic in breast cancer. In multivariate analysis, CEA retained its prognostic impact, but CA 15-3 lost its value. Similarly, Canizares et al. (13) found that CA 15-3 was prognostic by univariate analysis but not by multivariate analysis. In contrast to these findings (13)(14) and in agreement with our study, Kumpulainen et al. (16) recently reported that CA 15-3 is an independent prognostic factor in breast cancer. It is of interest that the two studies reporting a prognostic value for CA 15-3 based on multivariate analysis both used 30 units/L as the cutoff point, whereas the reports failing to find an independent prognostic impact used 40 (13) and 25 units/L(14).

In our study, CA 15-3 was also prognostic when we used a cutoff point of 25 units/L, but at this lower cutoff concentration, the prognostic impact was less than at 30 units/L [HR = 1.45 (P = 0.03) vs 2.16 (P <0.0001)]. Similarly, in this investigation, CA 15-3 was prognostic when we used a cutoff point of 40 units/L (HR = 2.65; P <0.0001), but at this high cutoff, only 8% of the patients would be regarded to have a poor outcome.

The most important group of patients with breast cancer for which new prognostic factors are required is the axillary node-negative subgroup. Currently, urokinase plasminogen activator and PAI-1 are the only validated biological prognostic factors for this subgroup (17). However, unlike CA 15-3, which can be measured in serum, assays of urokinase plasminogen activator and PAI-1 require tumor tissue. In this investigation, we showed that preoperative CA 15-3 concentrations are a significant prognostic factor in this subset of patients. Similar findings were reported recently by Gion et al. (15).

Although histologic factors such as tumor size, tumor grade, and lymph node status have been the cornerstone of assessing cancer prognosis for decades, emerging data suggest that circulating markers can provide additional or independent data. Thus, tumor markers such as {alpha}-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase were recently incorporated into the Union Internationale Contre le Cancer (UICC) staging system for germ-cell tumor of the testis (18). Furthermore, a consensus conference of the American Joint Committee on Cancer (AJCC) recently recommended that preoperative CEA concentrations should be added to the staging system for colorectal cancer (19)(20).

In conclusion, our study shows that CA 15-3 is both an independent prognostic factor and prognostic in different subgroups of patients with breast cancer. For node-negative patients, CA 15-3 concentrations could be of use in combination with other factors in deciding whether adjuvant chemotherapy should be administered. In node-positive patients, those with high CA 15-3 could be considered for more aggressive treatments. Clearly, CA 15-3 has the potential to help with individualized therapy in patients with breast cancer.


   Footnotes
 
1 Nonstandard abbreviations: PAI-1, plasminogen activator inhibitor-1; ER, estrogen receptor; HR, hazard ratio; CI, confidence interval; and CEA, carcinoembryonic antigen.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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This Article
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