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[Clinical studies on endocrine therapy for prostatic carcinoma (4): Initial response to endocrine therapy and prognosis].

We have already pointed out by the use of multivariate analysis that local response of the prostate is one of the important prognostic factors in patients receiving endocrine therapy. Herein, we investigated how the local response to endocrine therapy affects the survival rate or the survival period. We also studied the relationship between the local response and histopathological findings. The local response of prostate was not correlated with the stage progression. Sixty-seven percent of the patents in each stage had an initially favorable local response of the prostate, in which the primary tumor became flattened or reduced by endocrine therapy. By contrast, the local response of the prostate was well correlated with the prognosis in each stage. Patients with a flattened or reduced primary lesion following endocrine therapy showed a higher survival rate or a longer survival period than those with the unchanged lesion. This result has confirmed that the local response of prostate to endocrine therapy is useful in predicting clinical courses of patients. Grade of structural atypism (SAT), one of the pathological findings, had a correlation with local response of the prostate. With an elevation of the SAT grade, the proportion of patients with unchanged primary lesion was increased.

Humans

[Clinical studies on endocrine therapy for prostatic carcinoma (5): Analyses of relapse from endocrine therapy].

Prostate carcinomas are well known to be initially responsive to endocrine therapy. However, a significant number of the patients experience a relapse from endocrine therapy during the follow-up period. We clinically analyzed various aspects of the relapse which indicate a limitation in the effectiveness of endocrine therapy for prostate carcinoma. In a total of 372 patients, 117 (31.5%) had some evidence of local relapse such as regrowth of the primary lesion, or a generalized relapse such as re-elevation of total acid phosphatase, reactivation of previously present metastasis or the new appearance of metastasis, during endocrine therapy. Of these, one-fourth had local relapse alone and the remainder showed generalized relapse. The interval from the start of the treatment to the time of relapse tended to become shorter; 45.9 months (mean) in stage B, 36.8 in stage C and 29.3 in stage D, according to the stage progression. As to the non-relapse rate of the primary lesion, no differences were found among the stage, with the rate being approximately 90% at the fifth year in each stage. However, the generalized relapse-rate tended to increase with the stage progression. In the generalized relapse, the patients of stage C or D showed a non-relapse rate of 71.7% or 67.4%, respectively. Most of the generalized relapse appeared within five years following start of endocrine therapy in these advanced stages. The interval from relapse to prostate carcinoma-related death in patients with the generalized relapse was 9 approximately 21 months, and those in stage D tended to show a a poorer prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans

[Recent progress of endocrine therapy in breast cancer].

Recent progresses of endocrine therapy for advanced and early breast cancer was reviewed. The mechanism (s) of an antiestrogen, tamoxifen has been noted at least partly as a stimulation of TGF beta action in ER-positive breast cancer cells. The Early Breast Cancer Trialists' Collaborative Group (EBC TCG) has recently reported the effectiveness of endocrine therapy, oophorectomy for premenopausal patients, and tamoxifen for pre- and post-menopausal patients in the adjuvant treatment for operable breast cancer patients. Two kinds of newly developed endocrine therapy were mentioned; LH-RH analogues for premenopausal patients, and aromatase inhibitors for postmenopausal patients. These agents decrease the plasma estrogen levels, acting like the ablative surgery, and make us more comprehensive combinations of endocrine therapy of breast cancer.

Aromatase Inhibitors

[Selection of patients with breast cancer with regard to endocrine therapy].

Predictive tests assisting in selection of breast cancer patients for endocrine therapy have been reviewed. Information gained from histologic sections, such as degree of the tumor differentiation, degree of elastosis, Barr-body count and the DNA content, are valuable predictors of prognosis and response to endocrine therapy. The length of time between mastectomy and recurrence of metastasis is an important factor in predicting response to ablative endocrine surgery. The presence of various enzymes in the tumor tissue, blood groups, immunologic competence, altered metabolism of tryptophan, urinary excretion of steroids and in vitro hormonal responsiveness of the tumor tissue have not been widely used as predictors of tumor response to endocrine therapy. The determination of hormone receptors in primary or metastatic breast tumors is at present the most reliable test in selecting breast cancer patients for endocrine therapy. Future developments in hormone receptor assay may provide a means of tailoring endocrine therapy to the individual patient.

Adrenal Glands

Endocrine therapy for advanced breast cancer: a review.

