ARTICLE
Auteur(s) : Houda Bouanène1,
Imed Harrabi2, Salima Ferchichi1, Halima Ben
Limem1, Abdelhedi Miled1
1 Laboratory of biochemistry, CHU F.-Hached, Sousse,
Tunisie
2 Service of epidemiology, CHU F.-Hached, Sousse,
Tunisie
Many circulating markers are already in clinical practice and in
experimental use for the diagnosis, therapeutic monitoring, and in
the follow-up of ovarian cancer. They can also be useful in
targeted therapy. CA125 (cancer antigen 125) is a tumor marker that
is widely used to monitor ovarian cancer because it is
overexpressed in ovarian cancer cells and secreted into the blood.
Serum CA125 is used in monitoring treatment and detecting
recurrence in ovarian cancer. CA125 (originally named OC125) was
developed by Bast et al. [1]. It is a mucin-type O-linked
glycoprotein, but other details about its molecular nature remain
unclear [2]. The concentration of the serum antigen, CA125, changes
with the regression or progression of epithelial ovarian cancer [3,
4]. It is generally agreed that CA125 monitoring is an essential
part of the disease surveillance process in women with ovarian
cancer, and regular (typically every few months) monitoring
typically occurs [5]. Estimation of serum CA125 level has become a
standard component of routine management of women with advanced
ovarian cancer [6]. It helps to confirm the diagnosis of ovarian
cancer in women presenting with pelvic masses and is used in the
risk of malignancy index (RMI) [7]. The main issue with any serum
tumor marker is its utility in providing reliable and reproducible
information. Several factors that come into play in observed
changes in serial results include intra-individual biological
variation and the patient’s clinical condition. It is important to
note, however, that CA125 levels may also be elevated for other
reasons. In the present study, we conducted a logistic regression
analysis to determine factors that may be significant predictors of
elevated CA125 concentrations in Tunisian women suffering from
epithelial ovarian cancer.
Materials and methods
Study design
By use of a retrospective chart review, patients with
histologically confirmed epithelial ovarian cancers were recruited.
This study included Tunisian women who were treated at CHU Farhat
Hached, Sousse (Tunisia) between 1994 and 2006. Histology and
disease disease were defined according to the criteria outlined by
the Oncology Committee of the International Federation of
Gynecology and Obstetrics (FIGO). Patients were eligible if they
had at least 3 assessments of the CA125 concentration. CA125 serum
levels were determined before and during treatment.
Laboratory method
The serum CA125 values were quantitatively measured with a
commercially available automated microparticle enzyme immunoassay
method (Abbott AxSym system, Abbott Laboratories, Abbott Park,
Illinois), following the manufacturer’s recommendations. The
cut-off value for “normal” in this system was <35 U/ml. Patient
specimens with CA125 assay values exceeding 600 U/ml were diluted
to quantify the concentration of the tumor marker.
Statistical analysis
Statistical analysis of the data was performed using SPSS 11.5
software. Data are expressed as means ± standard deviation (SD).
The comparison of patient characteristics was performed using the
2 test to compare categorical variables and the t test
was used to compare continuous variables. A logistic model was
constructed for use in the multivariate analysis. In this model,
the effect of having an elevated serum CA125 concentration was
analyzed together with variables found to be statistically
significant predictors of CA125 concentration in univariate
analysis. Values of p < 0.05 were considered statistically
significant.
Results
The study group consisted of ninety epithelial ovarian cancer
patients, for whom at least three CA125 blood samples were
obtained. The patient characteristics are summarized in Table 1. The median age of patients at diagnosis
was 53 years (range 18-79). The distribution of initial CA125
concentrations from each patient is shown in figure 1. Pretreatment
serum CA125 levels ranged from 5 to 13,221 UI/ml with a mean of
1,049.04 ± 2,052.9 UI/ml. CA125 values were < 35 UI/ml in 10% of
the cases. Variables found to be statistically significant
predictors of the increase of CA125 concentration in univariate
analysis are shown in Table 2.
