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Molecular Oncology, Markers, Clinical Correlates |
1 Endocrinologie moléculaire et cellulaire des cancers (U 540), Institut National de la Santé et de la Recherche Médicale (INSERM), Montpellier, France; Departments of 2 Pathology and 3 Biostatistics, Cancer Center Val d’Aurelle, Montpellier, France; and 4 Department of Medical Nutrition and Biosciences, Karolinska Institute, Novum, Huddinge, Sweden
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Univariate analysis showed that Scarff-Bloom-Richardsson grade modified by Elston (SBR grade; P < 0.001), tumor size (P = 0.042), and MIB-1 proliferation index (P = 0.02) were significantly higher in tamoxifen-resistant tumors. A low level of total ERß, whether in percentage of positive cells or in quantitative immunocytochemical (QIC) score, was also associated with tamoxifen resistance (P = 0.004). ERßcx expression and lymph node status were similar between the two groups. The expression of ERß in the total population was positively correlated with ERßcx (r = 0.63, P < 0.001), and was independent of the other parameters. In a multivariate analysis, ERß expression was the most important variable (P = 0.001), followed by SBR grade (I+II versus III; P = 0.008), and MIB-1 (P = 0.016).
To conclude, tamoxifen resistance is associated with classical variables of aggressive tumors (high SBR grade, proliferation index, and tumor size) but not with node invasiveness. Low ERß level is an additional independent marker, better than ER
level, to predict tamoxifen resistance.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It has been established, however, both in cell lines (7 , 8) and in patients (9) , that tamoxifen is mostly active in ER-positive breast cancer, and that the assay of ER in cytosol or in tumor section is the first predictive marker used in practice to guide the clinicians in defining systemic therapy (10) .
The recent discovery of a second ER, named ERß (11)
, and of several of its variants, raised the question of the relative value of ER and ERß in predicting tamoxifen resistance or sensitivity in breast cancer patients. ERß binds antiestrogens and their hydroxylated metabolites (12)
with a higher affinity than does ER (13)
. Both the full-length ERß (ERß1) and its COOH-terminally truncated splice variant (ERßcx or ERß2), which is unable to bind tamoxifen, have been found in breast cancer (14
, 15)
. They are able to act as dominant negative of ER after heterodimerization (16)
, but their significance in antiestrogen resistance is controversial. It has been proposed that the action of tamoxifen on ERß stimulates tumor growth via AP-1 interactions (17)
. Conversely, ERß could inhibit the agonist activity of tamoxifen for instance on AF-1, the activating domain of transcription of ER (18
, 19)
. Finally, ERß might have no value in predicting tamoxifen efficacy or resistance.
To discriminate among these possibilities, we have quantified anonymously by immunohistochemistry the expression of total ERß protein and its variant ERßcx in 50 archival ER-positive breast carcinomas, which had been treated by tamoxifen as the only adjuvant therapy, and we have compared their value in tamoxifen-resistant and tamoxifen-sensitive tumors, defined according to the presence or absence of relapse within 5 years of standard tamoxifen therapy (20) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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10 fmol/mg protein); (d) adjuvant therapy exclusively by tamoxifen for 5 years (20 mg/d); (e) availability of paraffin blocks for analysis; and (f) complete clinical data and sufficient follow-up. The tamoxifen-resistant patients were defined as those patients who recurred while on adjuvant tamoxifen therapy (up to 5 years). The tamoxifen-sensitive patients were defined as those patients who had not recurred while on tamoxifen therapy during 5 years. Only 50 cases of 850 could be included in this study with 16 tamoxifen-resistant cases and 34 tamoxifen-sensitive cases. Histopathologic grading of tumor was obtained according to Scarff-Bloom-Richardsson (SBR) modified by Elston (21
, 22)
. Nodal status was obtained by histologic analysis of at least eight axillary nodes. Menopausal status was determined by clinical and hormonal analysis.
Immunohistochemical Assay.