More than 45,000 women will die of metastatic breast cancer in the United States in 1991. Endocrine therapy remains a major option for treatment of such patients, and results in complete plus partial response rates of 30% with a median duration of approximately one year. Postmenopausal status, increased age, a prolonged disease-free interval, bone and soft tissue metastases, and positive estrogen and progesterone receptors are all associated with an increased response to endocrine therapy. The use of additive hormonal therapy, specifically antiestrogens, progestins, and aromatase inhibitors, have replaced surgical ablative procedures in the majority of patients; response rates to antiestrogen therapy, progestin therapy, and aromatase inhibitors are similar, but antiestrogens have generally been associated with the most favorable therapeutic index. At present, there is no convincing evidence that either combinations of endocrine therapies or endocrine therapy combined with chemotherapy are associated with an improvement in survival for patients with metastatic disease. Future research efforts directed at defining the molecular mechanisms of endocrine activity should facilitate clinical trials of newer and potentially more effective agents. All patients with metastatic breast cancer should be considered for at least one trial of endocrine therapy provided their metastatic disease is not rapidly progressive or life-threatening.

Adrenal Cortex Hormones

Elastosis and response to endocrine therapy in human breast cancer.

Response to endocrine therapy in 51 patients with advanced breast cancer was compared with the amount of elastosis in histological sections from their primary tumours. There appeared to be an association between elastosis and response: tumours with no elastosis showed a lower rate of response than those with gross elastosis, indicating that this simple method might provide a useful predictive index for response to endocrine therapy. In addition, tumours with oestrogen-receptor activity (a feature associated with a high rate of response) but with no elastosis were unlikely to respond, suggesting that a combination of the 2 predictive indices might be more valuable than either taken alone.

Breast Neoplasms

High p62 and ALDH1A3 Reduce the Effectiveness of Endocrine Therapy in Luminal B Breast Cancer.

BACKGROUND/AIM: High expression of p62 and ALDH1A3 indicates a poor clinical outcome in luminal B breast cancer, and p62 is involved in the progression of ALDH1-positive luminal B breast cancer stem cells. However, the association between endocrine therapy and high p62 and ALDH1A3 expression, in luminal B breast cancer remains unclear. MATERIALS AND METHODS: Two datasets with gene expression and clinical data for patients with primary breast cancer (METABRIC, n=2,509; The Cancer Genome Atlas, n=1,084) were downloaded and statistically analyzed. To evaluate the association between the p62 and ALDH1A3 expression levels and endocrine therapy, including tamoxifen and aromatase inhibitor, in patients with luminal B breast cancer, disease-specific survival was examined using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: Patients with p62 high ALDH1A3 high luminal B breast cancer treated with endocrine therapy exhibited a poor prognosis. Moreover, patients with p62 high ALDH1A3 high luminal B breast cancer treated with tamoxifen showed a trend towards a poor prognosis, but those treated with aromatase inhibitors showed a significantly poor prognosis. These results suggest that endocrine therapy, especially aromatase inhibitors, exhibits a reduced effectiveness against p62 high ALDH1A3 high luminal B tumors. CONCLUSION: p62 and ALDH1A3 could be used together as a prognostic biomarker for predicting the efficacy of endocrine therapy for luminal B breast cancer.

ALDH1A3

[Factors influencing prognosis of stage D2 prostatic cancer following endocrine therapy: comparison between short-term cancer death and long-term survival group].

To clarify factors affecting prognosis following endocrine therapy, stage D2 patients who died from prostatic cancer within 3 years and those under well-controlled state longer than 5 years were compared with respect to background factors and response to endocrine therapy. Thirty-five and 18 cases, respectively, were studied. Differences between the two groups were bone pain, anemia, tumor grade, number of bone metastasis, and response to endocrine therapy. Performance status in long-term survival groups tended to be better than that in short-term cancer death groups.

Adenocarcinoma

Steroid receptor content in human prostatic carcinoma and response to endocrine therapy.

Biopsy material from primary prostatic carcinoma from 25 patients was analyzed with regard to cytosol content of methyltrienolone (a synthetic androgen) binding sites and the receptor content has been correlated to the clinical response to endocrine therapy. A dextran-coated charcoal technique was used and binding data were calculated from Scatchard plots. In 20 of the tumors detectable levels of methyltrienolone receptor were noted. One of the receptor-positive patients died during radiation therapy before onset of hormonal treatment, and a second patient, who had a highly differentiated carcinoma, so far has not received any endocrine therapy. Of the remaining 18 patients 15 responded well to castration, treatment with estrogens, or Estracyt (approximately 80%). The biopsies from two of the three receptor-positive non-responders contained the lowest measurable receptor levels. Five specimens lacked detectable amounts of methyltrienolone receptor. Four of these patients did not respond to therapy (approximately 80%), but one was "false" negative. Our data indicate that steroid receptor analysis may become an important tool in predicting the value of endocrine therapy in human prostatic carcinoma.