Univariate analysis was performed on the following parameters: age,
menopausal status, ascites, the presence of carcinosis, histology,
size of primary tumor and FIGO stage. Significant correlations were
observed between elevated levels of CA125 (> 100 UI/ml) and
age (p = 0.008), menopausal status (p = 0.03), ascitis (p = 0.02),
the presence of carcinosis (p = 0.003) and tumor histology (p =
0.02). In order to determine which potential predictors were
independently significant for CA125 elevation, we performed a
logistic regression analysis for all variables showing a
statistically significant value in univariate analysis. Logistic
regression showed that age (< 45 versus ≥ 45 years, odds ratio =
6.1, p = 0.016), menopausal status (odds ratio = 2.76, p = 0.034),
ascitis (present versus absent, odds ratio = 3.17, p = 0.023),
carcinosis (present versus absent, odds ratio = 5.31, p = 0.005)
and histological type (serous versus other histological subtypes,
odds ratio = 2.42, p = 0.001) retained a significant value in
predicting serum CA125 increase (Table
3).
Table 1 Characteristics of the patients
|
Characteristics
|
N
|
%
|
|
Age (yr)
|
|
|
|
< 45
|
9
|
10
|
|
≥ 45
|
81
|
90
|
|
Tumor size (cm)
|
|
|
|
< 10
|
19
|
21.11
|
|
≥ 10
|
53
|
58.88
|
|
No information
|
18
|
20
|
|
Histological type
|
|
|
|
Serous
|
46
|
47.44
|
|
Mucinous
|
13
|
11.26
|
|
Endometrioid
|
8
|
10.26
|
|
Other types
|
5
|
5.56
|
|
Unknown
|
18
|
21.79
|
|
Primary tumor
|
|
|
|
Unilateral
|
40
|
44.44
|
|
Bilateral
|
47
|
52.22
|
|
No information
|
3
|
3.33
|
|
FIGO stage
|
|
|
|
Low tumor stage(I, II)
|
12
|
13.33
|
|
High tumor stage (III, IV)
|
78
|
86.67
|
|
Menopause
|
|
|
|
Premenopause
|
33
|
36.67
|
|
Postmenopause
|
57
|
63.33
|
|
Ascites
|
|
|
|
Absent
|
23
|
25.56
|
|
Present
|
67
|
74.44
|
|
Carcinosis
|
|
|
|
Present
|
38
|
42.22
|
|
Absent
|
52
|
57.78
|
|
Site of metastases
|
|
|
|
Liver
|
4
|
4.44
|
|
Lung
|
2
|
2.22
|
|
Peritoneum
|
18
|
20
|
|
Multiple sites
|
15
|
16.67
|
|
Other
|
16
|
17.78
|
Table 2 Variables predictive of high CA125
concentration by univariate analysis
|
CA125 (UI/ml)
|
|
Variable
|
Mean ± SD
|
p value
|
|
Age
|
|
|
|
<45
|
818.33 ± 1962.714
|
0.008
|
|
≥45
|
1074.68 ± 2072.862
|
|
|
Primary tumor
|
|
|
|
Unilateral
|
1183.25 ± 2305.106
|
0.23
|
|
Bilateral
|
902.72 ± 1874.273
|
|
|
FIGO stage
|
|
|
|
Low (I. II)
|
364.92 ± 364.92
|
0.08
|
|
High (III. IV)
|
1154.29 ± 2179.250
|
|
|
Menopause
|
|
|
|
Premenopause
|
622.67 ± 1142.191
|
0.03
|
|
Postmenopause
|
1295.89 ± 2404.872
|
|
|
Ascites
|
|
|
|
Present
|
1061.04 ± 2597.364
|
0.02
|
|
Absent
|
1044.93 ± 1853.202
|
|
|
Carcinosis
|
|
|
|
Present
|
1161.37 ± 2196.515
|
0.003
|
|
Absent
|
888.56 ± 1882.322
|
|
|
Histological type
|
|
|
|
Serous
|
995.22 ± 1219.749
|
0.02
|
|
Other
|
312.67 ± 456.786
|
|
Table 3 Variables predictive of high CA125
concentration by logistic regression
|
Predictor variable
|
Odds ratio exp(B)
|
p value
|
|
Age
|
|
|
|
Less than 45 years
|
6.1
|
0.016
|
|
Greater or equal to 45 years
|
|
|
|
Menopause
|
|
|
|
Premenopause
|
2.763
|
0.034
|
|
Postmenopause
|
|
|
|
Ascite
|
|
|
|
Absent
|
3.178
|
0.023
|
|
Present
|
|
|
|
Carcinosis
|
|
|
|
Absent
|
5.312
|
0.005
|
|
Present
|
|
|
|
Histological type
|
|
|
|
Serous
|
2.429
|
0.001
|
|
Other histological subtypes
|
|
|
Discussion
Interpretation of rising CA125 levels in diagnosed patients