All of the tumor samples were fixed in formalin-alcohol solution and embedded in paraffin. The archived breast cancer specimens were studied by immunohistochemistry. The pathologist (ME-S) was blinded to the patient characteristics. Immunostaining was performed with ERß antibodies obtained in Dr. J-Å. Gustafsson’s laboratory (Department of Medical Nutrition and Biosciences, Karolinska Institute, Novum, Huddinge, Sweden). The chicken polyclonal ERß 503 IgY antibodies recognize total ERß proteins (both full-length ERß and its splice variants) and have been previously validated for immunohistochemistry (23
, 24)
, including validation by protein extinction with authentic ERß protein (23)
. The ERßcx polyclonal antibodies were raised in sheep against the 14-amino-acid peptides of the COOH-terminal region: MKMETLLPEATMEQ. Analysis was also performed by ER (clone 6F11, Novocastra, United Kingdom), progesterone receptor [PgR (clone PgR 636, Dako)], Ki67 (clone MIB-1, Dako), and two HER2/neu (c-ErbB2) markers [polyclonal A0485 (Dako, Denmark) and monoclonal CB11 (Novocastra)]. Adjacent sections of 5 µm each were deparaffinized in xylene and rehydrated with graded EtOH concentrations. Before staining, a heat epitope retrieval procedure was performed. Sections were pretreated by pressure cooking for 15 minutes in EDTA buffer (pH 7) for ERß and ERßcx, and by waterbath for 40 minutes at 95° for the other markers, with citrate buffer (pH 6) for ER, PgR, and HER2/neu, and Tris-EDTA buffer (pH 8) for MIB-1. For ER (1:50 dilution), PgR (1:100 dilution), MIB-1 (1:100 dilution), and c-ErbB2 (1:500 dilution for polyclonal antibody and 1:800 dilution for CB11 antibody), immunohistochemical labeling with the "Dako LSABR 2 System-HRP" was performed at room temperature with the automated Dako Autostainer (code no. K0675); and 3',3'-diaminobenzidine tetrahydrochloride (DAB) was used as a chromogen. The immunohistochemical procedure for total ERß marker was described previously (23)
. A similar protocol was performed for polyclonal sheep ERßcx antibody (1:300 dilution), except for the use of an appropriate secondary biotinylated antisheep antibody (Santa Cruz Biotechnology, Santa Cruz, CA). Negative controls were performed by the replacement of primary antibody by IgY nonspecific serum (Nordic, Netherlands) for ERß, mouse IgG1 nonspecific serum (X0931, Dako) for ER, PgR, and MIB-1 markers, with similar protein concentrations. Positive external controls were used in each experiment, sections of OVCAR cells, pellet-embedded in paraffin, were used for ERß, and a positive breast cancer sample was used for each other marker. Adjacent normal breast tissue was also used as an internal control for ER, PgR, MIB-1, and ERß. ERßcx specificity of immunostaining was established by preincubating the sheep polyclonal ERßcx antibody with a 10-fold excess of ERßcx peptide. It was also shown with pre-adsorbed ERßcx antiserum (1:2100 dilution), and with preimmune sheep serum for ERßcx (1:5000 dilution). In each ERßcx experiment, pre-immune sheep serum was used, in addition to a positive external control (breast cancer tissue overexpressing ERßcx). Archival material of mammary tumor recurrence and/or metastasis was obtained for six resistant patients and was analyzed with the same markers.
Quantitative Method.
Quantification was performed with a computerized image analyzer (Samba 2005 TITN, Alcatel, Grenoble, France) as described previously (23)
. Ten to twelve microscopic fields (G200) of invasive tumor, representative of all surface cut, were analyzed for ER, -ß, and -ßcx and for PgR. The highly stained fields were chosen for MIB-1 proliferation marker assessment. Results were expressed as the percentage of nuclear-stained epithelial cells, or as a quantitative immunocytochemical (QIC) score [(percentage of surface stained in epithelial cells) x (mean staining intensity) x 10] expressed in arbitrary units (AU). The percentage of nuclear staining of negative control was usually nil and, when weak, was subtracted. A semiquantitative method was performed for c-erbB-2 membrane staining, according to the Dako Hercept Test scoring.
Statistical Methods.
All of the parameters were analyzed by continuous values and by expression status. Receptor status were defined taking as cutoff points the median values observed in the 50 ER-positive cases (70% for ERß, 30% for ERßcx, 50% for ER, and 20% for PgR). Because the sensitivity of the assay may vary according to the receptors, these values may not indicate their relative level in the tumor. Univariate analysis comparing resistant and sensitive cases were performed by Fisher’s exact test for categorical variables and by the two-sample Wilcoxon test for all continuous parameters. The Wilcoxon test and the Spearman correlation coefficient were used to evaluate the relationship between ERß and ERßcx expression with the other parameters. P values < 0.05 were considered statistically significant. The multivariate analysis was carried out in two steps by first introducing all of the immunohistochemical variables in a stepwise backward logistic regression model (25)
Significant clinical variables were then introduced to investigate the relationships with the immunohistochemical variables. Statistical significance was measured by the likelihood ratio test. Odds ratios were used to summarize the effects. Statistical analyses were performed with Stata software (StataCorp, College Station, TX; ref. 26
).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The only differences were SBR grading and tumor size, which were more elevated in resistant cases.
