J.-C. Gazet

Bone marrow micrometastases in primary breast cancer : prognostic significance after 6 years follow-up

Using an antiserum to epithelial membrane antigen we have screened multiple bone marrow aspirates from 350 patients with primary breast cancer taken at the time of initial surgery. 89 (25%) patients were found to have micrometastases and their presence was related to pathological size (P less than 0.01), the presence of peritumoral vascular invasion (P less than 0.001), and positive lymph nodes (P less than 0.005) but not menopausal status. At a median follow-up of 76 months (range 34-108) 107 patients had relapsed with distant metastases. 48% (43 of 89) of these patients had micrometastases initially compared with 25% (64 of 261) who did not (P less than 0.005). The test predicts for relapse in bone (P less than 0.01) and other distant sites excluding bone (P less than 0.001) and is associated with a shorter overall survival (P less than 0.005). We conclude that the detection of micrometastases signals a high likelihood of early relapse and decreased survival in breast cancer.

FAILURE OF CHEMOTHERAPY TO PROLONG SURVIVAL IN A GROUP OF PATIENTS WITH METASTATIC BREAST CANCER

Overall survival of patients with primary breast cancer has not improved in the past ten years, despite increasing use of multiple-drug chemotherapy for treatment of metastases. Furthermore, there has been no improvement in survival from first metastasis, and survival may even have been shortened in some patients given chemotherapy. Chemotherapy probably does prolong survival in some patients, and further studies should be undertaken to identify these patients in advance.

DETECTION OF BREAST CARCINOMA METASTASES IN BONE: RELATIVE MERITS OF X-RAYS AND SKELETAL SCINTIGRAPHY

Of 1116 patients receiving primary treatment for breast carcinoma at the Royal Marsden Hospital since 1976, 651 had an abnormal bone scintigram either at primary diagnosis (378) or on subsequent follow-up (273) and 167 developed radiographically detectable bone metastases (21 at the time of primary diagnosis). Comparison of bone scintigrams and X-rays showed that scintigraphy was an inaccurate localiser of existing radiographic detectable metastases. If X-rays alone are used to detect bone metastases a limited examination with five plates will detect metastases with 92% accuracy. After primary surgery, routine X-ray screening for bone metastases is not necessary since it is possible to identify patients at risk on the basis of clinical examination, chest X-ray, and serum alkaline phosphatase and gamma-glutamyl transpeptidase levels.

Aminoglutethimide in treatment of metastatic breast carcinoma.

42 patients with metastatic breast carcinoma were treated with aminoglutethimide, which inhibits adrenal steroid hormone synthesis. Treatment was stopped in 2 patients before response could be assessed; of the other 40, 15 (37.5%) had an objective response, 1 (2.5%) showed a response in bone but not in soft tissue, and 4 (10%) had complete or very great relief of metastatic bone pain but no radiological evidence of improvement. 19 (53%) of 36 patients with bone metastases responded to treatment (15 had X-ray evidence and 4 had pain relief), as did 5 (45%) of 11 patients with soft tissue metastases, 2 (25%) of 8 with malignant marrow infiltration, 1 (14%) of 7 with lung metastases, and none of 13 with liver metastases. Response was commonest in patients who had previously responded to other forms of endocrine therapy. Side-effects, usually mild and transient, occurred in a few patients; the most important were an initial period of somnolence in 9 patients and a rash in 5.

PREDICTION OF ENDOCRINE RESPONSE IN BREAST CANCER BY IMMUNOCYTOCHEMICAL DETECTION OF OESTROGEN RECEPTOR IN FINE-NEEDLE ASPIRATES

An immunocytochemical technique has been developed to detect the oestrogen receptor (ER) in samples obtained by fine-needle aspiration of primary or secondary breast carcinoma tissue. 45 (75%) of 60 samples contained sufficient cells for analysis. 19 (90%) of 21 patients who responded to endocrine therapy had samples with ER-positive cells compared with only 7 (39%) of 18 of those who did not respond (p less than 0.001). This test, which causes little pain to the patient and does not need a surgical biopsy, is as accurate as any other method of predicting the response to endocrine treatment in breast cancer.

