Download Circulating Soluble Fas Concentration in Breast Cancer Patients

Vol. 5, 3529 –3533, November 1999
Clinical Cancer Research 3529
Circulating Soluble Fas Concentration in Breast Cancer Patients
Takayuki Ueno, Masakazu Toi,1 and
Takeshi Tominaga
Department of Surgery, Tokyo Metropolitan Komagome Hospital,
Tokyo 113-0021, Japan
ABSTRACT
Fas/Fas ligand (FasL) system, a major regulator of
apoptosis, is involved in cancer cell death induced by the
immune system and anticancer drugs. Fas is a cell-surface
receptor that exists in two forms, transmembrane and soluble. The former induces apoptosis by ligation of FasL or
agonistic anti-Fas antibody, whereas the latter inhibits Fasmediated apoptosis by neutralizing its ligand. In this study,
we examined circulating soluble Fas (sFas) concentration in
118 healthy people, 162 primary and 71 recurrent breast
cancer patients by ELISA. In the healthy group, men
showed higher sFas concentrations than women (P < 0.001).
In both sexes, sFas levels increased with age, and the agematched cutoff value was determined. The median sFas
concentration in primary and recurrent cancer patients was
0.815 and 1.510 ng/ml, both of which were higher than in
normal female controls (0.580 ng/ml; P 5 0.024 and P <
0.001, respectively). Among primary cancer patients, although no significant correlation was found between sFas
concentration and clinical parameters other than menopausal status, high-sFas patients had a worse prognosis than
low-sFas patients for both overall and disease-free survival
(P 5 0.013 and P 5 0.032, respectively). The multivariate
analysis confirmed that circulating sFas concentration was
an independent prognostic indicator (P 5 0.020 for overall
survival, P 5 0.025 for disease-free survival). We looked at
the recurrent cancer patients, and sFas levels were higher in
patients with liver metastasis compared with those with
other recurrent sites (P 5 0.010), and high-sFas patients
showed a worse prognosis than low-sFas patients (P 5
0.037). Our data demonstrate that, compared with healthy
female controls, breast cancer patients, especially those with
liver metastases, have higher circulating sFas levels. sFas
may be useful once these results are confirmed by larger
studies.
Received 1/11/99; revised 8/5/99; accepted 8/9/99.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
1
To whom requests for reprints should be addressed, at Department of
Surgery, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-0021, Japan. Phone: 81-3-3823-2101;
Fax: 81-3-3824-1552.
INTRODUCTION
Fas (Apo-1, CD95) is a cell-surface receptor that is a
member of the tumor necrosis factor/nerve growth factor receptor superfamily (1). By ligation of FasL2 (Ref. 2; CD95 ligand)
or agonistic anti-Fas antibody, Fas induces apoptosis in various
types of cells, including hepatocytes, T and B cells, and mammary epithelial cells (2). Fas-mediated apoptosis is deeply involved in cancer cell death brought about by the immune system
or anticancer drugs. After activation through T-cell receptor,
CTLs express FasL, which binds to Fas on the target cells,
including cancer cells, to induce apoptosis (3). It has been
reported that the loss of Fas function led to lymphoma in T
cell-deficient mice and in Em L-myc transgenic mice (4, 5),
suggesting that the Fas/FasL system plays an important role in
the regulation of tumor development. In addition, several studies
have suggested that the Fas/FasL system is involved in druginduced apoptosis in cancer cells (6, 7).
Fas is found in two forms, transmembrane and soluble. The
soluble form of Fas (sFas), which has five variants produced via
alternative mRNA splicing, inhibits Fas-mediated apoptosis by
neutralizing FasL or anti-Fas antibody (8 –10). Increased concentration of serum sFas has been reported in various diseases,
including not only autoimmune diseases but also neoplastic
diseases such as leukemia, lymphoma, and nonhematopoietic
malignancy (8, 11–14). In bladder cancer patients, the association between increase in serum sFas and poor prognosis was
indicated (15). These findings suggest that cancer cells upregulate or stimulate sFas production to protect themselves from
Fas-mediated apoptosis (16, 17). In this study, to clarify the
clinical significance of sFas, we examined serum sFas concentration in primary and recurrent breast cancer patients and
revealed the relationship between sFas concentration and clinical features including prognosis.