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, ERß immunoreactivity was detected in the nuclei of invasive breast cancer cells, where brown staining was totally abolished with an excess of antigen (23)
. Since the cytoplasmic staining was not fully abolished, only the nuclear staining was quantified. The absence of cross-reactivity between ERß and ER antibodies was also confirmed as shown in Fig. 1A-d and -e
. Nuclear intensity and staining distribution of invasive tumors were variable according to the patient. Staining distribution was either diffuse in all of the tumor, or was focal and generally localized in tumoral islets at the periphery of the tumor. Fig. 1A
shows a typical example of a tamoxifen-sensitive (Fig. 1A- a, -b, and -c)
and tamoxifen-resistant (Fig. 1A-d, -e, and -f)
invasive ductal breast carcinoma, with similar SBR grade (II) and size (pT2) and without nodal invasiveness. In the tamoxifen-sensitive case, there was a strong expression of ERß (Fig. 1A-a)
, with a low MIB-1 proliferation rate (Fig. 1A-c)
. The tamoxifen-resistant case showed a low ERß expression (Fig. 1A-d)
contrasting with a high ER level (Fig. 1A-e)
, and high MIB-1 staining (Fig. 1A-f)
. ERß nuclear staining was also detected in epithelial and myoepithelial cells of normal mammary glands, in stromal and inflammatory cells.
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. The nuclear staining mostly observed in cancer cells (Fig. 1B-a and -c)
contrasted with a weak cytoplasmic staining. Nuclear staining was also observed in some stromal endothelial cells and inflammatory cells such as lymphocytes and macrophages (Fig. 1B-a)
. The specificity of the ERßcx immunostaining was evidenced by three criteria: (a) nuclear signal was removed by adding a 10-fold excess of the antigen (Fig. 1B-b)
, (b) nuclear signal was removed by using an ERßcx pre-adsorbed antiserum (not shown), and (c) nuclear signal was removed by using the pre-immune serum (Fig. 1B-d)
. ERßcx reactivity varied according to patients (Table 2
and Fig. 3
).
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, total ERß level was significantly higher in sensitive tumors than in resistant cases, when comparing the percentage of stained nuclei or QIC score. The same difference was found with continuous values (Fig. 2A)
or status expression taking the median as a cutoff level of 70% of stained nuclei. Unlike total ERß, ERßcx level (either with percentage or with QIC score) did not differ between resistant and sensitive tumors. The difference between total ERß and ERßcx was significantly higher in sensitive tumors. The difference in ER levels between the two groups was not significant (Fig. 2)
. However the ER-positive tumors (50% of stained nuclei) were mostly seen in tamoxifen-sensitive patients. The ER/ERß ratio, estimated in adjacent sections of each tumor, and PgR expression were not different between the two groups. The proliferation rate assessed by MIB-1 was greater in the resistant group (P = 0.01), with 63% of resistant cases expressing more than 10% of stained nuclei as compared with 32% of sensitive cases. We found no HER2/neu (c-erbB2) overexpression in any of the 50 tumors, which is consistent for ER-positive tumors. We found no significant variation in ERß, ER, PgR, and MIB-1 levels between the primary tumor and recurrence or metastasis for the same patient, but the number (six cases) was too small to reach a conclusion.
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. It was correlated only with ERßcx expression (Spearman correlation coefficient, r, = 0.63, P < 0.001). The percentage of ERß-positive cells was always superior to the percentage of ERßcx-positive cells (Fig. 3)
. Interestingly, MIB-1 was inversely correlated with ER level (P = 0.003) but not with ERß levels. A positive correlation was observed, however, between ERß expression and MIB-1 proliferation index in the tamoxifen-resistant tumors (r = 0.51, P = 0.04), but no relationship was found in the tamoxifen-sensitive group. All 14 patients with a low MIB-1 proliferation index (<10%) and a high ERß status (70%) were tamoxifen sensitive (Fig. 4)
. ERßcx expression was associated with total ERß expression but was independent of all other variables.
