toremifene and Carcinoma

It has been proposed that knowledge of estrogen receptor beta (ER-beta) expression may refine estrogen receptor alpha (ER-alpha) predictivity of response to endocrine therapy. We challenged this hypothesis in ER-alpha-positive breast cancers subjected to preoperative antiestrogen treatment. Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months). ER-alpha and ER-beta (ERs) mRNA was determined by semiquantitative RT-PCR, before (on core needle biopsy) and after (on surgical specimens) neoadjuvant treatment. Study end points included: (1) relation between treatment response and ER mRNA expression; and (2) changes in ER expression after treatment. The response was clinically assessed as tumor size change at the end of the preoperative treatment. ER mRNA expression was assessable before and after treatment in 38 and 20 cases respectively. ER-beta was co-expressed with ER-alpha at variable levels and significantly correlated only with progesterone receptor (P = 0.0285). Objective clinical response, including patients with minor change (> or =25-<50% tumor shrinkage after treatment), was documented in 68.4% of cases and was independent of ER-beta levels or changes. ER-alpha levels were higher in tumors from patients in complete remission than in those from women achieving partial response or minor change compared with non-responsive patients (median expression values: 801 versus 516 versus 320 arbitrary units) and were consistently down-regulated by preoperative treatment. We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Humans; Neoadjuvant Therapy; RNA, Messenger; Selective Estrogen Receptor Modulators; Toremifene; Treatment Outcome; Tumor Burden

A 47-year-old woman was admitted to our hospital for advanced breast cancer with multiple liver metastases and liver dysfunction in January 2004. EC (EPI combined with CPA), weekly PTX, and AI were performed but were not effective for that tumor. Therefore, high-dose TOR was started. Liver dysfunction recovered after administration of TOR, and primary tumor and liver metastases were evaluated as a partial response (PR). The same therapy has been performed for six months with no evidence of deterioration.

Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Middle Aged; Nitriles; Quality of Life; Remission Induction; Toremifene; Triazoles

The purpose of this analysis was to determine predictors of early distant metastasis in elderly breast cancer patients receiving hormonal therapy.. We analyzed data from 938 patients in the North American Fareston Tamoxifen Adjuvant Trial>or=65 years old to determine predictors of early metastatic disease.. The median patient age was 73 (range 65 to 100). With a median follow-up of 34 months, 17 patients (1.8%) developed distant metastases. The median time to distant metastasis was 21 months. On univariate analysis, significant predictors of distant metastatic disease were as follows: progesterone receptor status (P=.032), lymphovascular invasion (P=.020), tumor grade (P=.007), tumor size (P<.01), and number of metastatic nodes (P<.01). On multivariate analysis, only the number of positive nodes (P=.029) remained significant. Patients with >or=4 positive nodes were more likely to develop early metastases than those with 0 to 3 positive nodes (odds ration 20.304; 95% confidence interval 2.777-148.456, P=.003).. Lymph node status in the elderly breast cancer patient treated with hormonal therapy alone is a strong predictor of early distant recurrence.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Mastectomy; Risk Factors; Tamoxifen; Time Factors; Toremifene

Node-positive breast carcinoma is an aggressive disease. Postmenopausal patients benefit from antiestrogen adjuvant therapy. Predictive markers could, however, be useful in selecting these patients for different modalities of adjuvant therapy. Recently, we showed that MMP-2 (72 kD type IV collagenase/gelatinase A) is correlated with unfavorable prognosis in premenopausal breast carcinoma patients. Expression of the immunoreactive protein for MMP-2 was evaluated prospectively in this study in paraffin tissue sections from primary tumors of 100 postmenopausal, node-positive breast carcinoma patients treated with an adjuvant antiestrogen therapy. A specific MMP-2 monoclonal antibody in an avidin-biotin immunohistochemical staining was used. Sixty nine percent of the samples were MMP-2 positive. Eighty three percent of the MMP-2 negative patients lived for 5 years without a recurrence, while only 67% of the patients with an MMP-2 positive primary tumor were recurrence-free at that time (p < 0.05; log rank analysis). MMP-2 positivity showed a significant correlation with shortened survival in patients with a small primary tumor (T1-2) and a low axillary tumor burden. One hundred percent of these patients with an MMP-2 negative breast carcinoma survived for 5 years, compared to 73% of the MMP-2 positive cases alive at that time (p = 0.02). In conclusion, we show here that MMP-2 is a prognostic indicator in postmenopausal patients with node-positive breast carcinoma with a low tumor burden, and that it predicts a risk for failure in antiestrogen adjuvant therapy. It might have predictive value in selecting the most efficient adjuvant therapy in this set of patients.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Matrix Metalloproteinase 2; Middle Aged; Neoplasm Recurrence, Local; Postmenopause; Prognosis; Prospective Studies; Risk Factors; Tamoxifen; Toremifene