MATERIALS AND METHODS
Patients. One hundred and eighteen healthy people, 59
men and 59 women, and 233 breast cancer patients, including
162 primary and 71 recurrent cancers, treated at Tokyo Metropolitan Komagome Hospital from 1990 to 1997 were enrolled in
this study. All cancer patients were female. Primary cancer
patients had no distant metastases. Patients with liver dysfunction (aspartate aminotransferase .35 IU/l or alanine aminotransferase .35 IU/l) were excluded from the study because it
was reported that hepatitis patients had increased levels of sFas
(18). The average age of the cancer patients was 55.1 years
(range, 30 – 88). Informed consent was obtained from all. Clinical stages were determined according to the criteria of the
Japanese Breast Cancer Society, which is based on the Union
International Contre Cancer criteria. All primary patients had
2
The abbreviations used are: FasL, Fas ligand; sFas, soluble Fas; ER,
estrogen receptor; PgR, progesterone receptor.
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3530 Soluble Fas in Breast Cancer Patients
Table 1
Circulating sFas concentration in normal control
Female
Age group No.
30s
40s
.50
Total
20
20
19
59
a
Male
sFas (ng/ml)
No.
sFasa (ng/ml)
0.200 (0.150–0.760)
0.695 (0.150–1.455)
1.240 (0.150–1.782)
0.580 (0.150–1.380)b
19
20
20
59
1.050 (0.233–2.042)
1.570 (0.150–2.415)
2.235 (1.160–2.725)
1.760 (0.705–2.440)b
a
Median (25th to 75th percentile).
Male controls showed higher concentration of sFas than female
controls (P , 0.001 by Mann-Whitney U test).
b
Fig. 1 Circulating sFas concentration. Circulating sFas levels in primary and recurrent breast cancer patients were significantly higher than
in normal controls (P 5 0.024 and P , 0.001, respectively). The
recurrent cancer patients with liver metastases showed higher sFas
levels than those with the other sites of recurrence (P 5 0.010). The
central box covers the middle 50% of the data values between the upper
and lower quartiles. The central line is at the median. The bars below
and above the box represent 10th and 90th percentile, respectively.
Circles demonstrate the distribution of more extreme values.
undergone either mastectomy or partial mastectomy with axillary lymph node dissection. Adjuvant treatments were applied
according to the following criteria, which did not take into
account circulating sFas concentration. Polychemotherapy, containing doxorubicin, 5-fluorouracil, and cyclophosphamide, was
given for 6 months to patients ,55 years with metastasized
lymph nodes, and hormonal therapy (tamoxifen) was given to
ER-positive patients for .2 years. One hundred and thirty-one
patients received adjuvant therapy, including 26 chemotherapy,
35 hormonal therapy, and 70 chemo-endocrine therapy. For all
patients, including patients with no adjuvant treatments, postoperative physical examinations were performed at least every 3
months. The median follow-up period of surviving patients was
46 months (range, 23– 87). Liver, lung, brain, and distant lymph
node metastases were diagnosed using computed tomographic
scan, and bone metastasis was diagnosed using X-ray and bone
scintigraphy. Among 71 recurrent cancer patients, 30 had single
recurrent sites, and 41 had multiple recurrent sites. Major recurrent sites were liver (n 5 16), lung (n 5 22), brain (n 5 6),
bone (n 5 39), and soft tissue (n 5 43). All recurrent patients
were provided with treatments: 29 with systemic chemotherapy,
12 with hormonal therapy, 20 with chemo-endocrine therapy, 9
with surgical resection, and 1 with radiation therapy.