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and 2
), SBR grade was found to be the most discriminant variable between the two groups of resistant and sensitive cases (P = 0.001), followed by ERß expression (P = 0.004), MIB-1 proliferation index (P = 0.02), and tumor size (P = 0.042). ER expression and nodal status were not significant. In the multivariate analysis, SBR grade (I+II versus III), MIB-1 proliferation index, and ER and ERß expression were introduced in a multivariate logistic regression model (25)
on a continuous scale (Table 4)
. Tumor size had no predictive value and was not included in the model. ERß expression was the most important independent variable (P = 0.001), followed by SBR grade (P = 0.008) and MIB-1 proliferation index (P = 0.016), whereas ER expression was at the limit of statistical significance (P = 0.060). According to this model, 43 (86%) of the 50 patients were correctly classified. The sensitivity and specificity were 81 and 88%, respectively. The positive and negative predictive values were 76 and 91%, respectively, assuming a prevalence rate of resistance equal to 32% (16 of 50). On the basis of expression status, the logistic regression model identified SBR grade (P = 0.003), followed by ERß (P = 0.013) and MIB-1 (P = 0.032). ER level was not significant. In a regrouping of the four variables, grade III tumors with elevated MIB-1 proliferation index and low ERß level were at a greater risk for tamoxifen-resistance.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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had a lower value, and ERßcx had no value. This should clarify the significance of the cytosolic radioligand assay of ER (10)
on which most of the clinical studies allowing introduction of this marker to predict breast cancer response to antiestrogen therapy were based (9
, 10)
. According to this pilot study, which should be confirmed prospectively on a larger scale, the assay of ERß by immunohistochemistry is better than that of ER in guiding the clinician, at least in HER2/neu-negative tumors. The few studies on the clinical value of ERß in terms of prediction of response to tamoxifen have been controversial. Our results agree with others reporting an association between ERß and response to tamoxifen treatment (27
, 28)
. They disagree. however. with the proposal that ERß overexpression is associated with tamoxifen resistance (29)
, and that the tamoxifen/ERß complex increases expression of AP-1-controlled genes involved in cell proliferation (17)
. Whether ERß actively protects breast cancer cells against tamoxifen-resistance is unknown. One possible mechanism, however, could be a dominant-negative effect of ERß after heterodimerization (16)
inhibiting the tamoxifen agonist activity of ER via the AF-1 domain (18
, 19) .
We have not discriminated between initial and acquired tamoxifen resistance, the median time for relapse being 3 years; some resistant cases could be secondary to the selection of cancer cells stimulated for growth by tamoxifen acting as an agonist via ER. The four patients who recurred more than 1 year after the 5 years’ therapy were included in the tamoxifen-sensitive group, with the assumption that these breast cancers were initially responsive to tamoxifen. When considering these four patients as tamoxifen resistant, the multivariate analysis gave a similar significance for ERß expression (P = 0.012).
Among the classical markers of aggressiveness (SBR grade, tumor size, MIB-1 proliferation), only lymph node invasiveness was not associated with tamoxifen resistance. This is in agreement with studies showing that node-positive tumors respond as well as node-negative tumors to tamoxifen therapy (30) and that cancer cells, having migrated to lymph nodes, retain the same antiestrogen responsiveness as the primary tumor.
The fact that ERßcx expression in breast cancer is not predictive of tamoxifen resistance in our study, suggests that the full-length ERß-1, or another ERß variant, may be involved in tamoxifen sensitivity. It is not excluded, however, that ERßcx plays a role in the initial tamoxifen resistance as suggested by studies in which tamoxifen responsiveness was evaluated after 3 months of neo-adjuvant therapy (31) . The absence of correlation of ERß with other classic prognostic parameters further supports its interest for breast cancer monitoring. The absence of correlation with PgR disagrees with other studies (29 , 32) but was supported by a recent study on 242 breast cancers (33) . The reasons for these discrepancies is unknown and could be due to different methods used for quantification and/or different sets of patients.
Our results do not exclude the involvement of other entities able to induce tamoxifen resistance, such as an increased expression of HER-2/neu (34)
and an altered expression of coactivator (35)
or corepressor (36)
. However they strongly suggest that the level of ERß in breast epithelial cancer cells contributes better than the level of ER in predicting tamoxifen-sensitivity of breast cancer patients. This should stimulate both large-scale clinical studies before entering ERß assay into clinical practice and basic studies to define the biological significance of the association between ERß level and tamoxifen responsiveness of breast cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Requests for reprints: Henri Rochefort, Endocrinologie moléculaire et cellulaire des cancers (U540) INSERM, 60 rue de Navacelles, 34090 Montpellier, France. Phone: 33-467043760; Fax: 33-467540598; E-mail: henri.rochefort{at}montp.inserm.fr
Received 2/27/04; revised 4/29/04; accepted 5/12/04.
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