R A Sellwood

Steroid-hormone receptors and survival after first relapse in breast cancer

Oestrogen receptors were measured in the primary breast tumours of 508 patients and progesterone receptors in those of 486 patients. Survival from mastectomy was significantly longer in patients with receptor-positive tumours. There was no significant difference between patients with receptor-positive and receptor-negative tumours in the relapse-free interval, but survival from first relapse was longer in patients with receptor-positive tumours. Axillary node status and tumour size indicated the probability of relapse but did not influence the length of survival after relapse. Response to tamoxifen or ovarian ablation was known in 65 of the 137 patients who relapsed. Survival from first relapse was significantly longer in patients who both responded to hormone therapy and had receptor-positive tumours. Patients who did not respond to hormone therapy and had receptor-positive tumours had the same survival characteristics as those with receptor-negative tumours who did not respond.

The definition of the no change category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast

In the criteria used for assessment of response to treatment for advanced breast cancer the definition of no change (NC) is clear; however, there is no indication of the duration of stabilization required for patients to qualify for this category of response. We have made the assumption that NC is a worthwhile category of response if the overall time to progression (TTP) and survival of this group is not significantly different from patients with partial remissions (PR). Two hundred and sixty-three evaluable patients treated with endocrine therapy and 302 evaluable chemotherapy-treated patients were studied and the TTP and survival curves for PR and periods of NC from 1 to 6 months compared. For the endocrine-treated patients the TTP and survival curves for NC became non-significantly different from the PR curves after 4 and 5 months respectively. For chemotherapy-treated patients the TTP curves became non-significantly different from PR at 4 months and for survival the period was 3 months. In order to define NC as a useful category of response and to eliminate the possibility that NC taken for a shorter period could simply represent a slowly progressive tumour, we suggest that the minimum period of disease stabilization be taken as 5 months for both endocrine- and chemotherapy-treated patients.

CONTROLLED TRIAL OF ADJUVANT CHEMOTHERAPY WITH CYCLOPHOSPHAMIDE, METHOTREXATE, AND FLUOROURACIL FOR BREAST CANCER

327 patients with cancer of the breast and involvement of axillary lymph nodes were randomised, after total mastectomy and axillary clearance, to receive either no additional treatment or oral cyclophosphamide 80 mg/m2 on days 1-14, intravenous methotrexate 32 mg/m2 on days 1 and 8, and intravenous fluorouracil 480 mg/m2 on days 1 and 8 (CMF), which was repeated every 28 days for twelve cycles. There was a significantly longer relapse-free survival (RFS) in patients treated with CMF. A prolonged RFS was seen in premenopausal patients, those with 1-3 nodes involved, and those with 4 or more nodes involved, but a similar trend in postmenopausal patients failed to reach statistical significance. RFS was greater in patients with CMF-induced amenorrhoea than in controls and in treated patients whose primary tumour contained progesterone receptors. Dose of chemotherapy did not have a significant effect on RFS. Survival was not influenced by treatment.

CONTROLLED TRIAL OF ADJUVANT CHEMOTHERAPY WITH MELPHALAN FOR BREAST CANCER

370 patients who had carcinoma of the breast with involved axillary lymph-nodes were randomised after total mastectomy and axillary clearance to receive either no additional treatment or melphalan 6 mg/m2 daily for 5 days every 6 weeks for sixteen cycles. There was a trend towards longer relapse-free survival (RFS) in patients treated with melphalan, but this was not significant either in the whole series or in sub-groups according to menopausal status or extent of nodal involvement. In patients receiving melphalan RFS was not significantly affected by either the occurrence of amenorrhoea or the dosage of melphalan received. Overall survival did not differ significantly between the two groups. The results of this trial suggest that there is no place for the use of melphalan as adjuvant therapy in the management of early breast cancer.

FIBROBLASTS FROM PATIENTS WITH BREAST CANCER SHOW ABNORMAL MIGRATORY BEHAVIOUR IN VITRO

In culture on collagen gels normal and transformed fibroblasts can be distinguished by their differential migratory response to changes in cell density. The effects of cell density on fibroblast migration may be expressed by a single numerical value, the cell density migration index (CDMI). Tumour-derived fibroblasts and skin fibroblasts from the majority of 24 breast-cancer patients examined had CDMI values characteristic of transformed cells. There was a significant correlation between the expression of abnormal CDMI values by tumour-derived fibroblasts and the presence of lymph-node metastases. Fibroblasts from 10 patients with benign breast disease had normal CDMI values.