Samples and Assay. Venous blood samples were drawn
into sterile vacuum tubes at detection of primary breast cancer
or recurrent cancer, prior to treatments being administered. They
were centrifuged at 3000 rpm for 10 min and stored at 220°C
until use. The level of sFas in the sera was determined by ELISA
method using an sFas ELISA kit (Mitsubishi Bio-clinical Laboratories, Inc., Tokyo, Japan). This ELISA system adopted a
specific sandwich method using peroxidase-labeled monoclonal
antibody to the extracellular domain of Fas (amino acids 110 –
120) and polyclonal antibody to the intracellular domain (amino
acids 305–319). This system detects the transmembrane-deficient type of sFas, which is the predominant form in humans.
Five-fold diluted serum was used for determination, and the
standard curve was drawn at concentrations from 0.015 to 2.0
ng/ml.
Hormone Receptor Assay. ER and PgR were measured
by the dextran-coated charcoal method using [3H]17b-estradiol
or by the EIA method. The cutoff values were determined as 5
fmol/mg protein for both hormone receptors.
Statistical Analysis. The distribution of sFas was drawn
by box plots (Fig. 1). Unpaired groups were compared by the
Mann-Whitney U tests or the Kruskal-Wallis rank tests. The x2
test was carried out for qualitative analysis. The survival curves
were drawn by the Kaplan-Meier method, and the difference in
prognosis between two groups was analyzed by the log-rank
test. The multivariate analyses were performed using the Cox
proportional hazards model. P , 0.05 was considered to indicate statistical significance.
RESULTS
In healthy controls, the median concentration of circulating
sFas was 1.135 ng/ml (25th to 75th percentile, 0.150 to 2.000;
mean 6 SD, 1.238 6 1.035). Men had significantly higher sFas
levels than women (P , 0.001; Table 1). The sFas level showed
a gradual increase with age in both sexes, and sFas was higher
in men than in women in all age groups (Table 1).
Among the 162 primary breast cancer patients, the median
sFas level was 0.815 ng/ml (25th to 75th percentile, 0.590 to
1.200), which was significantly higher than in the normal female
controls (median, 0.580 ng/ml; 25th to 75th percentile, 0.150 to
1.380; P 5 0.024; Fig. 1). Table 2 shows sFas concentrations by
clinical stage, menopausal status, ER/PgR status, nodal involvement, and adjuvant therapy administered. sFas concentrations
differed significantly by menopausal status (P , 0.001) but was
not significantly associated with any of the other clinical parameters.
The median sFas level in 71 recurrent breast cancer patients was 1.510 ng/ml (25th to 75th percentile, 1.140 to 2.263),
which was significantly higher than in both normal female
controls and primary cancer patients (P , 0.001, both; Fig. 1).
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Clinical Cancer Research 3531
Table 2
sFas concentration according to clinical parameters in
primary breast cancer patients
Clinical parameters
Clinical stage
I
II
IIIa
IIIb
Menopausal status
PrePost
ER
2
1
Unknown
PgR
2
1
Unknown
Nodal metastasis (n)
2
1
Adjuvant therapies
Chemotherapy
Hormonal therapy
Chemo-endocrine therapy
None
a
Median sFas
No. of
level (ng/ml)
patients (25th to 75th percentile)
35
103
13
11
0.730 (0.518 to 1.078)
0.810 (0.590 to 1.188)
0.880 (0.710 to 1.215)
1.030 (0.600 to 1.350)
P
NSa
0.643
85
77
0.680 (0.520 to 0.890) ,0.001
0.980 (0.730 to 1.350)
65
74
23
0.750 (0.545 to 1.177)
0.870 (0.650 to 1.280)
0.630 (0.282 to 1.077)
NS
0.070
81
57
24
0.870 (0.640 to 1.210)
0.750 (0.545 to 1.263)
0.660 (0.355 to 1.135)
NS
0.267
74
88
0.850 (0.595 to 1.270)
0.810 (0.610 to 1.190)
NS
0.959
26
35
70
31
0.935 (0.690 to 1.270)
0.860 (0.540 to 1.268)
0.770 (0.590 to 1.060)
0.895 (0.630 to 1.700)
NS
0.581
NS, not significant.
