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Molecular Oncology, Markers, Clinical Correlates |
Laboratoire d’Oncobiologie [M. F-P., F. S.] and Départements de Biologie [C. B.], de Statistiques Médicales [K. H.], d’Anatomie Pathologique [V. L. D.], and Médecine [M. T-H.], Centre René Huguenin de Lutte Contre Le Cancer, 92211 Saint-Cloud, France
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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High levels of c-erbB-2 (>500 IU/mg protein) were associated with estrogen receptor (ER) and progesterone receptor negativity, high histoprognostic SBR grade and high levels of uPA and p53. Univariate analyses showed shorter metastasis-free survival (MFS) and overall survival (OS) in patients whose tumors overexpressed c-erbB-2 in the overall population, in subgroups defined by ER and uPA status, and in patients with positive pathological nodal status, SBR grade II, progesterone receptor, and p53-negative tumors. Patients with ER-positive, c-erbB-2-positive tumors had a shorter MFS and OS than those patients with c-erbB-2-negative tumors. No difference was observed between adjuvant-treated and untreated patients (chemotherapy and/or hormone therapy) in the c-erbB-2-negative subgroup. There was a trend toward a longer short-term MFS in c-erbB-2-positive patients treated with chemotherapy, whereas an opposite effect was observed with hormone therapy.
Cox multivariate analyses showed that high levels of c-erbB-2 negatively influenced MFS in the overall population as well as in node-positive patients and in tamoxifen-treated patients, along with pN and uPA. Results for OS were comparable with those obtained for MFS. These results suggest that c-erbB-2 overexpression in breast cancer may be a better predictor of the response to tamoxifen than is ER status alone.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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The techniques used to assess c-erbB-2 status in breast cancer have included gene-based assays such as Southern blotting, PCR-based methods, in situ hybridization (1) , and, more recently, real-time reverse transcription-PCR (2) . Qualitative and quantitative c-erbB-2 protein measurements have been performed by means of IHC3 (on frozen and archived tissues), Western blotting, and ELISAs (1 , 3) . Most published data on c-erbB-2 were obtained with semiquantitative immunohistochemical methods on paraffin-embedded material. The results of breast cancer outcome studies have tended to conflict, and discrepancies between the results of different methods for detecting c-erbB-2 abnormalities have been described (3) . Nonetheless, nearly all studies reported, to date, have shown a strong negative relationship between c-erbB-2 and steroid receptor status. In most studies, a significantly worse prognosis was noted in c-erbB-2-positive patients, whatever the treatment, suggesting that c-erbB-2 could be a marker of the treatment response (1 , 3 , 4) . The aim of this study was to assess c-erbB-2 overexpression by using a quantitative biochemical technique in 488 primary breast cancer patients with long-term follow-up, and its relation to adjuvant therapy and other biochemical prognostic factors (c-erbB-2, uPA, p53, and EGFR). All these parameters were determined on surgical samples obtained for ER and PR assays.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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Evaluation of Prognostic Factors.
Tumor sampling was always performed by a pathologist, and fat
and necrosis were removed. Samples were taken opposite those frozen for
intraoperative histological diagnosis and were immediately frozen in
liquid nitrogen. The percentage of tumor cells was always checked by
the imprint method, and samples containing <20% of tumor cells were
eliminated.
The clinical size of the tumor was determined at diagnosis. At surgery, macroscopic tumor size was established and defined as the largest tumor diameter measured by the pathologist; the histological grade and hormone receptor status of the tumor, as well as the number of positive axillary lymph nodes, were also recorded at that time. Histological grading was performed according to Bloom and Richardson (5) and Scarff and Torloni (6) .