Aged

Randomised trial of chemotherapy versus endocrine therapy in patients presenting with locally advanced breast cancer (a pilot study).

Sixty patients with locally advanced breast cancer, but with no evidence of distant metastases were randomised to receive primary endocrine therapy or chemotherapy after assessment and 'Trucut' biopsy of the primary tumour. After 12 weeks all patients were assessed. Eight out of 30 (27%) of the patients who received chemotherapy showed complete clinical regression of the primary cancer, eight patients' tumours had regressed by more than 50%, and ten showed a 25-50% reduction in bi-dimensional diameter. Only four (13%) patients' tumours failed to reduce in size. Seven patients were judged to require mastectomy at the end of the 12 week period of treatment with chemotherapy. In contrast, only three out of 30 (10%) patients receiving endocrine therapy showed a greater than 50% reduction in tumour size, and four patients had a 25-50% reduction at 12 weeks. The remaining patients' tumours either stabilised (12 patients) or enlarged (11 patients). We conclude that primary chemotherapy in patients with primary breast cancer is more effective in rapidly reducing the size of the primary breast cancer than endocrine therapy (P = 0.001) and alters significantly the future management of these patients. However, at 65 weeks on completion of the follow-up, there is no significant difference in the number of patients' disease-free, locally or distant recurrent, or dead.

Adult

Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.

Adult

Estrogen receptor in human breast cancer in relation to tumor morphology and endocrine therapy.

The presence of estrogen receptors (ER) was determined in 111 human breast cancer specimens. In 61% of the tumors, specific estrogen binding was found and in 39% of the tumors ER was absent. In 69 tumors no correlation was found between the histological grading of the tumor and the level of ER. The values of ER in tumors from patients over 50 years of age were usually much higher than those for patients under 50 years of age. Different methods of endocrine therapy were applied in 20 patients. In 10 of 15 patients with ER positive tumors, endocrine therapy resulted in remission. Only 1 of 5 patients with ER negative tumors responded with remission. It is concluded that estimation of ER in tumor tissue is helpful in the selection of patients for endocrine therapy.

Adult

Intersite variation of estrogen receptors in human breast cancers and response to endocrine therapy. Which section of a large tumor is the best for estrogen receptor assay?

Estrogen receptor (ER) assays were performed by sucrose gradient centrifugation method at multiple sites in large breast cancers. Intersite variation of ER in a tumor was observed in 24 out of 35 cases. 16 tumors with relatively low ER levels showed different ER status with multiple assays. The results suggest that an assay performed on a small random part of a large tumor may not yield the true ER status. ER value at the largest cross-section was almost the same as the average ER values in each tumor. In addition, 21 cases were examined in relation to ER values at multiple sites in the large tumors and response to endocrine therapy. As the ER value at the largest cross-section was highly correlated with the therapeutic response to endocrine therapy of breast cancer, it would represent true ER status and level. The results suggest that the ER assay at the largest cross-section of a large tumor is an appropriate method to predict response to endocrine therapy.

Breast Neoplasms

Differential Effectiveness of Adjuvant Endocrine Therapy According to Menopausal Status, Body Mass Index, and Molecular Subtype in Hormone Receptor-Positive Breast Cancer.

The effectiveness of adjuvant endocrine therapy for hormone receptor-positive (HR+) breast cancer (BC) varies according to menopausal status, body mass index (BMI), and tumor biology. We evaluated the association between selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and BC-specific mortality according to menopausal status, BMI, and molecular subtype in a nationwide Korean cohort. We analyzed data from 31,030 patients with HR+ BC who were registered in the Korean Breast Cancer Society Registry, diagnosed between 2000 and 2008, and followed through 2013. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for BC-specific mortality after adjusting for demographic and clinical factors. Of the 31,030 patients, 19,634 received SERM therapy, and 3,354 received AI therapy. SERM use was associated with lower BC-specific mortality in premenopausal women (HR, 0.75; 95% CI, 0.63-0.91), whereas AI therapy was more strongly associated with lower BC-specific mortality among postmenopausal women (HR, 0.76; 95% CI, 0.61-0.94). Lower BC-specific mortality was observed among patients with a BMI ≥ 23 kg/m² who received SERM (HR, 0.84; 95% CI, 0.72-0.98) or AI therapy (HR, 0.78; 95% CI, 0.62-0.99). The strongest association with lower BC-specific mortality was observed in postmenopausal women with luminal B tumors (HR, 0.59; 95% CI, 0.42-0.83). The association between adjuvant endocrine therapy and BC-specific mortality differed according to menopausal status, BMI, and molecular subtype. These findings suggest that menopausal status, BMI, and molecular subtype are important considerations when evaluating endocrine treatment strategies.

