ANTICANCER RESEARCH 26: 3965-3972 (2006)
Prognostic Value of Pre-operative Serum
CA 15.3 Levels in Breast Cancer
ARANCHA MARTÍN1,2, MA DANIELA CORTE1,2, ANA MA ÁLVAREZ3,
JUAN CARLOS RODRIGUEZ1,2,4, ALEJANDRO ANDICOECHEA2,4,
MIGUEL BONGERA2,4, SARA JUNQUERA2, DIEGO PIDAL2,
MA TERESA ALLENDE1,3, JOSÉ L. GARCÍA MUÑIZ1,5 and FRANCISCO VIZOSO1,2,4
1Instituto
Universitario de Oncología del Principado de Asturias, Oviedo;
de Investigación and 4Servicio de Cirugía General, Hospital de Jove, Gijón;
3Servicio de Medicina Nuclear and 5Servicio de Cirugía General, Hospital Central de Asturias, Oviedo, Spain
2Unidad
Abstract. Background: CA15.3 (also known as MUC1) is the
most widely used marker in breast cancer. The aim of the
present work was the evaluation of the prognostic value of preoperative serum CA15.3 levels in patients with primary breast
cancer. Patients and Methods: This study included 818 women
with a histologically verified diagnosis of invasive breast cancer.
The serum values of CA15.3 were investigated at the time of
primary diagnosis by means of an immunoradiometric assay
based on the "sandwich" principle. The median follow-up
period of patients free of recurrence was 38 months. Results:
Pre-operative CA15.3 serum levels ranged from 6 to 452 U/ml.
Elevated CA15.3 levels (>30 U/ml) were found in 15.2% of
patients. Statistical analysis showed that pre-operative CA15.3
serum levels were significantly higher in patients with large size
tumors (T3 or T4) (p=0.0001), as well as in those with nodepositive tumors (p=0.0001) In the univariate analysis, high
CA15.3 levels were significantly associated with a lower
probability of both relapse-free and overall survival in the
overall group of patients (p=0.0001 and p=0.004, respectively)
and in the subgroup with node-positive breast cancer (p=0.001
and p=0.03, respectively). In addition, multivariate analysis
demonstrated that pre-operative levels of the antigen were
significantly and independently associated with relapse-free
survival in the overall group of patients, as well as in the
subgroup of patients with node-positive breast cancer (p=0.02
and p=0.01, respectively). Conclusion: These results show that
high pre-operative CA15.3 levels correlate with large size tumors
and the presence of lymph node metastases and suggest that this
antigen could be used as an additional prognostic marker.
Correspondence to: Dr. F. Vizoso, Hospital de Jove, Servicio de
Cirugía General, Avda. Eduardo Castro s/n, 33290 Gijón, Spain. Tel:
0034985 32 00 50, Fax: 0034985315710, e-mail: [email protected]
Key Words: MUC-1, breast cancer, prognosis, tumor markers.
0250-7005/2006 $2.00+.40
CA 15.3, also known as MUC1, episialin, polymorphic
epithelial mucin or epithelial membrane antigen, is the most
widely used marker in breast cancer. It is a large
transmembrane glycoprotein containing three main
domains: a large extracellular region, a membrane-spanning
sequence and a cytoplasmic domain. It was demonstrated
that MUC1 is overexpressed in breast cancer when
compared with normal breast tissue (4, 26), as well as that
an aberrant expression of MUC1 arises in the early stages
of the development of breast cancer (19). Thus, whereas
MUC1 expression is mostly confined to the apical side of
the glandular epithelial cells in normal tissue, its expression
can be found over the entire cell membrane in cancer cells.
Although the physiological function of MUC1 is unknown
at present, recent data suggest that MUC1 plays a role in
cellular adhesion, diminishing cell-cell and cell-extracellular
matrix interactions (11, 26). This property appears to be due
to the presence of large amounts of carbohydrate attached
to the extracellular region of MUC1 increasing its rigidity
and giving rise to a large, flexible rod-like structure that can
extend over 200 nm from the cell surface, further out from
the cell than any other membrane-associated protein.