ERs and PRs were assayed until 1988 by using the Dextran-coated charcoal method (7) , and thereafter using a commercial immunoenzymatic method (Abbott ER-EIA-monoclonal kit and Abbott PgR-EIA-monoclonal kit; Abbott Laboratories, North Chicago, IL). The detection cutoff was set at 10 fmol/mg protein until 1988 and then at 15 fmol/mg protein. Quality control was based on regular testing of both internal controls (pooled cytosols) and European Organization for Research and Treatment of Cancer controls (8 , 9) . For this study, frozen tumor specimens (mean weight, 0.22 g) were homogenized in hormone receptor buffer [10 mM Tris-HCl (pH 7.4), 1.5 mM EDTA, 10 mM Na2MoO4, 0.5 mM dithiotreitol, and 10% glycerol] and centrifuged for 1 h at 105,000 x g. The supernatants were aliquoted and stored at -80°C until analysis (p53 and uPA). The pellets were homogenized in Triton buffer containing 20 mM Tris-HCl, 125 mM NaCl, 1% Triton X-100 (pH 8.8), and left for 15 min at 0°C before centrifugation (100,000 x g for 1 h). The supernatants, consisting of membrane extracts, were collected and stored at -80°C until analysis (c-erbB-2 and EGFR). For each parameter, internal controls (pooled cytosols or membrane extracts) were used in each series of tests. Cytosol and membrane extract protein concentrations were determined using the BCA assay (Pierce Chemical Co., Rockford, IL). All assays were done in duplicate.
Enzyme Immunoassay for c-erbB-2.
The Triton c-erbB-2 Tissue Extract EIA kit (Ciba Corning
Diagnostics, Alameda, CA) is a double monoclonal antibody-based assay.
The two monoclonal antibodies, designated TAB 257 and TAB 259, are
specific for different epitopes of the external domain of the
c-erbB-2 molecule (10)
.
Assays for uPA, p53, and EGFR.
uPA and p53 in cytosol were assayed by using a luminometric immunoassay
(LIA-mat uPA and LIA-mat p53; Byk Sangtec Diagnostica, Bromma, Sweden)
based on a monoclonal antibody two-site incubation (11)
.
The Triton EGFR Tissue Extract EIA kit (Ciba Corning Diagnostics) is a
double monoclonal antibody-based assay. The two monoclonal antibodies
used in this assay are specific for the extracellular domains of the
protein (12)
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Statistical Methods.
MFS was defined as the time between diagnosis and the occurrence of the
first distant metastasis or the end of the study. Patients who died of
causes unrelated to breast cancer were considered as censored at the
time of death. Hereafter, "death" refers to breast cancer-related
death for OS.
Differences in the distribution of characteristics among patient
subgroups were analyzed using the 
2 test. The
optimal cutoff for dichotomized variables to discriminate low-risk and
high-risk patients were determined using log-rank statistics corrected
according to Hilsenbeck and Clark (13)
. Actuarial MFS and
OS rates were computed using the Kaplan-Meier method (14)
and compared using the log-rank test (15)
. A stepwise
selection procedure based on the Cox proportional hazards model
(16)
was used to assess the relative importance of the
prognostic factors. The multivariate analysis took into account all of
the variables cited in Table 1
and also adjuvant hormone therapy and adjuvant chemotherapy.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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. The optimal cutoff value for
c-erbB-2 was optimized at 500 IU/mg protein, which selected
13.3% of the patients as high risk. The mean c-erbB-2 level
was 327 (+/-433.1) IU/mg protein (range, 0–2640 IU/mg protein), and
the median value was 170 IU/mg protein.
Relationship between c-erbB-2 and the Other
Variables.
The relationships between c-erbB-2 and classical and
biological variables are presented in Table 1
. c-erbB-2
status was not related to age, clinical or histological tumor size,
pathological nodal, or EGFR status. ER-negative tumors were more likely
to be c-erbB-2 positive than were ER-positive tumors (28.1%
versus 8%). Similarly, PR-negative tumors were more likely
to be c-erbB-2 positive than were PR-positive tumors (21%
versus 7.5%). High levels of c-erbB-2 correlated
with high histological SBR grade, elevated uPA, and, to a lesser
extent, high levels of p53.
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Univariate Prognostic Analysis |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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Biological Variables.
ER status did not influence MFS. Patients with negative PR had
lower MFS (P < 0.01) than did those with positive PR
status. Shorter MFS was observed in patients with high levels of uPA
than in those with low levels of uPA (P < 0.0001).
Shorter MFS was observed in patients whose tumors contained high
concentrations of p53 (P < 0.01). With respect to
EGFR, patients whose tumors contained low or high levels had shorter
MFS than did those with intermediate levels (P <
0.01). Log rank test analyses of OS gave results similar to those of
MFS, except for ER-negative patients who had shorter OS than
ER-positive patients (P = 0.0043).
c-erbB-2 in the Overall Population.