continues to be a topic of conversation among clinicians [8]. It is
well known that CA125 is a tumor marker overexpressed in patients
suffering from ovarian cancer. This study aimed to focus on factors
that could predict an increased level of CA125 in patients with
ovarian cancer.
Some limitations of the current study should be noted. As in all
retrospective studies, there are limitations to this analysis. A
retrospective chart review always struggles with incomplete data
and the size of the patient cohort. 78 cases were excluded from the
study because of absence of the initial evaluation of the CA125.
However, our findings are consistent with previously published
reports of the tumor marker CA125 as a statistically significant,
independent negative prognostic factor in ovarian carcinomas [9,
10]. These data provide additional indicators of serum CA125
increase and revealed that CA125 levels are significantly higher in
postmenopausal patients. Various authors have described factors
influencing CA125 concentrations in healthy women, such as
menopausal status [11, 12] and age [11, 13]. Donna et al. [14] took
the menopausal status into account and found that CA125 levels are
lower in postmenopausal women who have undergone hysterectomy.
Arjun et al. [10] suggested that serum CA125 elevation is an
independent predictor of survival in apparently healthy
postmenopausal women and demonstrate that it would be a powerful
predictor of the subsequent diagnosis of ovarian cancer. As an
explanation, Malgorzata et al. [15] report that biological
variation in CA125 was greater in premenopausal than in
postmenopausal females and this could be due mainly to functional
activity of the ovaries and the menstrual cycle. In the current
study, we investigated these two factors in patients with
epithelial ovarian cancer, and found that patients who had the
highest values of serum CA125 were more frequently postmenopausal
and were significantly older. Based on the fact that older women
would be more likely to have accumulated a great number of
transformed ovarian surface epithelial cells than younger women
[16], we suppose that this could be the origin of increased CA125
since transformed human ovarian surface epithelial cells
recapitulated many features of natural ovarian cancer including a
subtype of ovarian cancer histology, formation of ascites, CA125
expression, and nuclear factor-kappaB-mediated cytokine activation
[17].
Increases in CA125 above 100 UI/ml have been shown to be
associated with ascites. Bergmann et al. [18] demonstrated that
high CA125 levels are closely related to the presence of ascites
whatever the origin. More recently, Yamazawa et al. [19] examined
differences in CA125 levels within endometrioid adenocarcinomas.
Serum CA125 levels and immunohistochemical staining for CA125 were
assessed. Discordance between serum levels and tissue
immunohistochemical staining of CA125 was found in endometrioid
adenocarcinoma of the uterine corpus revealing that elevated serum
level is closely related to the presence of disseminated cancer
cells in the peritoneal cavity [19]. The presence of ascites is
associated with median CA125 levels of 897 U/ml while levels were
230 U/ml in patients without ascites (p < 0.001) [20]. Thus,
ascites itself could induce elevation of CA125 serum levels
[21].