Accordingly, increased expression in primary tumors could
be expected to facilitate detachment of malignant cells, both
from adjacent normal cells and from the extracellular
matrix. Therefore, MUC1 might play a role in the initiation
of cancer invasion and metastasis development. In
accordance with this hypothesis, it was demonstrated that
breast cancer growth and dissemination are impaired in
MUC1-deficient mice (25).
MUC1 may also contribute to cancer progression by
modulating the immune response. Cancer cells expressing
high levels of MUC1 on the cell membrane have been
shown to inhibit the functions of cytotoxic T lymphocytes
(CTL) and lymphokine activating killer (LAK) cells. This
blockage may occur as a result of MUC1 masking cell
3965
ANTICANCER RESEARCH 26: 3965-3972 (2006)
membrane antigens involved in the immune recognition
process (6, 11, 26). Accordingly, it has been described that
high MUC1-associated marker levels in blood are predictive
of a poor response in patients with metastatic breast cancer
treated with immunotherapy (14). Additionally, it has been
shown that circulating MUC1 elicits an immunosuppressive
action either by switching CTL cells to a stage of anergy (1)
or by inducing apoptosis of activated CTL cells (7).
The MUC1 antigen is secreted by breast cancer cells and
can be radio-immunologically measured in serum with the
use of monoclonal antibodies DF3 and 115-D8, raised
against milk fat globule membranes and a membraneenriched fraction of a metastatic breast cancer, respectively.
MUC1 has most widely been used as a serum tumoral
marker during the follow-up and detection stages of breast
cancer recurrence, as well as a measuring tool of therapeutic
response in metastasis disease (5, 9, 20-23, 27, 29). However,
the prognostic value of the serum antigen levels prior to the
initial surgery has only been studied in a few investigations,
and high preoperative levels were generally reported to be
associated with a poorer patient outcome (12, 13, 18).
The aims of the present work were to investigate: i) the
pre-operative serum levels of MUC1 in a series of patients
with breast cancer, ii) their relationship with clinicopathological and biological parameters, and iii) their
potential prognostic and predictive values.
Patients and Methods
This study included 818 patients with histologically verified
diagnosis of invasive breast cancer, treated at Hospital de Jove
(Gijón, Spain) and Hospital Central de Asturias (Oviedo, Spain)
between 1989 and 2002 and in whom CA 15.3 serum levels were
determined pre-operatively. Patients were previously untreated and
did not present any other malignant tumors at the time of the
initial diagnosis. Patients with distant metastasis or with secondary
contralateral breast cancer were excluded from the study. In all
cases, distant metastases at initial diagnosis were excluded by
clinical, radiological and biochemical studies, according to standard
clinical practice. The median age was 59 years (range, 27-92 years).
Patient characteristics with respect to age, menopausal status and
clinical tumor stage are listed in Table I. The histological grade of
the tumors was determined according to criteria reported by Bloom
and Richardson (2), whereas nodal status was assessed
histopathologically.
Patients underwent either a modified radical mastectomy or a
partial mastectomy with axillary lymphadenectomy. Post-operative
radiotherapy was given to 337 patients (41.1%). The criteria for
systemic adjuvant therapy were as follows: i) node-negative patients
with ER- and/or PgR-positive tumors received tamoxifen (20 mg
per day for five years); ii) node-negative patients with ER- and PgRnegative tumors received six cycles of intravenous CMF
(cyclophosphamide, methotrexate and 5-fluorouracil) every 3 weeks,
if their tumors were either larger than one centimeter, moderatelyor poorly-differentiated, or if patients were younger than 35 years
old; iii) node-positive patients received six cycles of intravenous
3966
Table I. Pre-operative serum CA 15.3 levels in 818 patients with breast
cancer: correlation with different clinicopathological parameters.
Patient and Tumor
Characteristics
CA 15.3 (U/ml)
NÆ Median Range
Total
818
Age (years)
≤60
427
>60
391
Menopausal status
Pre-menopausal
250
Post-menopausal 568
Tumoral size
T1
379
T2
333
T3
54
T4
52
Nodal status
N(–)
516
N(+)
302
Histological grade
Well Dif.
268
Mod. Dif.
381
Poorly Dif.
