Steroid-Hormone Receptors and Survival After First Relapse in Breast Cancer

127

Summary Oestrogen receptor (ER) expression in breast cancer is regarded as a phenotype that may change during the natural history of the disease or during endocrine therapy. It has been suggested that in up to 70% of tumours that show acquired resistance the mechanism may be changed in ER status from positive to negative. This paper proposes an alternative hypothesis that ER expression is a stable phenotype in breast cancer. The paper reviews the literature on ER expression during the natural history of breast cancer in patients and also presents data on the effect of endocrine therapy on ER expression. If the alternative hypothesis is true it has important implications for treatment from chemoprevention to acquired endocrine resistance in advanced disease. Equally, if the hypothesis is true, attempts to develop laboratory models of endocrine resistance where ER-positive tumours become ER negative need to be re-evaluated.Keywords: breast cancer; oestrogen receptor; stable phenotypeThe oestrogen receptor (ER) is a 65 kDa oestrogen-binding protein expressed by 46-77% of breast cancers (Walt et al., 1976;Knight et al., 1977; Maynard et al., 1978;Brooks et al., 1980;Osborne et al., 1980; Croton et al., 1981;Howell et al., 1984;Hawkins et al.,1987a;Williams et al., 1987;Clarke and McGuire, 1988). It is a generally held view that ER expression is not a permanent phenotype in breast cancer cells Moolgavakar et al., 1980; Encarnacion et al., 1993; Morrow and Jordon, 1993;Nomura et al., 1985;Jordan, 1994;Paik et al., 1994). One reason for this view is the belief that patients with ER-positive primary breast tumours often develop ER-negative metastases in regional lymph nodes or distant sites. This has been interpreted to show that ER negativity correlates with more aggressive tumour biology and loss of cellular control. A second reason is the strong correlation between ER and therapeutic response to primary endocrine therapy (Samaan et al., 1981;Howell et al., 1984;Williams et al., 1987), which formed the basis for early hypotheses of endocrine sensitivity and resistance. Up to 60% of ER-positive tumours respond to hormone therapy (e.g. Tamoxifen), while for ER-negative tumours the figure is around 10% Samaan et al., 1981;Williams et al., 1987). Therapeutic response to endocrine therapy is not permanent and eventually all such tumours progress. As ER negativity is strongly associated with primary resistance to endocrine therapy it is generally accepted that when responding tumours subsequently progress that in the majority of tumours this is due to loss of ER expression by the tumour Moolgavakar et al., 1980;Nomura et al., 1985; Encarnacion et al., 1993;Morrow and Jordan, 1993;Jordan, 1994;Paik et al., 1994). This paper proposes the alternative hypothesis that ER is a stable phenotype in breast cancer cells.The discovery of monoclonal antibodies (Kohler and Milstein, 1975) subsequently led to specific antibodies being raised to ER (Green and Jensen, 1982 . The ER-ICA allowed assessment of tumour tissue sections (King ...

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confidence: 99%

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confidence: 99%

Oestrogen receptor: a stable phenotype in breast cancer

Robertson

1996

127

“…The The presence of oestrogen receptors (ERs) is associated with a prolonged survival in patients with both primary and recurrent breast cancer. This probability applies both to an increased effect of endocrine therapy in receptor positive patients (Alanko et al, 1985;Howell et al, 1984;Rose et al, 1985) and to qualitative differences between ER positive and negative tumours (Clark et al, 1987;Parl et al, 1984;Shek et al, 1987).The ER status of a given tumour should be regarded as a reflection of the average receptor content from cell clones with varying receptor contents. It is unknown whether clones with different receptor content metastasise to different organs or whether it is the 'average' ER content per se which reflects specific biological subtypes.…”

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confidence: 99%

Oestrogen receptor status of primary breast carcinomas and their metastases. Relation to pattern of spread and survival after recurrence

