Hormone receptors in the management of breast cancer.
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Adult↗
Biomedical subjects
C K Osborne
Publications and source records attributed to C K Osborne.
Bisantrene, an active drug in patients with advanced breast cancer.
We have previously reported that bisantrene has significant activity against a variety of tumors in the human tumor soft agar cloning assay. An update of that experience reveals that 26% of evaluable human breast cancer specimens were sensitive to bisantrene, which had activity equivalent or superior to that of doxorubicin. Because of the preclinical activity of bisantrene and its activity in the cloning assay, bisantrene was studied in a phase II clinical trial of 30 patients with advanced breast cancer refractory to standard agents. Six patients (20%) had objective complete or partial regressions, including one patient with complete regression of lymphangitic lung metastases lasting greater than 18 months, confirming the antitumor activity of this compound. Two of the six responding patients had failed doxorubicin treatment, implying a lack of complete cross-resistance. Bisantrene toxicity was acceptable in most patients, with reversible myelosuppression being the most frequent side effect. Phase III trials of this promising new agent are warranted.
Adult↗
Human breast cancer cell cycle synchronization by estrogens and antiestrogens in culture.
The mechanisms by which estrogens and antiestrogens modulate breast cancer growth have not been totally defined. We have examined the cell cycle kinetic effects of estrogens and antiestrogens in cultured human breast cancer cell lines. In a previous study, we showed that tamoxifen induces a transition delay in early to mid-G1 phase of the cell cycle. In the present study, we show that this cell kinetic alteration by tamoxifen is dose dependent and that other antiestrogens have identical effects. As little as 0.01 to 0.1 microM tamoxifen reduces the S and G2 + M fractions and increases the G1 fraction of MCF-7 cells growing in medium with 5% charcoal-stripped bovine serum. More than 90% of cells are in G1 72 to 96 hr after the addition of 1 microM tamoxifen, a concentration achieved in patients treated with the drug. Nafoxidine and trioxifene have identical activity. Partial reversal of tamoxifen growth inhibition is observed with a simple change to tamoxifen-free medium. Complete reversal of the tamoxifen effect is observed with the addition of 17 beta-estradiol. By 24 hr after the addition of estrogen, 60 to 70% of tamoxifen-inhibited cells have progressed through G1 and into S phase, indicating that tamoxifen-treated cells remain viable. This estrogen "rescue" effect is observed even in the absence of a change to tamoxifen-free medium. A 100-fold-lower concentration of estradiol can totally reverse the inhibitory effects of 1.0 microM tamoxifen. Stimulation of the progression of G1 cells to enter S phase is also observed when estradiol is added to cells maintained for four days in medium with stripped serum, even in the absence of tamoxifen. Similar effects are observed in the estrogen receptor-positive ZR75-1 breast cancer cells. No effects of antiestrogens or estrogens are observed in the receptor-negative MDA-231 cells, suggesting that these effects are mediated through the estrogen receptor. In summary, antiestrogens and estrogens have prominent effects on the cell cycle kinetics of endocrine-dependent human breast cancer cells. Antiestrogens cause an accumulation of cells in G1 phase. Estrogen reverses this block with a synchronous cohort of cells progressing through the cell cycle. These data have important implications for the design of rational clinical trials of combined chemoendocrine therapy.
Breast Neoplasms↗
Tumor-derived growth factor increases bone resorption in a tumor associated with humoral hypercalcemia of malignancy.
Evidence is presented that a tumor-derived transforming growth factor is responsible for stimulating bone resorption and causing hypercalcemia in an animal tumor model of the hypercalcemia of malignancy. Both conditioned medium harvested from cultured tumor cells and tumor extracts of the transplantable rat Leydig cell tumor associated with hypercalcemia contained a macromolecular bone resorbing factor with the chemical characteristics of a tumor-derived transforming growth factor.
Animals↗
An autopsy study of histologic progression in non-Hodgkin's lymphomas. 192 cases from the National Cancer Institute.
Histologic slides were reviewed from 192 autopsies of patients with non-Hodgkin's lymphomas admitted to the National Cancer Institute (NCI) from 1953 to 1975. Each autopsy was classified according to the systems of Rappaport and Lukes-Collins. Comparisons with the initial diagnosis were made. The initial histologic diagnoses of the autopsied population were similar in distribution to other published series of non-Hodgkin's lymphomas. Of the 56 cases which initially demonstrated nodular patterns of growth, the following distribution was found at autopsy: 25%, no lymphoma; 6%, nodular lymphoma; 32%, diffuse histiocytic (large cell) lymphoma (DHL); 21%, diffuse undifferentiated (non-Burkitt's) lymphoma (DUL); and 16%, the remaining diffuse morphologies. Of the 136 patients with initial diagnosis of diffuse lymphoma, the following distributions were observed at autopsy: 20%, no lymphoma; 0%, nodular lymphoma; 31%, diffuse histiocytic (large cell) lymphoma; 12%, diffuse undifferentiated (non-Burkitt's) lymphoma; 9%, Burkitt's tumor; 14%, diffuse poorly differentiated lymphocytic lymphoma; and 14%, the remaining diffuse morphologic types. One hundred and thirty-four cases which were initially diagnosed as follicular center cell type within the Lukes-Collins classification gave the following distribution at autopsy: 21%, no lymphoma; 25%, small noncleaved type; 17%, large noncleaved type; 23%, non-follicular center cell lymphomas (17% immunoblastic B); and the remaining 13% were distributed among the other follicular center cell types. This autopsy review demonstrates the rarity of nodular (follicular) lymphomas at autopsy, and the predominance of the diffuse histiocytic or "transformed" type. This study provides a comparison of the rate of histologic progression of lymphomas in the same patient population at autopsy with a previously published study of progression during life.