169
Histological type
Ductal
710
Lobular
58
Others
50
Estrogen Receptors
Negative
275
Positive
390
Unknown
153
Progesterone Receptors
Negative
312
Positive
288
Unknown
218
Ploidy
Diploid
141
Aneuploid
210
Unknown
467
S-phase
<7.4*
181
>7.4*
170
Unknown
467
17.4
6-9279
17
18
6-9279
6-980
17
17.6
6-9279
6-980
17
17
19.9
22.7
6-980
6-980
6-452
6-9279
16.5
18.9
6-980
6-9279
17
17.7
17.5
6-285.8
6-980
6-9279
17.7
16.4
15.6
6-9279
6-122
6-34.6
17.5
17.6
-
6-9279
6-980
-
16.8
18
-
6-9279
6-980
-
91.9
30.6
-
9-9279
1-1000
-
30.9
81
-
1-1000
6-9279
-
p
>30(%)
n.s.
124 (15.2)
p
n.s.
58(13.6)
66(16.9)
n.s.
n.s.
37(14.8)
87(15.3)
0.0001
0.0001
37(9.7)
52(15.6)
17(31.5)
18(34.6)
0.0001
0.0001
59(11.4)
65(21.5)
n.s.
n.s.
37(13.8)
55(14.4)
32(18.9)
n.s.
n.s
113(15.9)
7(12.1)
4(8)
n.s.
n.s.
43(15.6)
66(16.9)
-
n.s.
n.s.
44(14.1)
46(15.9)
-
n.s.
n.s.
19(13.4)
34(16.1)
-
n.s.
n.s.
29(16)
24(14.1)
-
*Median S-phase fraction value.
FEC (5-fluorouracil, epirubicin and cyclophosphamide) every 3
weeks, plus sequential tamoxifen if they had ER and/or PgRpositive tumors. Overall, 326 patients received chemotherapy, 382
patients received tamoxifen and 67 patients received both types of
systemic therapy. Every patient was followed for disease recurrence
and survival status by clinical, radiological and biochemical studies
every 3 months for the first 2 years and then yearly. The median
follow-up period of the patients still free of recurrence was 38
months. The end-point was disease-free (relapse-free) survival. The
median follow-up period in surviving patients was 43 months. One
hundred and seventy-six patients developed tumor recurrence and
95 of them died from causes directly related to it.
Martín et al: Serum CA 15.3 in Breast Cancer Prognosis
Breast carcinoma samples were obtained at the time of surgery.
Immediately after surgical resection, tissues were processed for
pathological examination while the remainder was washed with
cold saline solution, divided in aliquots, rapidly transported on ice
to the laboratory and stored at –70ÆC pending biochemical studies.
The tissue samples from tumors were obtained with informed
consent of the patients.
Tissue processing. Specimens from neoplastic and surrounding
healthy tissues were processed at the same time. They were
pulverized at –70ÆC utilizing a microdismembrator (Braun Biotech
International, Melsungen, Germany) and homogenized in TRIShydrochloride buffer (10 mM of TRIS, 1.5 mM of EDTA, 10%
glycerol, 0.1% of monothioglycerol). Homogenates, kept at 4ÆC,
were centrifuged at low speed (800 g for 10 min. at 4ÆC) and the
supernatant was ultracentrifuged at 100,000 xg for 60 min at 4ÆC.
Flow cytometry. DNA content was evaluated in 351 tumors by flow
cytometry (Bectron Dickinson, San José, California, USA) on
nuclei stained with propidium iodide. DNA ploidy was expressed
as DNA index. Proliferative activity was expressed as the fraction
of cells in the S-phase of the cell cycle and calculated according
to the recommendations from the DNA Cytometry Consensus
Conference (9), with the CellFit software program (Bectron
Dickinson). Median S-phase fraction value was used as the cut-off
point. Tumors were divided into those with a high or a low Sphase fraction.
Hormone receptor assays. Estrogen (ER) and progesterone (PgR)
receptor measurements were performed in cytosol extracts by a
solid phase enzyme immunoassay based on the "sandwich" principle
(ER-EIA and PgR-EIA Monoclonal from Abbot Laboratories,
Diagnostics Division, Wiesbaden, Germany). Values of ER and
PgR were expressed as fentomols per milligram of protein. Protein
concentration was quantified according to the described Bradford
method (3). For data analysis, a value higher than 10 fmol/mg total
protein was considered as positive for ER and PgR.