In addition, the patients with liver metastasis (median, 2.710
ng/ml; 25th to 75th percentile, 1.340 to 3.440) showed significantly higher concentrations than those with other sites of recurrence (median, 1.430 ng/ml; 25th to 75th percentile, 1.140 to
2.040; P 5 0.010; Fig. 1). There was no significant difference in
sFas concentration between patients with multiple sites of recurrence (median, 1.730 ng/ml; 25th to 75th percentile, 1.140 to
2.615) and those with single sites of recurrence (median, 1.435
ng/ml; 25th to 75th percentile, 1.130 to 2.060; P 5 0.409).
We evaluated the prognostic value of sFas with cutoff
values set at a median, a 75th percentile, and a 90th percentile
of female controls by age decades, and the cutoff value at the
75th percentile provided the most significant difference in
prognosis (log-rank test). Thus, we determined the agematched cutoff value as a 75th percentile of female controls
in each age group (shown in Table 1). Between primary
cancer patients with high sFas levels (above the cutoff value;
n 5 18) and those with low levels (below the cutoff value;
n 5 144), there was no significant difference in age, type of
adjuvant treatment, or clinical parameters including tumor
size, lymph node metastases, hormone receptor status, and
clinical stage. All primary cancer patients had no metastases.
Survival analysis demonstrated that patients with high sFas
concentrations had a worse prognosis than those with low
concentrations in both overall survival and disease-free survival (P 5 0.013 and P 5 0.032, respectively, log-rank test;
Fig. 2, A and B). Furthermore, multivariable analysis confirmed that the circulating sFas concentration was an independent prognostic indicator in overall and disease-free survival (P 5 0.020 and P 5 0.025, Cox proportional hazards
Fig. 2 A, overall survival curves in primary breast cancer patients. B,
disease-free survival curves in primary breast cancer patients. C, overall
survival curves in recurrent breast cancer patients. All survival curves
were drawn by the Kaplan-Meier method. Bold lines, circulating sFas
more than the age-matched cutoff value (n 5 18 in primary cancer
patients and n 5 32 in recurrent cancer patients); thin lines, circulating
sFas less than or equal to the cutoff value (n 5 144 in primary cancer
patients and n 5 39 in recurrent cancer patients). In primary breast
cancer, patients with high sFas concentrations had a worse prognosis
than those with low sFas concentrations in overall survival (P 5 0.013,
log-rank test; A) and in disease-free survival (P 5 0.032; B). The
significant difference in overall survival was also seen in recurrent
cancer patients (P 5 0.037; C).
model; Table 3). For recurrent cancer patients, high-sFas
patients (n 5 32) had a worse prognosis than low-sFas
patients (n 5 39) in overall survival after detection of recurrence (P 5 0.037, log-rank test; Fig. 2C), but sFas concentration was not an independent prognostic indicator by multivariable analysis, which showed that liver metastasis was an
independent predictor (data not shown).
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3532 Soluble Fas in Breast Cancer Patients
Table 3 Multivariable analysis in primary breast cancer patients
(Cox proportional hazards model)
A. Overall survival
Circulating sFas: high vs. lowb
Lymph node metastasis: 1 vs. 2
ER: 2 vs. 1
Tumor size: .2.0 cm vs. ,2.0 cm
Adjuvant therapies
Chemotherapy
Hormonal therapy
Chemo-endocrine therapy
B. Disease-free survival
Circulating sFas: high vs. low
Lymph node metastasis: 1 vs. 2
ER: 2 vs. 1
Tumor size: .2.0 cm vs. ,2.0 cm
Adjuvant therapies
Chemotherapy
Hormonal therapy
Chemo-endocrine therapy
a
b
Hazard ratio
95% CIa
P
4.178
7.475
1.564
1.358
1.250–13.961
1.361–41.065
0.563–4.340
0.136–13.537
0.020
0.021
0.391
0.794
3.164
0.644
2.958
0.254–39.394 0.371
0.037–11.085 0.762
0.380–23.057 0.301
4.022
7.610
1.029
0.371
1.190–13.596
1.950–29.705
0.407–2.603
0.112–1.230
2.239
0.710
2.086
0.335–14.976 0.406
0.099–5.113 0.734
0.423–10.282 0.366
0.025
0.004
0.951
0.105
CI, confidence interval.