Adolescent↗
Anaphylactoid reactions associated with bisantrene infusions.
Nine of ninety-three patients receiving Bisantrene on an every three week schedule developed an anaphylactoid reaction with a variety of symptoms. Most reactions occurred in patients who had multiple exposures to Bisantrene. Investigators utilizing Bisantrene in ongoing clinical trials should be aware of this life threatening toxicity.
Anaphylaxis↗
Characterization of insulin regulation of lipid synthesis in MCF-7 human breast cancer cells.
Stimulation of lipid synthesis by insulin in MCF-7 human breast cancer cells is characterized by an increase in acetate incorporation into long-chain fatty acids. The effects occurs in the absence of an increase in glucose uptake by the cells, and cannot be explained by a decrease in turnover of cellular fatty acids. Differential substrate experiments as well as direct measurement of enzyme activities indicate that insulin stimulates increases in activity of the first enzyme of the de novo pathway, acetyl CoA carboxylase. [32Pi] incorporation into phospholipids is also stimulated by insulin. Thin layer chromatography reveals five peaks of [32Pi]-labeled phospholipids corresponding in mobility to the following standards: lysophosphatidylcholine, sphingomyelin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine. [32Pi] incorporation into each of these peaks is stimulated, although the degree of stimulation varies.
Breast Neoplasms↗
Mitoxantrone: modest activity in a phase II trial in advanced prostate cancer.
Thirty-seven patients with metastatic prostate cancer refractory to endocrine therapy were treated in a phase II trial of mitoxantrone. Starting doses were 12 and 10 mg/m2 iv every 21 days for good-risk and poor-risk patients, respectively. Of the 35 evaluable patients, two had objective partial regression and five had stable disease. Response duration ranged from 7 to 17+ months. The drug was very well tolerated by these elderly patients; myelosuppression was the major toxic effect. We conclude that mitoxantrone has modest activity and acceptable toxicity in patients with advanced prostate cancer.
Adenocarcinoma↗
Multiple estrogen receptor assays in human breast cancer.
A review of assay results from more than 6000 patients revealed 232 patients in whom multiple breast cancer specimens were analyzed for estrogen receptor (ER). All assays were performed in a single laboratory. Specimens were considered estrogen receptor positive (ER+) if the ER level was greater than 10 fmol/mg protein and estrogen receptor negative (ER-) if the ER level was less than 3. ER values between 3 and 10 fmol/mg protein were considered borderline. Simultaneous assays were performed in 58 patients with 3% major discordance (i.e., one assay ER- and one assay ER+). Major discordance for sequential biopsies was 19% (16 of 82) when the initial assay was ER+ and 13% (eight of 63) when the initial assay was ER-. (Apparent change from ER- to ER+ status was observed in five of nine patients with primary tumors less than 2 cm in diameter, suggesting that an inadequate amount of tissue may have been submitted for initial ER analysis.) There was no significant relationship between the time interval between sequential biopsies and the rate of discordance. Marked decreases in ER levels and 78% discordance were seen if rebiopsy was performed within 2 months of tamoxifen treatment. When these tamoxifen cases were excluded from the analysis, neither intervening endocrine therapy nor chemotherapy significantly altered discordance rates.
Adult↗
Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase.
We have studied the effects of tamoxifen on the cell cycle kinetics of the endocrine-responsive MCF-7 human breast cancer cells. Tamoxifen inhibits proliferation of MCF-7 cells. The tritiated thymidine labeling index is markedly reduced by tamoxifen, indicating a reduction in the fraction of cells in S phase. Flow cytometry of mithramycin-stained cells reveals that cells accumulate in G1 phase, with a concomitant depletion of S- and G2-M-phase cells with tamoxifen. Mapping of G1-phase cells by morphology of prematurely condensed chromosomes demonstrated that tamoxifen-treated cells accumulate in early G1. These studies indicate that tamoxifen inhibits proliferation of MCF-7 human breast cancer cells by invoking a transition delay early in the G1 phase of the cell cycle.
Breast Neoplasms↗
Androgen priming and cytotoxic chemotherapy in advanced prostatic cancer.