FIBROBLASTS FROM RELATIVES OF PATIENTS WITH HEREDITARY BREAST CANCER SHOW FETAL-LIKE BEHAVIOUR IN VITRO

Fetal and normal adult skin fibroblasts show distinctive migratory behaviour when plated on three-dimensional collagen gels. Skin fibroblasts from 13 of 15 patients with hereditary breast cancer showed fetal-like behaviour compared with only 1 of 12 age-matched healthy controls (p less than 0.015; Wilcoxon signed-rank matched-pairs test). In addition, 10 of 15 first-degree relatives of patients with hereditary breast cancer showed a fetal-like fibroblast phenotype, compared with none of 7 surgical controls (p less than 0.009; chi 2 test). These results suggest that abnormalities expressed by skin fibroblasts may help identify people at increased risk of breast cancer developing.

Variation of receptor status in cancer of the breast.

One hundred and nineteen patients with breast cancer had 2 or more lesions removed for oestrogen (REc) or progesterone receptor (RPc) assay, either synchronously (on 38 occasions) or after an interval (on 91 occasions). In all but 7 both receptors were assayed for each lesion. The assays did not agree on the presence or absence of REc alone, RPc alone or the combination of both receptors in 11, 13 and 16% respectively of the synchronous samples, compared with 23, 30 and 43% of the asynchronous samples. The differences between the synchronous and asynchronous samples were significant for the combined receptors (P = 0.007) but not for REc (P = 0.176) or RPc alone (P = 0.077). Variation between asynchronous biopsies was greater when the earlier lesion contained RPc (18/37 disagreed) than when it did not (8/50) disagreed, P = 0.0023). This was not true for oestrogen receptor. In those remaining receptor positive there was only a weak correlation between the first and second values (Spearman rank correlation coefficient, rho = 0.39 for REc, P less than 0.02, and 0.45 for RPc, 0.05 less than P less than 0.1). Receptor levels and receptor status may change with time. Biopsy is most appropriate at the time when systemic treatment is proposed.

A Controlled Trial of Adjuvant Chemotherapy with Melphalan Versus Cyclophosphamide, Methotrexate, and Fluorouracil for Breast Cancer

The hypothesis that chemotherapy may be more effective when there is only a slight tumor burden has led to its use after mastectomy in patients at high risk of recurrence. The preliminary results of a trial of melphalan (l-PAM) as adjuvant therapy carried out by the National Surgical Adjuvant Breast Project (NSABP) [1], suggested that melphalan therapy could significantly prolong postoperative relapse-free survival (RFS). Because of the importance of these findings we decided, in March 1975, to repeat the trial at the breast unit at Guy’s Hospital. Results from the Istituto Nationale Tumori in Milan on the use of a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with involved axillary nodes after mastectomy [2] suggested that postoperative RFS could be prolonged by chemotherapy. These findings led to the establishment, in March 1976, of a three-armed trial in the University Hospital of South Manchester comparing no adjuvant treatment, melphalan, and CMF. Because of the similarity of protocols and interests at Guy’s Hospital and in Manchester, we decided in 1979 to amalgamate the trials. We now report the results of the combined randomised trial comparing adjuvant melphalan, adjuvant CMF, and no adjuvant therapy.

The expression of milk fat globule antigens within human mammary tumours: Relationship to steroid hormone receptors and response to endocrine treatment

The value of steroid hormone receptors for the management of advanced carcinoma of the breast is often limited by the lack of availability of fresh tissue. Differentiation antigens may be estimated on paraffin-embedded fixed material by immunostaining, and the aim of this study was to determine whether staining with the monoclonal antibody raised to human milk fat globule (HMFG-1) could replace receptor measurements. The indirect immunoperoxidase technique was used to stain formalin-fixed paraffin-embedded tumour samples from 168 patients. All received tamoxifen or ovarian ablation as first-line systemic therapy, and all were evaluable for response (UICC criteria). One hundred and sixty-seven had oestrogen (ER) and progesterone receptors (PR) estimated. HMFG-1 staining was assessed as the percentage of tumour cells stained, and by the site of stain. The proportion of cells stained was highly correlated with both ER (P less than 0.0001) and PR (P less than 0.0001) and with response. When greater than or equal to 30% cells stained, 53 of 69 (77%) responded; when 20-29% stained 10 of 19 (53%) responded, when 10-19% stained seven of 19 (37%) responded, and when less than or equal to 9% cells stained 16 of 61 (26%) responded (P less than 0.0001). The median survival of patients with tumours that stained greater than or equal to 30% cells was 36 months, and with no cells stained, 11 months (P less than 0.0001). ROC (receiver operator characteristic) curves found that the optimum threshold for sensitivity and specificity of response prediction was greater than or equal to 20% cells stained. Coxs multiple regression analysis of 42 variables indicated that PR was the most important predictor of survival (P less than 0.000001), but that after PR the percentage of cells stained with HMFG-1 was the most important (P less than 0.0001). We conclude that immunostaining for HMFG-1 gives similar information to receptor status, and has the advantage that fixed archival tissue may be used.