Aromatase Inhibitors

Endocrine therapy for desmoid tumors.

Two female patients with desmoid tumors (aggressive fibromatosis) showed tumor regression after endocrine therapy. In one patient, tumor response to tamoxifen has been maintained over several years of treatment. In the second patient, who had inoperable mesenteric fibromatosis, the tumor progressed on tamoxifen but regressed after treatment with Zoladex (goserelin acetate, ICI, Melbourne, Australia) and medroxyprogesterone acetate (MPA). To the authors' knowledge this is the first report of the use of Zoladex in the treatment of desmoid tumors. This review of the literature reveals that the biology of this disease is related to the endogenous hormonal environment and that estrogen receptors have been documented in desmoid tumors. Thirty-five cases are identified where endocrine agents have been employed, with a response rate of 51%. Furthermore, tumors may respond to second-line hormonal therapy after failing to respond to initial endocrine treatment. Endocrine treatments have also been used in other disorders of fibroblastic origin. The authors recommend that endocrine treatment be employed in inoperable desmoid tumors or where there has been postsurgical recurrence. In addition, the role for endocrine therapy in other soft tissue neoplasms should be determined.

Adult

Clinical course of bone metastasis from prostatic cancer following endocrine therapy: examination with bone x-ray.

X-ray findings of bone metastatic lesions from 81 cases of stage D2 prostatic cancer were examined before and following endocrine therapy. Untreated lesions were classified into five types; osteoblastic (15%), mixed, but mainly osteoblastic (31%), mixed, but mainly osteolytic (17%), osteolytic (10%), and undetermined with a positive bone scan (27%). Patients with two mixed types had a tendency of widely speeded areas of metastasis and elevated serum prostatic acid phosphatase. Temporal enlargement of sclerotic lesion immediately after the start of therapy did not indicate disease progression. In many cases, changes from osteolytic to osteoblastic patterns were noticed in the same lesion regardless of the effects of endocrine therapy. Remodeling to the sclerotic pattern appeared as curative changes. From these findings, it was concluded that the natural course of bone lesions showed a tendency to change from the osteolytic to osteoblastic type and relapse was often accompanied by an increase of the osteolytic type lesion. Evaluation of therapeutic effects based on remodeling, changes in number and areas of lesions, and the appearance of new lesion correlated well with prognosis.

Aged

Predicting response to endocrine therapy in human breast cancer: a hypothesis.

We hypothesize that the presence of progesterone receptors in human breast tumors may be a sensitive marker for predicting response to endocrine therapy. Progesterone receptors were found in 56 percent of tumors with estrogen receptors, but were absent in tumors without estrogen receptors. Preliminary clinical correlations show that only those breast tumors with progesterone receptors regressed after endocrine therapy.

Breast Neoplasms

Prevention of breast cancer recurrence with adjuvant cytotoxic or endocrine therapy.

The paper provides a brief summary of the scientific hypotheses underlying adjuvant trials of systemic treatment in primary breast cancer, the history of the first and second generation of adjuvant studies of cytotoxic and endocrine therapy, and a brief description of the main findings of the international overview of all available randomized trials of adjuvant systemic treatment. In short, the overview has provided conclusive evidence that both adjuvant endocrine therapy (ovarian ablation and tamoxifen) as well as cytotoxic polychemotherapy can prevent disease recurrence and prolong overall survival. However, the treatment benefit appears to be only moderate and may not be considered clinically worthwhile in some patient subsets, e.g. those with a relatively favourable outcome with local treatment alone. Refinements in the use of prognostic factors to select patients for treatment--particularly in node-negative disease--are thus warranted, as well as further research aimed at improving treatment efficacy.

Antineoplastic Agents