High, above the cut-off value; low, below the cut-off value.
DISCUSSION
In this study, we demonstrated that circulating sFas concentration was increased in breast cancer patients, particularly
recurrent cancer patients, and that sFas concentration was an
independent prognostic indicator for both overall and diseasefree survival. The sFas function has not yet been fully elucidated, but there are several investigations suggesting the role of
sFas in cancer progression. sFas has been reported to play an
important role in the regulation of apoptosis as an inhibitor of
Fas-mediated apoptosis (8 –10). Recent studies have revealed
that the Fas/FasL system is an important mechanism for tumor
escape from the immune system: expression of FasL on tumor
cell surfaces and emission of soluble form of FasL (19 –24).
sFas is thought to be another mechanism for tumor immune
evasion (16, 17), and it was documented that there was an
inverse correlation between serum sFas levels and anti-autologous tumor cytotoxicity in bladder cancer patients, suggesting
that sFas is related with tumor immune evasion in cancer patients (15). In addition, because the Fas-mediated apoptosis has
been demonstrated to be involved in anticancer drug-induced
apoptosis (6, 7), it is conceivable that sFas causes resistance to
treatments by inhibiting Fas-mediated apoptosis in cancer cells.
Although the precise functions of sFas remain to be clarified,
these functions related to the immune evasion or drug resistance
may contribute to the poor prognosis for both overall and
disease-free survival in high-sFas patients. Because the number
of patients with high sFas concentration was small in this study,
further clinical studies will be needed to confirm our results.
We determined the age-matched cutoff value in this study.
Seishima et al. (25) first reported that sFas concentration in
healthy people increased with age and differed in sex. Therefore, it is important to take account of age and sex in evaluation
of serum sFas concentration, and we showed the prognostic
value of sFas using the age-matched cutoff value of women.
This age-matched cutoff value will be useful to further assess
the circulating sFas concentration in various diseases. The sFas
values in healthy controls were different among studies (12–15,
18, 25). Although the exact reason for the difference is unclear,
several factors seem to be involved, including differences in
control groups, in sensitivity of the antibodies, and in characters
of the standards.
Recurrent cancer patients with liver metastasis showed a
remarkable increase in sFas level in this study. As is well
known, the appearance of liver metastasis is a predictor of poor
prognosis for a variety of solid tumors, including breast cancer.
However, little is known about the reason. It may be possible
that this notable elevation in sFas contributes to rapid progression of metastatic liver tumors. In colon cancer, no difference in
sFas levels was reported between primary patients and patients
with liver metastasis (12). Thus, the mechanism of sFas induction might differ depending on tumor type.
The expression mechanism and cellular origins of sFas are
still unclear. In gastric cancer, sFas-mRNA expression was
demonstrated in cancer cells and lymphocytes of metastasized
lymph nodes by in situ reverse transcription-PCR (26). It was
further reported that all of the following express sFas mRNA:
activated peripheral blood mononuclear cells of healthy donors,
hepatocytes, and several tumor cell lines, including leukemia,
osteosarcoma, and glioma (9, 10, 16, 27, 28). Interestingly, it
was reported that an Adriamycin-resistant breast cancer cell line
(MCF7Adr) produced sFas, although the wild-type (MCF7) did
not (29), indicating that cancer cells may change the expression
level of sFas, depending on their phenotypes. These findings
suggest that circulating sFas derives from various origins, including cancer cells, stromal cells, and other visceral cells.
In conclusion, this study demonstrates that circulating sFas
concentration is increased in breast cancer patients, especially
those with liver metastases. The patient number is small in this
study. Larger clinical studies are important to establish the
clinical significance of sFas. The determination of sFas may be
useful once additional studies confirm the results of the present
study.
ACKNOWLEDGMENTS
We thank Mariko Muta, Eiko Isobe, and Masahiro Fuwa for
technical and statistical assistance.
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Circulating Soluble Fas Concentration in Breast Cancer
Patients
Takayuki Ueno, Masakazu Toi and Takeshi Tominaga
Clin Cancer Res 1999;5:3529-3533.
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