Hormone manipulation has been standard therapy for metastatic adenocarcinoma of the prostate for many years. Recently cytotoxic drugs have been studied, but their effectiveness has been limited, indicating the need for new therapeutic approaches. Based upon the hypothesis that cytotoxic drugs are most effective against actively proliferating cells, we have designed a clinical pilot study employing cyclical androgen priming to transiently stimulate tumor cells followed by cytotoxic chemotherapy with cyclophosphamide and methotrexate. There were nine responders (43%) out of 21 patients entered in the study, with a median duration of response that has not been reached at 9+ months. Survival was significantly better in responders than in non-responding patients. These results are similar to those of other studies in which chemotherapy was used alone. Chemotherapy toxicity with this schedule was mild. However, the androgen priming frequently resulted in increased bone pain, and there was one episode of spinal cord compression, suggesting that tumor stimulation was achieved. These results demonstrate the need for additional basic studies of the effects of testosterone on tumor cell kinetics before further clinical trials of this approach are initiated.
Aged↗
Steroid hormone receptors and carcinoma of the breast.
The estrogen receptor (ER) assay has become a standard practice in the management of advanced breast cancer. Tumors lacking ER respond infrequently to endocrine therapy, whereas response rates of 50-60% are observed in ER+ tumors. Recent studies indicate that the ER status of the primary tumor is a good predictor of the endocrine dependence of metastatic tumors at the time of subsequent relapse. Furthermore, the absence of ER in the primary tumor is an important independent prognostic indicator of higher rate of recurrence and shorter survival. Quantitative analysis of ER and assay of progesterone receptor (PgR) are useful for increasing the accuracy of selecting patients for hormonal therapy; tumors with a high quantitative ER content or those with a positive PgR display the highest objective response rates. Preliminary analysis suggests that the presence of PgR may be the best available tumor marker of hormone dependence.
Adolescent↗
Histologic progression in non-Hodgkin's lymphoma.
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Adult↗
Methods for determining chemosensitivity of MCF-7 cells in double-layer agar culture: labeling index depression and colony count inhibition.
An autoradiographic technique has been developed to determine the percentage of MCF-7 human breast adenocarcinoma cells in double-layer agar (DLA) culture that exhibit nuclear incorporation of 3H-thymidine (3H-TdR) after in vitro drug exposure. Depression of this percentage, termed the labeling index, correlated closely with colony count inhibition--relative to the respective control values--for cultures exposed to each of several agents including varying concentrations of 5-fluorouracil and adriamycin. If a similar autoradiographic technique can be applied to cultures from human tumor biopsy specimens, this may then lead to a clinically useful chemosensitivity assay especially applicable when DLA-cultured cell quantities are small.
Adenocarcinoma↗
Estrogen receptor, a marker for human breast cancer differentiation and patient prognosis.
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Breast Neoplasms↗
Combined chemo-hormonal therapy in breast cancer: a hypothesis.
Results of treatment for advanced breast cancer have plateaued indicating the need for new treatment approaches. One such approach, combined endocrine therapy and cytotoxic chemotherapy, has had limited success in current clinical trials. This lack of synergism could be due to the effect of endocrine therapy on tumor cell kinetics, which could inhibit the activity of the cytotoxic drug. Proper sequencing of the two treatment modalities may increase the therapeutic ratio.
Antineoplastic Agents↗
Adjuvant therapy for stage II, estrogen receptor negative breast cancer.
The estrogen receptor (ER) assay provides information which correlates with the proliferative potential, pathology and prognosis for patients with breast cancer. A review of our natural history data correlating ER and axillary node involvement at the time of mastectomy with prognosis allows the identification of a high risk subset of patients with early recurrence and poor survival. Patients with ER negative, stage II disease had a significantly higher recurrence rate, and poorer overall survival was observed in spite of systemic therapy instituted at relapse. Based on this data we initiated a pilot study of intensive adjuvant therapy for women with ER negative, stage II breast cancer. At a median follow-up of 19 months for 39 treated patients, both a disease free and overall survival advantage is apparent for treated patients. Morbidity was low, with no therapy related hospitalizations. We have demonstrated the feasibility of intensive therapy for this high risk group. For a definitive answer the patient resources of a cooperative group will be needed.
Actuarial Analysis↗
Potential and problems with growth of breast cancer in a human tumor cloning system.
A human tumor cloning system has been utilized to culture 431 patients' breast cancer specimens. Overall, 288 or 67% of the specimens formed colonies in soft agar. Of the primary lesions 188/260 (72%) formed colonies and 100/171 (58%) of the metastatic lesions formed colonies. The median number of colonies per 500,000 nucleated cells plated was 47 for the primary lesions and 30 for the metastatic lesions. Growth from a variety of metastatic sites ranged from 22% for intradermal lesions to 77% for solid visceral metastases. Methods to increase the number of colonies from a specimen are reported including increasing the number of nucleated cells plated and making a variety of changes in the growth media. None of these methods has had a major impact on colony growth. The antitumor activity of standard anticancer agents such as adriamycin and medroxyprogesterone in the assay is presented. In addition, in vitro results with two new anthracene derivatives demonstrate good antitumor activity for the derivatives. The cloning assay represents a new model for both the basic and clinical studies of human breast cancer.
Anthracenes↗