LOW-DOSE AMINOGLUTETHIMIDE IN TREATMENT OF ADVANCED BREAST CANCER

The clinical and endocrine effects of low-dose aminoglutethimide without hydrocortisone in patients with advanced breast cancer were investigated. In a dose escalation study low-dose aminoglutethimide alone (62.5-125 mg twice daily) was as effective as conventional doses with hydrocortisone in lowering serum oestrone and oestradiol concentrations but caused minimum adrenal inhibition, as assessed by serum dehydroepiandrosterone sulphate. 11 of 57 (19%) evaluable patients had tumour regression by objective criteria on this treatment, but the frequency of side-effects was similar to that with conventional doses. Low-dose aminoglutethimide is active in the treatment of breast cancer. It appears to work by inhibition of the aromatase enzyme system in peripheral tissues rather than adrenal suppression.

Aminoglutethimide for the treatment of advanced postmenopausal breast cancer

A group of 213 unselected postmenopausal women with advanced breast cancer were treated with aminoglutethimide, 250 mg 4 times a day, and hydrocortisone, 20 mg 2 times a day. Follow-up is 10 months to 4 years from the start of treatment. In 190 assessable patients, there were 6 complete responses (CR), 47 partial responses (PR), 25 stable disease (SD), and 3 mixed responses. Overall objective response rate was 28% and with SD was 41%. Median duration of objective response was 14 months. Objective response by site was: soft tissue, 31%; nodes, 27%; bone 23: liver, 22%; and lung, 16%. A further 32% of patients with bone deposits had SD, and 19 of 60 patients with progressive disease had pain relief. Years after menopause, age and tumor-free interval did not affect response rates. Thirty-eight % of patients responding to previous endocrine therapy responded to aminoglutethimide compared with 19% of patients who had progressed on previous endocrine therapy. A group of 213 patients were assessable for toxicity. Main side effects were drowsiness (33%), rash (23%), and nausea (15%). Eleven patients stopped treatment because of toxicity. Median survival from start of treatment was 28 months for PR-CR and for SD and 10 months for progressive disease (p less than 0.001). Median survival from first metastasis was 43 months for PR-CR, 40 months for SD (not significantly different), and 22 months for progressive disease (p less than 0.001). Aminoglutethimide is an effective endocrine therapy in advanced postmenopausal breast cancer, particularly for bone deposits. Disease stabilization is associated with symptomatic and survival benefit similar to CR-PR.

TREATMENT OF DISSEMINATED BREAST CANCER WITH TAMOXIFEN, AMINOGLUTETHIMIDE, HYDROCORTISONE, AND DANAZOL, USED IN COMBINATION OR SEQUENTIALLY

222 patients with disseminated breast cancer have been randomised to receive either a combination of hormone therapies using tamoxifen, aminoglutethimide with hydrocortisone, and danazol (TAD), or tamoxifen alone. The response to the combination was significantly better (43%) than that to tamoxifen alone (31%). Patients who relapsed after response or failed to respond to tamoxifen were subsequently treated with aminoglutethimide and then, if possible, with danazol. Some patients who received TAD were subsequently treated with alternative endocrine therapy, which was usually medroxyprogesterone acetate. Of the 111 patients who initially received tamoxifen, 43 responded to the tamoxifen and/or subsequent endocrine therapy. Of the 111 patients who initially received TAD, 50 responded. Although the duration of response to TAD was the same as for tamoxifen, the TAD patients achieved remission more quickly. The total time in endocrine remission for patients receiving TAD is 303 months to date, compared with 264 months for patients receiving tamoxifen. Survival for patients randomised to receive TAD or tamoxifen is the same.

Mitomycin C, melphalan and methotrexate combination chemotherapy for palliation of disseminated breast cancer

SummaryFifty-seven patients with metastatic breast carcinoma have been treated with mitomycin C (10 mg/m2 IV 6-weekly), melphalan (6 mg/m2 POx3 days, 3-weekly), and methotrexate (35 mg/m2 IV 3-weekly) to assess the efficacy and toxicity of this regimen. Of 48 evaluable patients 19 (40%) responded for a median period of 5 months and 12 (25%) had stabilisation of disease. Of the 12 patients previously treated with adriamycin only one responded, whereas 18 of the 36 patients without previous chemotherapy responded. Although healing of bone metastases was infrequent control of hypercalcaemia was commonly seen. Generally the treatment was well tolerated and treatment was stopped in only five patients because of toxicity. Cummulative marrow toxicity was observed but was not a significant problem in the first 6 months of treatment. Mitomycin C, melphalan, and methotrexate (MMM) appears to provide an effective, well tolerated chemotherapy combination for metastatic breast carcinoma.