Cyclical tumour variations in premenopausal women with early breast cancer.

The hormonal milieu at the time of tumour excision may have a significant impact on survival in premenopausal patients with breast cancer, with those undergoing surgery between days 3 and 12 of the menstrual cycle having a worse prognosis. To investigate possible mechanisms which might explain this finding, histological features of tumours from 363 patients included in two studies from Guy's Hospital have been reviewed. Axillary nodal involvement occurred in 71/115 (62%) of patients whose primary tumour was excised between days 3 and 12 of the cycle, compared with 116/248 (47%) of patients undergoing surgery at other phases of the cycle (chi 2 = 7.04, P < 0.01). Vascular invasion was observed in 54/115 (47%) of primary tumours removed between days 3 and 12 and 82/248 (33%) of tumours removed at other times (chi 2 = 6.47, P < 0.02). Multivariate analysis of factors influencing survival indicated that both axillary nodal status and phase of the cycle were highly significant independent predictors of prognosis.

Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.

PURPOSE: An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS: Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS: As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION: Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.

Association of c-erbB-2 expression and S-phase fraction in the prognosis of node positive breast cancer.

An immunohistochemical study was performed on 211 primary breast carcinomas for c-erbB-2 expression. All patients had involvement of axillary lymph nodes and all were randomised onto one of the Ludwig Breast Cancer Trials I-IV between July 1978 and August 1981. c-erbB-2 overexpression significantly correlated with high S-phase fraction, four or more positive axillary nodes involved, estrogen receptor negative primaries, progesterone receptor negative primaries, high grade tumours and DNA aneuploidy. With a nine year median follow-up c-erbB-2 positive tumours had worse disease-free survival (p = 0.0002) and overall survival (p less than 0.0001). Multivariate analyses using proportional hazard regression models demonstrated that c-erbB-2 positivity continued to predict a poor outcome even when accounting for the effects of other prognostic factors.

The relationship between micrometastases in the bone marrow, histopathologic features of the primary tumor in breast cancer and prognosis.

The pathologic features of the primary tumors in 285 patients with breast cancer at the time of initial presentation, and with no clinical evidence of distant metastases, have been analyzed. The results have been compared with the detection of tumor cells in the bone marrow by use of an immunocytochemical method using antisera raised against the epithelial membrane antigen (EMA). The authors found EMA-positive cells (i.e., tumor cells) in the bone marrow of 77 (27%) patients and a significant association between the presence of such EMA-positive cells in the bone marrow and tumor size (P = 0.006) and peritumoral vascular invasion (P = less than 0.001). A possible relationship with estrogen receptor negativity (P = 0.06) also was noted.

Prognostic significance of peritumoral vascular invasion in breast cancer.

A prospective study of 232 patients with primary invasive breast cancer (UICC Stages I, II and III) and histologically confirmed axillary node status was carried out to assess the prognostic significance of several readily available clinical and pathological characteristics. In addition to the recognised utility of tumour size and axillary lymph node status, the presence or absence of cohesive clumps of malignant cells in peritumoral vascular spaces (both lymphatic and blood vessels) was found to be prognostically important.

Immunocytochemistry in the identification of vascular invasion in breast cancer.

Immunocytochemical stains were used to find out whether they would increase the accuracy of detecting lymphatic and vascular invasion by primary breast cancer cells over conventional histological methods. Immune probes for type IV collagen were of value in confirming the conventional diagnosis of vascular invasion while stains for factor VIII assisted in differentiating small blood vessels from lymphatic channels. Antibodies to type IV collagen also increased the accuracy and rate of detection achieved by conventional histology.

Adjuvant aminoglutethimide therapy for postmenopausal patients with primary breast cancer: progress report.

A group of 122 postmenopausal patients with histologically proven node-positive primary breast cancer have been randomized to receive aminoglutethimide-hydrocortisone or placebo aminoglutethimide-placebo hydrocortisone for 2 years. Median follow-up is 17 months. In general, treatment was well tolerated, but 15 patients required a reduction in the dose of aminoglutethimide, and of these four patients were unable to continue therapy due to side effects. Primary staging, incidence of extensive node involvement, and estrogen receptor were similar in the treatment and control arms. Dehydroepiandrosterone sulfate (DHA-S) and estrone were measured in a subgroup of patients, and significant suppression of DHA-S levels throughout the duration of the treatment period as seen in patients receiving the active drug. No significant suppression of either DHA-S or estrone levels was seen in the controls. Patients were monitored for metastases by serial liver function tests, carcinoembryonic antigen, and chest X-rays, and of 26 relapsing patients only three patients were not detected by this screen. We conclude that adjuvant aminoglutethimide is moderately well tolerated. It is capable of suppressing DHA-S throughout 2 years of treatment. A further 280 patients will be entered into the study to assess the survival benefit for those taking aminoglutethimide-hydrocortisone.

Effects of endocrine therapy on steroid-receptor content of breast cancer.

In order to determine the mechanisms of relapse following response to endocrine therapy, we have measured the oestrogen receptor (RE) content of biopsies of breast cancer in patients receiving various types of endocrine treatment. RE content fell in responding (means of 260.2 to 12 fmol/mg protein) and in nonresponding (means of 155.1 to 31.8 fmol/mg protein) patients who had measurable receptor at the start of treatment. Some of these patients, and a further group of responders to endocrine therapy, were monitored until relapse. Tumour biopsies at the time of relapse showed that 10/14 tumour samples contained significant RE (mean of 86.7 fmol/mg protein; range less than 10-271 fmol/mg protein) after successful endocrine therapy. No relationship could be found between RE content and plasma gonadotrophin or steroid-hormone concentration, but the fall in RE content correlated with reduced numbers of tumour cells in the biopsy. These results indicate that relapse following successful endocrine therapy in breast cancer does not appear to be due to the emergence of RE-negative tumour cells. The fall in RE content during response to endocrine therapy may be due to reduced tumour-cell content of the biopsy.

Role of plasma carcinoembryonic antigen in diagnosis of gastrointestinal, mammary, and bronchial carcinoma.

Our studies have confirmed that raised plasma levels of carcinoembryonic antigen (C.E.A.) occur with many but not all malignant tumours, particularly those of the gastrointestinal tract, breast, and bronchus. However, the incidence of raised values may reach 30% in diseases associated with inflammation or regeneration or both. Consequently, it cannot serve yet as a routine screening test for cancer. Effective surgical therapy results in high plasma C.E.A. levels returning to normal. Subsequent rises appear to develop with tumour recurrence or spread. At present the most useful role for C.E.A. seems to be in monitoring patients during the post-therapeutic followup period. Further basic work is required before C.E.A. can become of routine medical value.