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There is controversy whether high-dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional-dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time-to-treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory.Determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer. PANELISTS: Nine breast cancer experts from diverse geographic sites and practice settings.Boolean MEDLINE searches of 'breast cancer' and 'chemotherapy' and/or 'blood cell' or 'bone marrow transplants'.We used a modified Delphi-panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional therapy on a 9-point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning.In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those withor = 10 cancer-involved lymph nodes; 2) uncertain in those with 4-9 cancer-involved nodes; and 3) inappropriate in women withor = 3 cancer-involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to 'favorable' sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to 'unfavorable' sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.

We have attempted to initiate a much needed constructive dialogue regarding the participation of African-American patients in clinical cancer research trials. It was our intent to provide a greater understanding of the historical context and evolving nature of clinical research trials pertaining to cancer. Some of the same challenges hold true for acquired immunodeficiency syndrome (AIDS)-related clinical research. Physicians interested in becoming a member of SOCRATES should contact Dr Roach at the University of California San Francisco.

The multiple forms of cytoplasmic ER and PgR were electrophoretically characterized by PAGE under non-denatured conditions and SDS PAGE under denatured conditions. The ordinary PAGE and SDS PAGE were modified in such a way as to reveal the authentic multiple forms of the hormone receptors studied. The experimental conditions were well-defined. The standard protein criteria for evaluation of molecular weights were established. The high polymers containing main activity can be revealed by 3% PAGE under non-denatured conditions and all the multiple forms can be revealed by 3% SDS PAGE under milder SDS coupling reaction. The multiple forms commonly occurring are monomer, dimer, tetramer and hexamer for both ER and PgR. For PgR, there are two monomer components A and B, dimer AB. Tetramer 2AB and hexamer 3 AB. Octamer 4 AB is observed sometimes.

Cytosol from immature rabbit uteri was classified into six groups according to range of molecular weights. The molecular sieve can be achieved by AMICON ultrafiltration using membranes of different pore sizes. The results revealed that almost 50% of the total activity of ER and PgR was confined to the largest fraction with a molecular weight greater than 300,000. A detailed study by electrophoretic characterization in later experiments demonstrated that the cytoplasmic ER and PgR exist mainly in high polymer forms.

Similar ER activities were observed in the different sections and in both branches of rabbit uterus, while PgR activities varied greatly from branch to branch and from section to section in the left branch of the uterus. The total ER activity was much higher than the total PgR activity in both branches. In the dog uterus, both ER and PgR showed higher activity in the right branch, but both appeared to be equally distributed in the sections and in each branch. The total ER and PgR activities were equally distributed in both branches.

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.

Activation and inhibition of estrogen and progestin receptor functions by endogenous biological factors present in the cytosol preparations were demonstrated by assaying mixed cytosol preparations from human breast tumors and immature rabbit uteri. Both activation and inhibition of receptor-hormone binding reaction could be observed by tumor-rabbit uterus or tumor-tumor combinations. The activation of tumor progestin receptor by rabbit uterus cytosol was markedly profound.

The effects of Dithiothreitol (DTT) on the estrogen receptor molecule were studied. DTT was evaluated for its potential abilities to preserve the integrity of the estrogen receptor. Storage at various extremes of pH was also considered for its possible adverse or positive effect. Cytosol was prepared utilizing rabbit uterus. Six aliquots of the cytosol were stored at 4 degrees C for 15 days. Two samples were adjusted to each pH, 6.0, 7.0, and 8.0, and to one sample of each pH was added DTT, 0.154 mg/ml. Aliquots of stored cytosols were analyzed for estrogen receptor (ER) on day 1, 3, 7, and 15 after adjusting the aliquots to pH 7.4. There was degradation of ER with time; degradation was less with DTT. The degradation also increases with the lower pH. The cytosol stored at 4 degrees C and pH 8.0 with DTT was the best environment in these experiments for stability of ER.