CA 15.3 assay. We investigated the serum values of CA 15.3 at the
time of primary diagnosis, prior to surgical intervention. Antigen
levels were analyzed with an immunoradiometric assay based on
the "sandwich" principle. The CENTOCOR CA 15.3 (Fujirebio
Diagnostics, INC., USA) utilizes two monoclonal antibodies
(115D8, DF3) that react with a circulating antigen, CA 15.3,
expressed by human breast carcinoma cells. One of these
antibodies, 115D8, was raised against antigens of human milk fat
globule membranes. The DF3 antibody was prepared against a
membrane-enriched fraction of a human breast carcinoma.
Polystyrene beads coated with a mouse monoclonal anti-CA15.3
were incubated with a sample or the appropriate standards and the
control. Unbound materials were removed by aspiration of the
fluid and washing of the beads. In a second step, the beads were
incubated with a mouse monoclonal anti-CA 15.3 labeled with I125
that detects CA15-3 bound to the bead during the first incubation
step and the unbound labeled antibody was removed by washing of
the beads. The bound radioactivity was detected in a gamma
scintillation counter, and was proportional to the CA 15.3
concentration in the specimen. A standard curve was obtained from
the same assay to convert cpm into CA 15.3 unit values from the
specimens and the controls. The detection limit of the assay was
established at 6 U/ml. The reproducibility of the CENTOCOR
CA15.3 was tested in a panel of 6 samples (7.7, 23.7, 33.9, 52.8,
93.6, 121.9 U/ml), in six laboratories, on three separate days with
three different sets of reagents. The coefficients of variation were:
12.4%, 10.0%, 10.2%, 10.2%, 8.5% and 8.4%, respectively. A
linearity study was performed with plasma from breast cancer
patients (192 U/ml and 109 U/ml), diluted in standard units/ml CA
15.3, with the mean recovery of 108% and 109%, respectively. The
cut-off value for clinical use was established at 30 U/ml.
Statistical analysis. After analyzing the distribution of CA 15.3 values
by the Kolmogorov-Smirnov test, non-parametric rank methods
were used. The pre-operative CA 15.3 serum levels were expressed
as median (range). Patients were subdivided into groups based on
different clinical and pathological parameters. Comparison of the
CA 15.3 levels between groups was made either with the MannWhitney or the Kruskal-Wallis tests. Probabilities of relapse-free
survival were calculated with the Kaplan-Meier method. Differences
between curves were evaluated with the log-rank test. The Cox's
regression model was also used to examine several combinations
and interactions of different prognostic factors in a multivariate
analysis. The following variables were included in the analysis: age,
menopausal status, tumor size, axillary node involvement,
histological type, histological grade, ER and PgR content, CA 15.3
serum levels and type of adjuvant systemic therapy. Ploidy and
S-phase fraction were not included due to the absence of
corresponding data in a significant number of tumors. Statistical
significance was considered at 5% probability level (p<0.05).
Results
Pre-operative serum CA 15.3 levels ranged from 6 to 452
U/ml, their distribution is represented in Table I. Elevated
serum CA 15.3 levels (>30 U/ml) were found in 15.2% of
the patients. The distribution of pre-operative serum levels
according to patient and tumor characteristics including:
age, menopausal status, tumor size, axillary node
involvement, histological type, histological grade, ER and
PgR status, ploidy and S-phase fraction, is also provided in
Table I. Statistical analysis revealed that pre-operative
serum CA 15.3 levels were directly related to tumor size
and lymph node involvement. These levels of CA 15.3 were
significantly higher in patients with T3 or T4 tumors than
in patients with T1 or T2 tumors (p=0.0001), as well as in
patients with node-positive tumors than in patients with
node-negative tumors (p=0.0001). Likewise, our results
demonstrated a higher percentage of patients with elevated
CA 15.3 levels among those with larger tumors, as well as
in the group of patients with node-positive tumors than in
those with node-negative tumors (Table I). However,
statistical analysis showed that there was no significant
relationship between CA 15.3 levels and age, menopausal
status, histological type, histological grade, ER and PgR
content, ploidy, or S-phase tumor fraction (Table I).