An important finding of our study was the high correlation of
CA125 levels with carcinosis. To our knowledge, no previous study
of CA125 has considered the effects of carcinosis. Interestingly,
our analysis of the concentrations of serum CA125 revealed that
high CA125 concentrations were significantly associated with the
presence of carcinosis.
Histological findings revealed that there was a significant
increase in CA125 levels in women with serous histotype. In a study
by Lindblom et al. in ovarian cancer, an increase in serum
concentrations of cancer antigen marker CA125 may predict serous
adenocarcinoma [22]. The results were in accordance with the
observations reported by Ivanov who found that in patients with
epithelial ovarian cancer the preoperative levels of CAl25 have no
relationship with increased age, but are very much correlated with
the histological type, mainly with a serous component [20].
In the current study, we observed increased CA125 serum levels
in patients with high FIGO stages and unilateral tumors. The trend
was, however, not statistically significant. According to Ivanov et
al. [20] the serum CA125 level was, on the contrary, reported to be
correlated with high stage. He observed that the levels were 783
U/ml in patients with high stage III-IV and 145 U/ml in patients
with lower stage (p < 0.001). We also evaluated the incidence of
bilateralism of the primary tumor but again we were unable to show
any statistical influence on serum CA125 level (p = 0.23). There is
considerable evidence to support the hypothesis that serum CA125
levels do not reflect the total amount of this tumor marker. These
results could be explained by the study done by Armin et al. [23]
that proves absence of correlation between serum CA125 and CA125
tissue staining. Moreover, it has been reported that basement
membranes surrounding the tissues in which the tumors arise, as
well as peritoneal barriers, hinder such high molecular weight
proteins as CA125 from entering the circulation [24]. However, this
retention mechanism alone cannot fully explain the lack of serum
CA125 in some patients with advanced stage disease where the
basement membrane of the tissue of origin has ruptured, and it has
thus been proposed that an unidentified mechanism for CA125 tissue
retention must exist, being active with differential efficiency in
different gynecological cancers [25]. Armin et al. [24] reported
that in patient with advanced stage ovarian cancer, serum CA125 was
normal but CA125 tissue staining was positive and precisely
co-localized with mesothelin staining, raising the possibility that
mesothelin may be able to trap CA125 in the tissue when it is
overexpressed in the same location. This information raises
hypotheses regarding the molecular mechanisms involving CA125 that
may mediate the formation and spread of secondary tumor growth.
Although CA125 is expressed both by normal and tumor cells [2, 26]
cell-surface expression and release of soluble proteolytic
fragments of CA125 into the extracellular space [27] appear to be
associated with the conversion from benign to cancer cells [28].
Furthermore, variations in the MUC16 (Mucin 16) gene, witch
encodes the protein CA125 [29], may cause changes in the CA125
protein because it is a multivalent molecule (i.e., the antibody
used to trap and detect it can bind in many portions of the
molecule). In most circumstances, serum laboratory tests detect one
molecule and quantify it, with no genotypic information required.
However, given the molecular complexity of the CA125 tumor antigen,
patients with different genotypes of MUC16 may display differences
in the amount of the CA125 protein product it encodes. Thus, the
assumption that clinicians are measuring the same biomarker between
patients with different genes is subject to question. This is
clinically significant, as our reference values of CA125 do not
take into account which allele of the gene women carry [28].
Finally, in our study we have shown for the first time that
carcinosis is independently predictive of high CA125 concentration.
Our results support the emerging evidence showing that high CA125
level may be predicted by age, menopausal status, the presence of
ascites, the serous histological subtype. Through this study we
have proven how clinicopathological parameters allow for such
variation of CA125 levels across women with ovarian cancer. Since
clinicians make important decisions based on this tumor marker, use
it to monitor chemotherapeutic response, success of surgery, and
decide initiation of palliative care, results provided by this
study should lead to the best interpretation of rising CA125 levels
and consequently to more appropriate management of epithelial
ovarian cancer patients.
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