Joseph C. Allegra

The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer.

In a retrospective study we determined the relation between estrogen receptors and the response rate to cytotoxic chemotherapy in 70 patients with metastatic breast cancer. Thirty-four of 45 patients with low or absent estrogen-receptor values (less than 10 fmol per milligram of cytoplasmic protein) had objective responses to chemotherapy, whereas only three of 25 patients with higher values (greater than 10 fmol per milligram of cytoplasmic protein) responded (P less than 0.0001). There were no statistically significant differences between the two groups in age, menopausal status, disease-free interval, Karnofsky index or prior therapy. Differences in sites of involvement or type of chemotherapy did not account for the increased response rate in receptor-negative patients. We conclude that estrogen-receptor values are an important predictor of response to cytotoxic chemotherapy in metastatic breast cancer.

Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer

Abstract The influence of estrogen receptor status on response rate to endocrine therapy in 85 patients with metastatic breast cancer was determined in a retrospective study. The specific purpose of this study was to assess the role of estrogen receptor determinations in the light of a host of clinical variables known or suspected to influence response rates to endocrine therapy. Thirty-four of 52 patients whose tumors contained significant amounts of estrogen receptor (> 10 fmole/mg cytoplasmic protein) had objective responses to endocrine therapy while only 333 patients whose tumors did not possess estrogen receptor ( 10 fmole/mg cytoplasmic protein) responded ( P 0.0001 ). A quantitative relationship was found between the amount of estrogen receptor and response rate. The quantity of estrogen receptor was not associated with the duration of response. The predictive value of the estrogen receptor assay was not associated with the receptor dissociation constant. Prior treatment with endocrine or chemotherapy did not diminish the ability of estrogen receptor determinations to predict response to subsequent endocrine therapy. Response rate in estrogen receptor positive tumors was not affected by extent of disease, site of involvement with metastatic tumor, or prior therapy. We conclude that these negative prognostic factors are less important in predicting response to endocrine therapy than estrogen receptor values.

Changes in multiple or sequential estrogen receptor determinations in breast cancer

Estrogen receptor (ER) analyses are widely used in the management of patients with breast cancer. Few data are available concerning variations in ER as a function of time and therapy. We examined patients in whom multiple biopsies and receptor analyses were either performed simultaneously or over time with or without intervening chemotherapy or endocrine therapy. In 27 patients with simultaneous assays from different metastatic sites, concordant results were obtained in 23 (85%) with respect to classifying a tumor as ER+ or ER–. In 34 patients, multiple assays were performed over time. The receptor concentrations were concordant in patients receiving no intervening therapy. In 10 patients receiving hormonal therapy, the median receptor concentration changed from 66 femtomoles per mg cytoplasmic protein pretherapy to 8 femtomoles post therapy (P < 0.05). This change suggested that hormonal therapy selectively eliminates ER+ cells. In 19 patients receiving intervening chemotherapy, the median receptor concentrations pre and post therapy were similar. We conclude that simultaneous assays from multiple metastatic sites are highly concordant and unlikely to change over time without intervening therapy, but marked changes occur following therapy with a decrease in receptor concentration after endocrine therapy. Cancer 45:792‐794, 1980.

Current concepts in cancer. Receptors in breast cancer

Estrogen Receptor and Endocrine Therapy of Breast Cancer SINCE the pioneering work of George Beatson,1 who induced tumor regressions in patients with advanced breast cancer by oophorectomy, it has ...

Estrogen receptor values in patients with benign breast disease.

Tissue specimens from 55 female patients with benign breast disease were assayed for estrogen receptor. Twenty‐one of 55 patients (38%) had tumors which contained significant amounts of estrogen receptor (>10 femtomoles/mg protein). Fibroadenomas possessed estrogen receptor more frequently than fibrocystic disease or other benign breast tumors. Estrogen receptor positivity did not correlate with laterality of the tumor; location or size of the largest nodule. Patients with estrogen receptor positive tumors had a mean age of 26.9 years compared to 36.4 years for patients with estrogen receptor negative tumors (p < 0.01). Twenty of 46 (43%) premenopausal patients had benign tumors which were estrogen receptor positive compared to zero of 8 postmenopausal patients (p < 0.05).

The effects of 17β estradiol and tamoxifen on the ZR-75-1 human breast cancer cell line in defined medium

Abstract The effects of 17β estradiol and tamoxifen on the ZR-75-1 human breast cancer cell line in serum free hormone supplemented medium are described. Addition of 17β estradiol leads to a marked stimulation of the breast cancer cells manifested by increases in cell number, precursor incorporation into macromolecules, liquid synthesis, and thymidine kinase activity. Concentrations of 17β estradiol as low as 10−11 M stimulate growth; 10−10 M 17β estradiol is maximally effective. Addition of the antiestrogen tamoxifen in cells devoid of estradiol leads to a period of estrogen reversible inhibition followed by cell death. 10−8 M tamoxifen has little effect on growth whereas 10−6 M tamoxifen is maximally effective. Hundred-fold lower concentrations of 17β estradiol when added simultaneously blocks antiestrogenic inhibition almost completely. These data obtained in a totally defined serum free system provide strong evidence for the absolute and direct growth dependence of some human breast cancer cells on estrogens.

Combined effects of methotrexate and 5-fluoropyrimidine on human breast cancer cells in serum-free culture

Abstract The combined effects of methotrexate and 5 -fluoropyrimidines on the growth of a human breast cancer cell line in serum-free hormone-supplemented medium, lacking nucleosides, have been studied. All combinations of methotrexate (10–50 nM) and 5 -fluorodeoxyuridine (10–100 nM) resulted in at least additive inhibition of cell growth and when analyzed by 50% response isobologram demonstrated synergism. Combinations of methotrexate (10–50 nM) and 5 -fluorouracil (0.04–0.4 μM) gave enhanced inhibition as compared to single agents, but 50% response isobologram revealed only additive effects. The combination was most effective when methotrexate was added to the cultures prior to the 5 -fluoropyrimidines or when the drugs were added simultaneously. The addition of 5 -fluoropyrimidine prior to methotrexate appears to decrease the effect of the antifol on purine synthesis and lessen the cytotoxicity of the combination in this cell line.

The Regulation of Progesterone Receptor by 17β Estradiol and Tamoxifen in the ZR-75–1 Human Breast Cancer Cell Line in Defined Medium

The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the ZR-75-1 human breast cancer cell line in defined medium is described. ZR-75-1 cells maintained in serum free hormone supplemented medium minus estradiol lack progesterone receptor activity. Readdition of estradiol to these cells leads to a marked stimulation of progesterone receptor activity (0 to greater than 100 fmols of specifically bound progesterone per million cells). Tamoxifen (10(-6)M-10(-8)M) does not stimulate progesterone receptor activity in this cell line. The presence of progesterone receptor activity is not directly related to growth. Withdrawal of insulin in the continued presence of estradiol has no effect on progesterone receptor concentration although net cell growth ceases. Conversely, withdrawal of estradiol in the continued presence of insulin induces a cessation of net cell growth accompanied by a loss of all progesterone receptor activity within 3-5 days.