The new antiestrogen toremifene (TOR) is currently on the market for the treatment of advanced breast cancer in postmenopausal women. TOR is known to exhibit a similar efficacy profile as tamoxifen (TAM) in the treatment of advanced breast cancer and there are studies to suggest that the beneficial side effects of TAM on bone and blood lipids are also achieved with TOR. However, the data concerning the action of TOR on the endometrium is sorely lacking. In light of the estrogenic effect of TAM on the uterus and the 2-3-fold increased incidence in endometrial carcinoma detected in patients receiving TAM therapy, it is imperative to investigate the effect of TOR on endometrial carcinoma. We compared the actions of TAM and TOR on the EnCa101 human endometrial tumor model and find that both antiestrogens have similar growth stimulatory effects. To investigate a potential mechanism of antiestrogen-stimulated endometrial tumor growth, we have examined known activators of the AP-1 signal transduction pathway, the protein kinase C (PKC) family of isozymes, in the EnCa101 human endometrial tumor model. We find that increased PKC isozyme expression correlates with hormone-independent breast cancer as well as antiestrogen-stimulated endometrial cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Cell Division; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Protein Kinase C; Tamoxifen; Toremifene; Tumor Cells, Cultured

Previous studies have revealed that protein kinase C (PKC) is responsible for malignant progression. In the present study, we investigated the potent inhibitory effects of an antiestrogen, toremifene, on PKC-mediated cellular adhesion. A phorbol ester, phorbol 12-myristate 13-acetate (PMA), significantly enhanced alpha2beta1 integrin-dependent adhesion of MCF-7 breast carcinoma cells. This PMA-induced adhesion was partially inhibited by incubating cells with toremifene prior to PMA exposure in a time- and dose-dependent manner. FACS analysis demonstrated that the PMA-induced alpha2beta1-dependent cellular adhesion was accompanied with elevated expression of alpha2beta1+integrin subunit on the cell surface. However, toremifene did not affect the elevated expression levels of these integrins but rather the avidity of alpha2beta1 integrin. We concluded that toremifene inhibited cellular adhesion activated by PMA, probably through mechanism which inhibits PKC.

Topics: Breast Neoplasms; Carcinogens; Carcinoma; Cell Adhesion; Enzyme Repression; Estrogen Antagonists; Humans; Protein Kinase C; Tetradecanoylphorbol Acetate; Toremifene; Tumor Cells, Cultured

The antitumor effects of toremifene were studied in vitro using 10 anaplastic thyroid carcinoma cell lines and were compared with those of tamoxifen. The antitumor effect of toremifene was dose-dependent and the IC50 values for these cell lines ranged 20.1-58.5 microM. Although the cell lines expressed multidrug resistance gene mRNA, multidrug resistance-associated protein gene mRNA and insulin-like growth factor-1 (IGF-1) receptor mRNA to various degrees, nine of them lacked estrogen receptor expression as evaluated by immunocytochemistry. These data indicate that toremifene, as well as tamoxifen, is cytolytic at relatively high doses for multidrug-resistant anaplastic thyroid carcinoma cell lines.

Topics: Antineoplastic Agents, Hormonal; Carcinoma; Cell Division; Humans; Receptors, Estrogen; Tamoxifen; Thyroid Neoplasms; Toremifene; Tumor Cells, Cultured