Patients whose tumors contained high levels of c-erbB-2
had lower MFS (P < 0.0005) than did those with low
levels of c-erbB-2 (Fig. 1)
. The 5-year MFS rate was 62.6% in patients with high
c-erbB-2 levels and 84.2% in patients with low
c-erbB-2 levels. Patients whose tumors contained high
c-erbB-2 levels had shorter OS than those with low
c-erbB-2 levels (P < 0.0001): the
respective 5-year OS rates were 67.7% and 88.4%.
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Pathological Tumor Size and c-erbB-2 Status.
For MFS and OS, c-erbB-2 status added prognostic information
to large tumor size (>20 mm; P < 0.001), but not to
small tumor size.
Lymph Node Status and c-erbB-2 Status.
Among the 226 node-negative patients, MFS was not significantly
different between those with low c-erbB-2 expression and
those with high c-erbB-2 expression, whereas slightly
shorter OS was observed in patients with high c-erbB-2
expression (P = 0.032). In the node-positive group, MFS
and OS were significantly longer in patients with low
c-erbB-2 expression than in those with high
c-erbB-2 expression (P < 0.001).
Histological Grade and c-erbB-2 Status.
For MFS and OS, c-erbB-2 added prognostic information to SBR
grade II patients (P = 0.035 and 0.004, respectively).
For OS, c-erbB-2 added also prognostic information to SBR
grade III patients (P = 0.018).
Hormone Receptor and c-erbB-2 Status.
c-erbB-2 added prognostic value to ER status (Fig. 2,a and b)
. Among ER-positive patients, we
observed a lower MFS and OS in c-erbB-2-positive patients
than in c-erbB-2-negative patients (P =
0.025 and 0.00063, respectively). MFS and OS were significantly shorter
in ER-negative, c-erbB-2-positive patients than in
ER-negative, c-erbB-2-negative patients (P =
0.04 and 0.03, respectively). Among PR-positive patients, no
statistical difference was observed for MFS, whereas a shorter OS was
observed for c-erbB-2-positive patients (P =
0.005). Among PR-negative patients, MFS and OS were shorter in
c-erbB-2-positive patients than in
c-erbB-2-negative patients (P = 0.02 and
0.0054, respectively).
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. Among patients with low levels of uPA,
c-erbB-2-positive patients had shorter MFS and OS than
c-erbB-2-negative patients (P = 0.04 and
0.0096, respectively). Among patients with high levels of uPA (>1.14
ng/mg protein), MFS and OS were shorter in c-erbB-2-positive
patients than in c-erbB-2-negative patients
(P = 0.02 and 0.0018, respectively).
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a), but not to high p53 values (Fig. 4
b). MFS and
OS were significantly shorter in the low-p53
c-erbB-2-negative group than in the low-p53
c-erbB-2-positive group (P < 0.001). No
statistical difference was observed in the high p53 patients group.
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c-erbB-2 Status and Adjuvant Treatment.
Among patients with c-erbB-2-negative expression, MFS did
not differ between those treated with adjuvant tamoxifen and those who
did not receive tamoxifen (Fig. 5
a) or between those treated with chemotherapy and those who
did not receive chemotherapy (Fig. 5
b).In patients’
c-erbB-2-positive expression MFS curves (Fig. 5
c)
showed an adverse effect of tamoxifen during the first 5 years of
follow-up, but the difference with untreated patients was not
significant. With regard to chemotherapy (Fig. 5
d), patients
with c-erbB-2-positive expression benefited from the
treatment during the first 5 years of follow-up relative to the
untreated group.
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a) and P = 0.009 for OS], whereas no
significant difference was observed in ER-positive,
c-erbB-2-negative patients (Fig. 6
b).
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Multivariate Analysis |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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were tested in multivariate
Cox regression analyses for their relationship with OS and MFS, both in
the overall population and in subgroups defined by lymph node status
(Table 3)
and adjuvant therapy (Table 4)
.
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Subgroup Defined by Nodal Status.
In node-negative patients, c-erbB-2 was not found to be an
independent factor. For MFS, higher uPA values were the only adverse
prognostic selected factor in this subgroup. Larger clinical tumor size
was related to a shorter OS.
