A. P. M. Forrest

Primary systemic therapy for operable breast cancer

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.

Primary systemic therapy for operable breast cancer--10-year survival data after chemotherapy and hormone therapy.

Between 1984 and 1990, 94 women presenting to the Edinburgh Breast Unit with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) were given preoperative systemic therapy. Initially, all women received hormone therapy, with CHOP (cyclophosphamide 1 g m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2) to a maximum of 2 mg and prednisolone 40 mg per day orally for 5 days) chemotherapy being administered to those who failed to respond by 3 months. After April 1987, first-line hormone therapy was only offered to women with oestrogen receptor (ER)-moderate/-rich (> 20 fmol mg(-1) protein) tumours, and CHOP was reserved for those women whose tumours failed to respond to hormone therapy and for those with ER-negative/-poor tumours. Response data have been published previously (Anderson et al, 1991). After a median follow-up of 7.5 years, there is no difference in survival between those women given initial hormone therapy and those given chemotherapy, with neither group having yet reached its median survival. The two key factors that predicted for a poor survival were the number of involved axillary nodes after preoperative systemic therapy (P < 0.00001) and a lack of response to preoperative therapy (P < 0.05). These data suggest that many women with ER-moderate/-rich tumours will have a good prognosis after preoperative hormone therapy alone. However, it is possible to identify, by their post-systemic therapy axillary node status, a group of women who still have an appalling prognosis after preoperative chemotherapy or hormone therapy.

Response to endocrine manipulation and oestrogen receptor concentration in large operable primary breast cancer

Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%.

Relation between immunocytochemical estimation of oestrogen receptor in elderly patients with primary breast cancer and response to tamoxifen.

The relation between oestrogen receptor status of primary breast cancer as determined immuncytochemically on fine-needle aspirates and the response to tamoxifen therapy has been assessed in 52 patients. The proportion of cells staining correlated well with the likelihood of response, which emphasises the importance of tumour heterogeneity.

Oestrogen receptor concentration in primary breast cancer and axillary node metastases

SummaryThe primary tumour and 1–3 invaded, axillary nodes from each of 24 patients were examined both histologically for the proportion of the specimen constituted by malignant epithelial cells (‘cellularity index’) and biochemically for oestrogen receptor concentration. Both malignant epithelial cell content and oestrogen receptor concentration were significantly higher in the nodal metastases than in the primary tumours, malignant cells constituting approximately half of the former tissue and three quarters of the latter. On average, receptor concentrations were 1.6 × (protein basis) to 2.3 × (wet weight basis) higher in nodes than in the primary tumours, probably due at least in part to the difference in cellularity. When, to eliminate the effect of the latter, receptor concentration in each tumour deposit was ‘corrected’ using the appropriate ‘cellularity index’, the difference in receptor concentration between primary and node was significantly diminished, but not quite eliminated. In one patient, progestogen receptor concentrations were also studied and found to be higher in the nodes than in the primary tumour. If the actual quantity of receptor is to be used for predictive/prognostic purposes, then either a different ‘cut-off point’ should be used for invaded nodes from that used for assessment on the primary tumour, or receptor concentrations should be corrected for differences in cellularity.

DNA analysis of breast tumour fine needle aspirates using flow cytometry.

Cellular DNA was analysed by flow cytometry in fine needles aspirates (FNA) from both benign and malignant breast lesions in order to determine the feasibility of flow cytometric analysis. In 22 of 26 (84%) benign and 69 of 74 (93%) malignant aspirates, sufficient cells were present to produce good quality DNA histograms. DNA in all 22 benign lesions was diploid. In contrast, of the 69 cancers with sufficient cells for analysis, 40.6% had a diploid DNA content alone, whilst 59.4% had an additional DNA aneuploid line. These results indicate that the majority of FNAs provide sufficient material for flow cytometric analysis of DNA profiles. Such aspirates taken in a sequential manner may also prove to be an ideal method of studying tumour response to therapy.

Does the oestrogen receptor concentration of a breast cancer change during systemic therapy

The effect of systemic therapy on tumour oestrogen receptor (ER) concentration has been studied in 88 patients with large, operable, primary tumours (total 89) of the breast. In 26 patients, tumour was not available for study on one occasion (usually post-treatment). Forty-five patients were treated initially by endocrine therapy but, of these, 13 who had failed to respond went on to receive chemotherapy also. Seventeen patients with low concentrations of ER (less than 20 fmol mg-1 protein) were treated directly by chemotherapy. Patients underwent an incisional biopsy for confirmation of diagnosis and determination of pre-treatment ER by radioligand binding assay, followed by systemic therapy for 3 months (or 6 months for both endocrine and cytotoxic therapies). Response was assessed clinically and mammographically before mastectomy. ER concentration was then determined in the post-treatment tumour specimen. No significant change in ER concentration was seen in any treatment group except when the patients had received tamoxifen; there, receptor concentration fell to very low levels, presumably due to interference with the assay. There was no relationship between tumour response to systemic treatment and change in ER concentration. It is concluded that changes in ER concentration are unlikely to play a major role in the early response of breast tumours to systemic therapy.

METABOLISM OF ANDROGENS BY HUMAN BREAST TISSUE

Abstract Evidence for the conversion of dehydroepiandrosterone through testosterone to 5α-dihydrotestosterone has been sought in three breast cancers, two fibroadenomas, one specimen of fibroadenosis, and six specimens of normal breast tissue from the same patients. Significant in-vitro activity was demonstrated in all tissues.

Oestrogen receptors and the response to endocrine therapy in advanced breast cancer.

The relationship between oestrogen-receptor protein (ER) content of the tumour and the response to endocrine therapy was determined in 119 patients, in a collaborative prospective study. Twenty-eight of the 80 patients with measurable ER responded to treatment according to UICC criteria, compared with only 3/39 without ER. It was found that site of biopsy did not influence the result, but tumour content of the tissue sample was significantly related to the presence of receptors. The organizational problems of such a study are discussed.

The cytochemical detection of oestrogen receptors in fine needle aspirates of breast cancer; correlation with biochemical assay and prediction of response to endocrine therapy.

A total of 98 breast aspirates from patients with breast cancer have been fixed and stained for oestrogen receptors using the Abbott ERICA kit. In a preliminary series of 41 aspirates, cytochemical staining index (% cells staining x mean intensity) related to the receptor concentration determined biochemically on a subsequent biopsy with a correlation coefficient of +0.65. In a second series of 56 aspirates examined after lysis and cytocentrifugation, the correlation coefficient was +0.73. For 14 patients, the response of the primary tumour to endocrine therapy was assessed objectively by serial clinical and mammographic measurements (Forrest et al., 1986) and was found to relate strongly to the cytochemical staining of the initial aspirate. The potential and limitations of this technique are discussed.