The potential relationship between pre-operative serum
CA 15.3 levels and relapse-free survival was evaluated in
the 818 patients included in the present study. All patients
3967
ANTICANCER RESEARCH 26: 3965-3972 (2006)
Table II. Multivariate analysis of the association of pre-operative serum
CA 15.3 levels with relapse-free and overall survival.
Tumor characteristics
Relapse-free survival
p
RR CI (95%)
Figure 1. Relapse-free survival as a function of pre-operative serum CA
15.3 levels in 807 patients with breast carcinoma.
were dichotomized into two different groups with regard to
the cut-off point of serum CA 15.3 levels considered of
clinical use (30 U/ml). Univariate analysis demonstrated
that elevated CA 15.3 levels were significantly associated
with a lower probability of both relapse-free and overall
survival in the overall group of patients. As it can be seen
in Figure 1, there were significant differences between
relapse-free survival (p=0.0001) curves calculated for each
patient subgroup, classified according to their pre-operative
serum CA 15.3 levels. However, when the survival analysis
was performed separately in node-negative and
node–positive breast cancer patients, our results only
showed significant differences between relapse-free survival
(p=0.001) curves for the node-positive breast cancer
patients (Figure 2A and B). In addition, there was a
significant relationship between serum CA 15.3 levels and
relapse-free and overall survival in patients with nodepositive breast cancer who underwent adjuvant
chemotherapy (p=0.009 and p=0.002, respectively) (Figure
2C). However, the serum antigen levels did not correlate
with relapse-free survival in those patients who underwent
adjuvant systemic therapy only as anti-estrogenic treatment
with tamoxifen (Figure 2D).
On the other hand, multivariate analysis demonstrated
that pre-operative CA 15.3 levels were significantly and
independently associated with relapse-free survival in the
overall group of patients, as well as in the subgroup of
patients with node-positive breast cancer (Table II). This
3968
Tumoral size
T1
T2
T3
T4
Nodal status
N (–)
N (+)
Histological grade
Well Dif.
Mod. Dif.
Poorly Dif.
CA 15.3 levels
<30
≥30
Progesterone Receptors
Negative
Positive
Adjuvant tamoxifen
Yes
No
Overall survival
p
RR CI (95%)
-
-
1
2.0
2.2
4.4
-
0.003
1.1-3.7
1.0-5.7
2.0-10.0
0.0001
1.7-4.9
0.01
0.3-0.8
-
1
1.3
1.5
8.7
0.5-3.6
0.1-12.7
2.8-27.0
-
-
1
0.3
0.1-1.0
-
-
-
-
0.0001
1
4.1
2.8-5.9
1
1.4
2.2
0.8-2.3
1.3-3.8
1
1.6
1.0-2.3
1
2.9
0.004
0.02
-
-
1
0.5
0.001
1
1.7
1.2-2.4
-
-
Negative Nodal Status
Tumoral size
T1
T2
T3
T4
Histological grade
Well Dif.
Mod. Dif.
Poorly Dif.
Progesterone Receptors
Negative
Positive
-
0.01
0.009
1
1.3
3.1
0.5-3.0
1.4-6.9
-
-
1
1.6
1.1-2.5
1
1.7
1.1-2.7
-
-
0.04
Positive Nodal Status
Adjuvant tamoxifen
Yes
No
CA 15.3
Negative
Positive
0.01
-
0.01
-
RR=relative risk; CI=confidence interval.
same analysis showed that only tumor size, nodal status and
adjuvant anti-estrogenic therapy with tamoxifen were
factors significantly associated with both relapse-free and
overall survival in the whole group of patients (Table II).
Martín et al: Serum CA 15.3 in Breast Cancer Prognosis
Figure 2. Relapse-free survival as a function of pre-operative serum CA 15.3 levels in 512 patients with breast carcinoma and negative nodal status (A),
in 295 patients with breast carcinoma and positive nodal status (B), in 196 patients with node-positive breast carcinoma who underwent adjuvant
chemotherapy (C) and in 153 patients with breast carcinoma with positive nodal status who underwent adjuvant anti-estrogenic therapy with tamoxifen (D).