In node-positive patients, a higher uPA value, a larger number of positive lymph nodes, a larger tumor size, and higher c-erbB-2 expression were significant independent predictors of shorter MFS and OS. For OS, 50 years of age or more was also a predictor of shorter OS.
Patients Receiving Chemotherapy.
Multivariate analysis showed that higher uPA values, a larger tumor
size, and a larger number of positive lymph nodes were adverse
significant predictors of MFS and OS.
Patients Receiving Tamoxifen.
Multivariate analysis showed that a larger number of positive lymph
nodes and higher c-erbB-2 expression were significant
adverse predictors of MFS and OS. Higher uPA values were also
predictive of shorter OS.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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In this study we used a simple, reproducible biochemical assay, which is sensitive, quantitative, and appropriate for routine analysis. Another multicenter study using the same assay method showed a comparable c-erbB-2 distribution in terms of the median, geometric mean, and range (19) . In the same study, very low c-erbB-2 values (defined as less than the geometric mean minus one SD) were suggested as a negative prognostic factor, but this was not confirmed (2 , 20) . The cutoff of 500 IU/mg protein was chosen on the basis of so-called "optimal cutoff" corrected as suggested by Hilsenbeck and Clark (13) . The optimal cutoff used in our study identified a relatively low percentage of tumors overexpressing c-erbB-2 protein, but was consistent with the rate of c-erbB-2 gene amplification usually found in breast cancer. IHC was performed by using CB11 (Novocastra) monoclonal antibody on 20 paraffin-embedded tumors; we also found a strong correlation between c-erbB-2 expression measured by IHC and biochemical c-erbB-2 concentrations (data not shown).
We observed a strong correlation between c-erbB-2 protein overexpression and steroid receptor negativity, as generally described in the literature, with a variety of techniques (1) . We also observed an association between c-erbB-2 overexpression and histoprognostic grade (SBR). Most previous studies have suggested that c-erbB-2 positivity is related to higher SBR grade (21 , 22) . Significantly higher c-erbB-2 values were also found in tumors with high p53 and uPA protein levels; several previous studies have shown a close correlation between c-erbB-2 and p53 positivity (23) , whereas others have not (24) . We found no published data on the possible link between c-erbB-2 and uPA.
High c-erbB-2 values were associated with significant shorter MFS and OS in the overall population (1 , 3) . Regarding MFS and OS, when we analyzed c-erbB-2 status in combination with clinical and biological prognostic factors, we found that c-erbB-2 overexpression added information to nodal status, tumor size, SBR grade, and ER. The same was true when c-erbB-2 was combined with uPA and EGFR. In contrast, c-erbB-2 status defined a group of patients with a poor prognosis among those usually considered to have good prognosis, such as patients with low p53 values. As shown by Sjörgen et al. (25) , the combination of newer prognostic markers such as c-erbB-2 with conventional markers can identify new subgroups of patients with a poorer prognosis.
Multivariate analyses applied to the overall population and to node-positive patients identified c-erbB-2 overexpression associated with shorter MFS and OS along with positive nodal status, high levels of uPA, and larger tumor size. In node-negative patients, c-erbB-2 was not a significant predictor for any prognostic criterion for MFS and OS, in keeping with reports by Borg et al. (26) and Carlomagno et al. (27) , and we confirmed the strong prognostic value of uPA (11) . EGFR and p53 were not selected as major prognostic factors when all other clinical, histological, and biological variables were included in the Cox model.
The predictive value of c-erbB-2 in patients receiving hormone therapy is still unclear. Some studies indicate that c-erbB-2-positive tumors exhibit a poor response to hormone therapy (21 , 26, 27, 28, 29) . Carlomagno et al. (27) first studied the interaction between c-erbB-2 and hormone treatment in a randomized trial of adjuvant tamoxifen and showed that tamoxifen shortened survival in node-negative patients whose tumors overexpressed c-erbB-2. On the contrary, a recent study by Elledge et al. (30) in ER-positive metastatic breast cancer showed that c-erbB-2 overexpression was not associated with a poorer response to tamoxifen or a more aggressive clinical course. In our study, multivariate analysis showed that high levels of c-erbB-2 were associated with shorter MFS and OS in tamoxifen-treated patients (45.5% of whom were ER positive). Moreover, in tamoxifen-treated patients, when classical factors alone were tested by multivariate analysis (i.e., without c-erbB-2), ER was the first variable to be selected (data not shown). When c-erbB-2, uPA, EGFR, and p53 were also tested, c-erbB-2 replaced ER. These results suggest that c-erbB-2 overexpression may be better than ER status as a predictor of the response to tamoxifen and that the effect of c-erbB-2 may not be solely mediated by ER down-regulation. Indeed, tamoxifen seemed to be detrimental in the small group of ER-positive, c-erbB-2-positive patients when compared with their untreated counterparts.