Kamby¹,

Rasmussen²,

Kristensen³

1989

Summary Immunohistochemical antibody techniques for detection of oestrogen receptors (ER) were applied to formalin fixed, paraffin embedded sections from 62 primary breast cancers, the metastases of their original regional lymph nodes (29 cases), bone marrow carcinosis (43 cases) and liver metastases (20 cases). Forty per cent of the primary tumours and 31% of the regional lymph node metastases were ER positive; in contrast, less than 20% of liver and bone marrow metastases were ER positive. The The presence of oestrogen receptors (ERs) is associated with a prolonged survival in patients with both primary and recurrent breast cancer. This probability applies both to an increased effect of endocrine therapy in receptor positive patients (Alanko et al., 1985;Howell et al., 1984;Rose et al., 1985) and to qualitative differences between ER positive and negative tumours (Clark et al., 1987;Parl et al., 1984;Shek et al., 1987).The ER status of a given tumour should be regarded as a reflection of the average receptor content from cell clones with varying receptor contents. It is unknown whether clones with different receptor content metastasise to different organs or whether it is the 'average' ER content per se which reflects specific biological subtypes. The purpose of the present study is to describe and to compare the immunohistochemical ER content in primary breast cancer, involved regional lymph nodes and subsequent distant metastases. Moreover, prognostic importance of site-specific differences has been investigated. Materials and methodsThe patients all participated in a prospective investigation programme for patients with recurrent breast cancer. The organisation and results of this study have been published previously (Kamby et al., 1987b obtain tissue for histological verification of metastasis (Kamby et al., 1987a).All metastatic sites detected within 1 month after the diagnosis of the first site of metastasis were grouped together and designated as the sites of first recurrence. The sites of metastases were recorded according to anatomical location. When the number of sites was calculated, the presence of recurrence in each anatomical location counted for one, irrespective of the number of tumour deposits within each site.Among the 394 evaluable patients who entered the investigation programme, 111 patients had histologically verified liver metastases and/or bone marrow carcinosis. Of these, paraffin embedded specimens from the primary tumour were available from 76 patients. In 14 cases, either the primary tumour specimen (eight patients) or the metastatic tissue (six patients) was not evaluable by the immunohistochemical method. This leaves 62 patients with immunohistochemical ER determination of both the primary tumour and a metastasis. Twenty-nine of the patients had locoregional metastases at the time of primary diagnosis. The ER status of these metastases was also determined.The ER analyses were made on sections from formalin fixed and paraffin embedded tissue blocks from the primary tumour, the co...

“…oestrogen receptor (ER;Howell et al, 1984), c-erbB-2 (Berger et al, 1988Paik et al, 1990;Gullick et al, 1991;Perren. 1991) and DNA (Yuan et al, 1991) are of prognostic use and can be assessed by flow cytometry.…”

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confidence: 99%

“…Positive oestrogen receptor status has been shown to be linked to node-negative disease, indicating superior prognosis, and predicts for a lower histological grade (Howell et al, 1984). Overexpression of c-erbB-2 has been shown to be linked with poor prognosis (Wright et al, 1989;Perren, 1991), shorter relapse-free survival, adverse nodal status (Slamon et al, 1987;Gullick et al, 1991) and poor histological grade (Berger et al, 1988).…”

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confidence: 99%

Are fine-needle breast aspirates representative of the underlying solid tumour? A comparison of receptor levels, ploidy and the influence of cytokeratin gates

Brotherick

Shenton²,

Lennard³

1995

Summary Fifty-three solid and 33 fine-needle aspirate (FNA) samples (20 paired) of human breast carcinomas were examined by flow cytometry. Experiments were conducted to assess whether FNA samples were phenotypically representative of the solid tumour. Quantification of oestrogen receptor (ER), epidermal growth factor receptor (EGFR), c-erbB-2 receptor levels and ploidy were examined on the total and C)1okeratin-positive cell populations. The absolute number of molecules of cytokeratin per cell expressed on the FNA (n = 33) and solid tumour (n = 53) samples showed no significant difference. but. on a proportional basis. there was a significant difference between the two samples (P = 0.004). with lower expression exhibited by the FNAs. Examination of paired data showed no significant difference in the percentage of cytokeratinpositive cells (P = 0.51) or in the number of cytokeratin molecules expressed (P = 0.25). While the correlation for ER expression between paired tumour and FNA samples in the absence of cytokeratin gating was P = 0.06. r = 0.18. clear correlation was shown when a cytokeratin gate was used (P = 0.005, r = 0.4).Repeating this experiment for EGFR. it was found that no correlation was seen between FNA and solid tumour (P = 0.2. r = 0.14) in ungated populations, but use of the cytokeratin gate improved the correlation (P = 0.05. r = 0.3). A similar finding was seen with c-erbB-2 expression (P = 0.2. r = 0.1) without cytokeratin gating and when it was employed (P = 0.05. r = 0.4). Ploidy data showed concordance in 18/20 cases. Three cases of aneuploidy were missed by FNA, and this was because of an insufficient number of cells for analysis. The presented data suggest that FNAs are representative of solid tumours and may be useful for measuring receptor levels on clinical material when cytokeratin gating is used. However. observation by light microscopy is still necessary to confirm the presence of tumour cells in FNAs subjected to flow cytometry.