Endocrine therapy for advanced carcinoma of the breast: effect of tumor heterogeneity and site of biopsy on the predictive value of progesterone receptor estimations.

This study was carried out to assess the influence of site of biopsy and tumor heterogeneity upon the value of progesterone receptor (PR) measurements for prediction of response of patients with advanced carcinoma of the breast to tamoxifen or ovarian ablation. One hundred eighty-one assessable patients were studied. Sixty-nine % of responders and 31% of nonresponders were PR positive. The times to progression and survival were not significantly different for responders whether they were receptor positive or receptor negative. PR was measured on operable primary tumors (97), inoperable primary tumors (59), and secondary deposits (69). The proportion of responders who had PR-positive biopsies from these sites was 59%, 88%, and 61%, respectively, and the proportion of PR-positive nonresponders was 30%, 27%, and 42%, respectively. Ten to 12 separate PR measurements were made on seven tumors, and in four of them, there were PR-positive and PR-negative areas which could account for false positive and false negative results. We conclude that the optimum prediction of response was seen when the biopsy was performed on inoperable primary tumors. Errors in prediction of response at this site were, in part, explained by within-tumor heterogeneity of PR; the greater errors in prediction when measurements were made on operable primary tumors or on secondary deposits are presumed to be related to the additional effects of change in receptor status with time and between-tumor-site heterogeneity, respectively.

Endocrine therapy for advanced carcinoma of the breast: relationship between the effect of tamoxifen upon concentrations of progesterone receptor and subsequent response to treatment.

In some cell lines and tumors of mammary origin, tamoxifen causes an increase of progesterone receptor (PR) as a result of its partial estrogen agonist activity. In this study we have assessed the effect of tamoxifen on PR in patients with advanced carcinoma of the breast in order to test if those with a rise in PR are more likely to respond to endocrine therapy. PR was measured before and a median of 13 days after treatment with tamoxifen in a group of 52 patients with either locally advanced (n = 28) or recurrent (n = 24) carcinoma of the breast. Controls were a group of patients with operable disease who had two biopsies with no intervening tamoxifen (n = 51) or with intervening tamoxifen (n = 58). In the test group PR was higher in the second biopsy than the first in 21 patients, and 19 of these responded to continued endocrine therapy (90%). In the remaining 31 patients PR was either lower in the second biopsy (n = 19) or was negative in both biopsies (n = 12), and 11 of the total of 31 patients (35%) responded to continued endocrine therapy. The prediction of response and time to progression was better when both biopsies were taken into account than either the first or the second alone. The prediction of survival was similar for the group selected by an increase in the second biopsy and the group with PR present in the second biopsy. The controls without tamoxifen showed a marked variation in the level of PR in the first and second biopsies, suggesting heterogeneity of PR across the tumors studied. However, the PR level was significantly higher in the second biopsy in the controls given tamoxifen and in the test group compared with those with no intervening treatment (p = 0.031). This study indicates that some effect of tamoxifen upon PR can be demonstrated in human mammary tumors in vivo and that, by taking a second biopsy for PR estimation during treatment with tamoxifen, a more precise indication of subsequent response is obtained. The value of a single estimation of PR before treatment on secondary deposits is limited, and if one biopsy only is performed, it is of greater predictive value if taken after a few days treatment with tamoxifen.

Progesterone receptor measurement by isoelectric focusing: a potential microassay.

Sixty-two selected breast cancers were used to compare the conventional dextran-coated charcoal (DCC) assay with a new method of separating progesterone receptor by isoelectric focusing in flat beds of agarose gel. Ninety assays were performed. Isoelectric focusing indicated correctly the presence of receptor in 92% and the absence of receptor in 86% of assays, when compared with the DCC assay. The relationship between the results of the two methods was linear. Isoelectric focusing underestimated receptor to a variable extent, finding relatively less receptor at higher absolute levels of binding than at lower levels. The lower limit of sensitivity of isoelectric focusing was 30 fmol/ml cytosol. The protein concentrations of cytosols prepared from 46 needle biopsy samples (mean weight 25 mg) ranged from 0.5 to 30 g/l (median 4 g/l, 10th percentile 0.75 g/l). Isoelectric focusing is a satisfactory method of progesterone receptor measurement and can be applied to samples too small for conventional techniques.

Wise pattern mastectomy with immediate breast reconstruction.

A new technique of immediate breast reconstruction is presented. This technique uses a silicone implant placed in a subpectoral pocket, using de-epithelialised skin from the lower breast to augment the submuscular pocket, thus producing a compound myodermal flap. The technique is simple, and the resulting scar is cosmetically satisfactory; when combined with reduction mammoplasty on the opposite breast, this technique produces satisfactory breast symmetry.

Diagnosis of appendicitis in childhood.

A retrospective study of the diagnostic value of the blood white cell count was carried out in 187 children who had had an appendicectomy for suspected appendicitis. All had preoperative measurement of the total white cell count. Normal appendices were present in 43 children (23%), with a mean white cell count of 9.5 x 10(6)/l (95% confidence interval 8.4-10.6). The 144 children with appendicitis had a mean white cell count of 16.1 x 10(6)/l (95% confidence interval 15.3-16.9). A white cell count of 10 x 10(6)/l gave the best discrimination, and 91% of patients with a white cell count which equalled or exceeded this value had appendicitis compared with 27% of patients with a lower total white cell count (P less than 0.0001). Only one patient of 46 with gangrenous or perforated appendicitis had a white cell count below 10 x 10(6)/l. In children with suspected appendicitis a low white cell count should lead to review of the diagnosis and to further observation when doubt about the need for surgery persists.

Dibromodulcitol, mitomycin C and vinblastine (DMV) chemotherapy in advanced breast cancer.

A combination of dibromodulcitol 500 mg orally, mitomycin C 10 mg i.v. and vinblastine 10 mg i.v. all given on day 1 and repeated every 4 weeks was given to 40 patients with advanced breast cancer. All but one had received previous endocrine therapy. The response rate (CR + PR) in 24 previously untreated patients was 66% and was 37% in 16 previously treated patients. The survival of responders was significantly longer than non-responders. Thirty-two per cent of patients experienced nausea and vomiting. There was little myelosuppression or thrombocytopenia on the day of starting a new course of therapy but the haemoglobin dropped by 2 g/dl in 32% of patients during therapy. Thus DMV is a relatively non-toxic active regimen for patients with advanced breast cancer.

Non-invasive ultrasound localization of impalpable breast lesions.

Thirty patients presenting through the Breast Screening Programme with impalpable breast abnormalities clearly visible on ultrasound, underwent non-invasive ultrasound localization. The patient was scanned so that the ultrasound abnormality lay below the probe and the skin at this site marked with a skin marker. In all cases the abnormality was easily identified and removed at surgery. All the surgical biopsies contained either a carcinoma (17 cases) or fibroadenoma (13 cases). This non-invasive technique is a simple and accurate method for localizing small ultrasonically visible breast abnormalities.

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.

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.