Discussion
In order to develop an adequate plan for the management
of breast cancer is essential the identification, at an early
stage, of patients at a higher risk of recurrence is
essential. Presently, circulating markers seem ideal
candidates to provide alternative information on the
tumor phenotype at the relapse stage. However, the
potential prognostic value of the pre-operative serum
marker levels has rarely been evaluated (8).
The present study demonstrates a percentage (15.2%)
of patients with clinically non-metastatic breast cancer
showing high serum CA 15.3 levels (>30 U/ml) at the
time of diagnosis. These antigen levels correlated
positively and significantly with both tumor size and
axillary lymph node involvement. In addition, elevated
3969
ANTICANCER RESEARCH 26: 3965-3972 (2006)
serum levels of the antigen were notably associated with
a poor patient outcome.
Our results are in accordance with other studies showing
that pre-operative CA 15.3 levels correlate with tumor size
and nodal status in primary breast cancer (15, 21, 24, 28).
The relationship between pre-operative CA 15.3 and these
well-known prognostic factors suggests a potential prognostic
interest of the antigen.
Nevertheless, there are conflicting results in the literature
regarding the prognostic significance of pre-treatment CA
15.3 levels. Thus, high pre-operative serum levels of the
antigen have been associated with a poor outcome in the
overall group of patients (14, 28), or only in the subgroup
of patients with node-positive breast cancer (13, 24).
Likewise, Gion et al. (8) reported a direct relationship
between CA 15.3 levels and prognosis in patients with nodenegative breast cancer, whereas other authors failed to find
any prognostic role of the antigen in node-negative cases
(13, 17, 24). These discrepancies may be due, at least in
part, to several aspects, such as different categorization of
the antigen according to cut-off points, some authors not
evaluating node-negative and node-positive cases separately,
or that multivariate analysis was not performed in some
studies. In addition, it is also worth mentioning that
prognostic evaluation in breast cancer is difficult because
treatments, especially regarding adjuvant ones, have
changed frequently in the last 15 years, making
homogeneous populations difficult to evaluate. Preliminary
reports have shown a weak prognostic role of CA 15.3 levels
in a small patient series without performing a multivariate
analysis (12, 13, 18). Multivariate evaluation of preoperative serum CA 15.3 levels as a prognostic factor has
only been studied in the last seven years (8, 14, 17, 24, 28).
In the majority of these studies, a cut-off value of 30 U/ml
or an approximated one was used. Considering this cut-off
value of the antigen level, the multivariate results of the
present work indicate that preoperative CA 15.3 is a
significant predictor of relapse-free survival in the overall
group of patients. However, once the nodal status after
surgery was known, the antigen was only an independent
prognostic factor when predicting relapse-free survival in
the subgroup of patients with node-positive breast cancer.
This finding is in accordance to data reported by Shering et
al. (24). In addition, our results after univariate analysis
suggest that among women with node-positive breast cancer
who receive chemotherapy, elevated pre-operative CA 15.3
serum levels correlate with outcome, but did not in those
similar patients who receive anti-estrogenic therapy with
tamoxifen. Nevertheless, more recently, Gion et al. (8) also
reported that the relationship of the antigen levels with
prognosis is continuous in patients with node-negative
breast cancer who did not receive any type of systemic
adjuvant therapy, with the risk of relapse increasing
3970
progressively from approximately 10 U/ml. Thus, further
studies should be performed on other independent case
series to confirm the observed prognostic relationships.
In summary, our results indicate that an initially elevated
CA 15.3 level reflects tumor extension, with significantly
higher values in patients with larger tumors or in those with
nodal invasion and that the antigen is a marker of enhanced
risk of recurrence, at least in patients with node-positive
breast cancer. Therefore, taking into account that
circulating CA 15.3 is a non-invasive, reproductive and
objective tool, we consider that CA 15.3 levels obtained at
the time of the initial diagnosis might be an additional
prognostic indicator for breast cancer patients.
Acknowledgements
Supported by grants of ISCII, Red de Centros de cancer RTICC
(C03/10) and Obra Social Cajastur.
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Received March 28, 2006
Revised July 27, 2006
Accepted August 21, 2006
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