The relatively short survival following chemotherapy in patients with metastatic carcinoma of the breast and the introduction of antiestrogens has led to renewed interest in the hormonal therapy of breast cancer. Pritchard et al. (Cancer Treat. Rep., 64: 787-796, 1980) have recently stated that response to the antiestrogen tamoxifen (TAM) strongly predicts a subsequent response to oophorectomy in premenopausal patients. The Southwest Oncology Group administered TAM to pre- and postmenopausal women with first recurrence of breast cancer. Following response and subsequent relapse, or after no response, patients underwent an oophorectomy while continuing on TAM. None of 14 premenopausal patients who responded to TAM had a response to oophorectomy plus TAM, while 5 of 22 had a remission with oophorectomy plus TAM after initially failing with TAM alone. The reverse was seen in postmenopausal women; 4 of 18 responders to TAM subsequently responded to oophorectomy plus TAM, but none of 18 TAM failures responded to oophorectomy plus TAM. These results suggest that in the premenopausal women the TAM dose may be insufficient to block all estrogen action and that oophorectomy, by removing the major source of estrogen, can result in a more effective antiestrogen action of TAM leading to a response. No explanation is readily available for the results in postmenopausal patients.

Methods for improving the estrogen receptor (ER) and progestin receptor (PgR) assay were studied. Using DCC procedure as the basis, the extraction and incubation of ER and PgR is more efficiently achieved by phosphate buffer as compared with water, tris and veronal buffers. The multiple extractions of hormone receptors by any solvent system used is more complete than a single operation of homogenization and centrifugation. The utilization of combined extraction first with water and then phosphate buffer, followed by incubation of the cytosol in phosphate buffer with hormone is also an efficient procedure for the assay of both ER and PgR.

Twenty-six evaluable patients with advanced soft tissue and bony sarcomas refractory to chemotherapy were treated with vincristine plus high-dose methotrexate and leucovorin rescue. A 14% response rate was observed among 14 patients presenting with refractory soft tissue sarcomas. No responses were observed among 12 patients with bony sarcoma. Toxic reaction with nausea, vomiting, nephrotoxicity, and myelosuppression was manageable. While this study did demonstrate activity of this regimen in doxorubicin-refractory patients, the duration of the responses was relatively brief. Thus, the clinical utility of such a regimen is questionable.

Patients with advanced breast cancer who had not previously received chemotherapy were treated on a three-arm prospective study: adriamycin day 1 plus 5-FU on day 1 and 8 (AF), adriamycin day 1, plus 5-FU day 1 and 8, and cyclophosphamide day 1 (AFC), and adriamycin day 1 plus 5-FU day 1 and 8, cyclophosphamide day 1 and methotrexate day 1 (AFCM). These courses were repeated every 21 days. The response rate was 44/105 (42%) AF, 44/103 (43%) AFC and 52/105 (49%) AFCM. The length of response was 22, 33 and 35 weeks, respectively, for AF, AFC and AFCM (P = 0.21). The median survival, 64 weeks, was equal in all three limbs. The major toxicity was leukopenia. Twenty-eight percent developed a WBC of less than 2,000/microliter, which resulted in seven deaths (2.2%).

A phase II trial was conducted to determine the clinical activity of amsacrine (m-AMSA) in patients with heavily pretreated solid tumors, myeloma, and lymphoma at the University of Arizona Cancer Center. Additionally, m-AMSA was evaluated at other Southwest Oncology Group institutions in breast cancer, myeloma, melanoma, and oat cell cancer of the lung. At a dose of 120 mg/m2 given iv every 28 days, 12 partial responses were observed in 221 patients evaluable for response. Some antitumor activity was observed in breast cancer (four responses of 65 patients), non-Hodgkin's lymphoma (three of nine), Hodgkin's disease (two of five), and sarcoma (two of 15). A partial response was also documented in one of two patients with cervical cancer. Among the 135 patients treated at the University of Arizona who were extensively evaluated for toxic effects, only myelosuppression and anemia were seen in a significant number of patients. At this dose and schedule, 29% of patients developed leukopenia of less than 3000 cells/mm3, 16% developed a thrombocytopenia of less than 100,000 cells/mm3, and 29% had an acute fall in hemoglobin of greater than or equal to 2 g/100 ml. In addition, two patients suffered grand mal seizures which were not clearly drug-related. These results suggest that further study of m-AMSA in lymphoma, sarcoma, and cervical cancer is warranted.

Extraction of ER and PgR with 10 mM molybdate in TEDG buffer greatly facilitated their solubilization and a much higher receptor value was observed. However, since molybdate also affects the hormone receptor binding reaction, the apparent receptor activity assayed with molybdate is different from the actual receptor activity normally assayed without molybdate. A correction factor obtained by assaying cytosol with and without adding molybdate can be used to convert the apparent value into the actual value. The mathematical evaluation involving two separate effects of molybdate on receptors is illustrated.