Data on the relation between c-erbB-2 and the response to chemotherapy are conflicting. In some cases, c-erbB-2 overexpression is associated with resistance to chemotherapy consisting of conventional doses of cyclophosphamide, methotrexate, and fluorouracil (CMF regimen; Refs. 31 and 32 ). However, Muss et al. (33) showed that in patients treated with different doses (low, moderate, and high) of FAC adjuvant chemotherapy (fluorouracil, doxorubicine, and cyclophosphamide), c-erbB-2 overexpression was predictive of increased tumor sensitivity to high-dose FAC. The same authors (34) confirmed this finding in a second set of patients from the same trial. Paik et al. (35) , in a retrospective study including patients with axillary lymph node-positive, hormone receptor-negative breast cancer randomly treated with either L-phenylalanine mustard plus 5-fluorouracil or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicine, observed a clinical benefit of doxorubicine (L-phenylalanine mustard, 5-fluorouracil, and doxorubicin versus 5-fluorouracil) in patients with c-erbB-2-positive tumors. In our study, c-erbB-2 was not selected as an independent factor in patients receiving different chemotherapy protocols, including various combinations of FAC and CMF. The most consistent feature of chemotherapy was the presence of 5-fluorouracil and an anthracycline, the dose of which varied. The only group receiving uniform chemotherapy in this study consisted of 61 node-negative patients who received one course of FAC. In this subgroup, a trend toward longer MFS was found in patients with high c-erbB-2 levels, but the difference was not statistically significant (data not shown). This is in keeping with the results of Muss et al. (33) , Thor et al. (34) , and Paik et al. (35) , who observed a benefit when patients with c-erbB-2-positive tumors were treated with an anthracycline (30, 31, 32) .
In conclusion, we confirm the absence of significance of c-erbB-2 expression in node-negative patients using multivariate analysis. Regarding hormone therapy (tamoxifen), c-erbB-2 overexpression provided additional information relative to ER. A combination of c-erbB-2 and biological prognostic factors could be of clinical value by defining subgroups that might benefit from more aggressive treatment, particularly in vaccine therapy approaches based on anti-c-erbB-2 antibodies. Randomized trials or trials stratified according to c-erbB-2 status are required to determine the precise predictive value of c-erbB-2 expression on the breast tumor response to classical therapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 The Ligue contre le cancer des Yvelines, de
l’Essonne et des Hauts de Seine supported this work. 
2 To whom requests for reprints should be
addressed, at Laboratoire d’Oncobiologie, Centre René Huguenin
de Lutte Contre Le Cancer, 35 rue Dailly, 92211 Saint-Cloud, France.
Phone: 33-01-47-11-15-15, ext. 3463; Fax: 33-01-47-11-15-68; E-mail: m.ferrero-pous{at}stcloud-huguenin.org
3 The abbreviations used are: IHC,
immunohistochemistry; EGFR, epidermal growth factor receptor; ER,
estrogen receptor; PR, progesterone receptor; CMF, cyclophosphamide,
methotrexate, and 5-fluorouracil; MFS, metastasis-free survival; OS,
overall survival; CI, confidence interval; FAC, fluorouracil,
doxorubicine, and cyclophosphamide; SBR, Scarff, Bloom, and
Richardson; EIA, enzyme immunoassay.
Received 3/22/00; revised 9/20/00; accepted 10/ 3/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSUnivariate Prognostic AnalysisMultivariate AnalysisDISCUSSIONREFERENCES |
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1.14 ng/mg
protein; n = 438) and high uPA levels
(b; n = 50), using a cutoff of 500
IU/mg protein for c-erbB-2 overexpression.
